Use of bosentan for digital ulcers related to systemic sclerosis: a real-life retrospective French study of 89 patients treated since specific approval.

OBJECTIVES: Ischaemic digital ulcers (DUs) are a common complication of systemic sclerosis (SSc). This study aimed to characterize patients with SSc and ongoing DUs treated with the endothelin receptor antagonist bosentan in clinical practice in France. METHOD: An observational, retrospective, longitudinal study was conducted in 10 French expert centres. Medical records from randomly selected adult SSc patients who received treatment with bosentan for DU prevention from March 2007 to December 2010 were analysed. The primary objective was to determine the profile of patients at treatment initiation. Secondary objectives were to monitor bosentan dosing, treatment schedule, and reasons for treatment termination. RESULTS: The study included 89 patients (mean age 52 years, 69% female, 44% diffuse cutaneous SSc). At bosentan treatment initiation, the mean duration of Raynaud's phenomenon was 15 ± 12 years, and the mean time since first episode with DU was 6.5 ± 7 years. Most patients had a history of at least two episodes with DUs, separated by < 12 months (61%), and had received intravenous iloprost (63%). Previous DU complications included auto-amputation (8%), surgical amputation (6%), osteitis (6%), and gangrene (4.5%). Active smokers (25%) had a history of significantly more surgical amputation (p = 0.004) and osteitis (p = 0.004) than non-smokers. At least one active DU at bosentan initiation was detected in 82% of patients. Bosentan was used according to prescription guidelines and was well tolerated; six patients (7%) withdrew from treatment because of raised liver enzymes. CONCLUSIONS: Patients treated with bosentan for DU prevention in France have severe, refractory, ongoing ulcerative disease. Active smoking was correlated to a history of DU complications. Tolerance of bosentan was comparable to previous studies.

[Lyme disease acrodermitis chronica atrophicans: misleading vascular signs]. / Acrodermatite atrophiante de Lyme : des signes vasculaires parfois trompeurs.

Lyme disease acrodermatitis chronica atrophicans is a tertiary form of Lyme borrelliosis. It occurs at least six months, but also up to several years, after a tick bite. This rare condition is probably underestimated because of the difficult diagnosis. Clinical presentations of acrodermatitis chronic atrophicans are quite variable depending upon the duration of the disease. Complimentary explorations are difficult to interpret and rarely specific. Only rare configurations allow formal diagnosis of Borrelia burgdoferi infection. We present a patient who exhibited an atypical clinical presentation of Lyme disease acrodermatitis chronic atrophicans. The clinical outcome was quite favorable with treatment, confirming the diagnosis. Such treatments, which are well tolerated and highly effective, are essential since an untreated disease can lead to potentially severe neurological involvement.

Cutaneous iontophoresis of treprostinil in systemic sclerosis: a proof-of-concept study.

Ischemic digital ulcer (DU) is a serious complication of systemic sclerosis (SSc). Intravenous prostanoids are the only approved treatment for active DUs, but they induce dose-limiting side effects and require hospitalization. Our objective was to evaluate the effect of iontophoresis (a noninvasive drug delivery method) of treprostinil in SSc patients. Three studies were conducted: a pharmacokinetic study in 12 healthy volunteers showed that peak dermal concentration was reached at 2 hours, whereas plasma treprostinil was undetected. Then, a placebo-controlled, double-blind incremental dose study assessed the effect of treprostinil on digital skin blood flow in 22 healthy subjects. The effect of the highest dose was then compared with that of placebo in 12 SSc patients. Treprostinil significantly increased skin blood flow in healthy subjects (P = 0.006) and in SSc patients (P = 0.023). In conclusion, digital iontophoresis of treprostinil is feasible, is well tolerated, and increases digital skin perfusion. It could be tested as a treatment for SSc-related DUs.

[Secretan's syndrome: myth or pathomimia?]. / Le syndrome de Secrétan : mythe ou pathomimie ?

UNLABELLED: Secretan's syndrome is a rare condition involving generally trauma-induced hard edema of the dorsal aspect of the hand. The cause is poorly understood but factitious trauma is often suspected. CASE REPORT: A 42-year-old woman presented with a fortuitous edema on the back of the right hand. The minimally depressible edema was associated with moderately intense mechanical pain. Routine laboratory tests were normal. An extensive imaging work-up (bone x-ray of the hand and wrist, bone scintigraphy, computed tomography phlebography, lymphoscintigraphy, magnetic resonance imaging) was equally non-contributive. The diagnosis of self-inflected trauma was suggested by the atypical nature of the edema, the absence of any organic disorder on the tests performed, and the patient's attitude concerning her disease. In this clinical context, the diagnosis of Secretan's syndrome was retained. Outcome was compatible, with secondary development of complex regional pain syndrome. DISCUSSION: Three forms of Secretan's syndrome have been recently described: benign; hyperplastic; and mixed. The cause remains poorly defined. Certain authors report that it is most likely related to pathomimia. Treatment can combine physiotherapy and psychological counseling. CONCLUSION: Secretan's syndrome is a poorly-understood and rarely-described condition that may be underdiagnosed. Physicians specialized in vascular medicine should be aware of this syndrome and its difficult diagnosis by elimination.

[Minimal work-up for Raynaud syndrome: a consensus report. Microcirculation working group of the Société française de médecine vasculaire]. / Bilan étiologique minimal du phénomène de Raynaud : un consensus d'experts.

About ten to fifteen percent of the French population suffer from Raynaud's phenomenon. Most of the time, it is considered as primary Raynaud's phenomenon, without underlying disease. The aim of this expert consensus from the "microcirculation group" for the French Society of Vascular Medicine and the French Society for Microcirculation, was to define clinical guidelines in patients consulting for Raynaud's phenomenon. The recommended minimal screening includes clinical examination, nailfold capillaroscopy and antinuclear antibodies. In particular, the aim of this screening is to identify patients with a significant risk for scleroderma, who would need a careful follow up.

[Chromametry, a promising technique for the quantification of skin changes in chronic venous disorders]. / La chromamétrie, une technique prometteuse pour la quantification de l'atteinte cutanée dans l'insuffisance veineuse chronique.

OBJECTIVE: The development and validation of new clinimetric tools is essential for the progress of clinical research in the field of chronic venous insufficiency. Chromametry is a simple, quick and non-invasive technique that measures the color of the skin. The aim of this study was to evaluate the ability of this technique to quantify skin pigmentation as a marker of severity of chronic venous disease and to assess the variability of measurements obtained in this condition. METHODS: Chomametry was performed on three different sites on each lower limb in 42 patients undergoing a spa treatment in La Léchère (Savoie) for chronic venous disorders (CVD). Four series of measurements were taken by two investigators for each patient, at two sessions two to four days apart. RESULTS: The chromameter readily measured the pigmentation index (PI). The PI increased with higher clinical class (CEAP classification) for measurements made at the malleolar level (r=0.48; P<0.001) and the supra-malleolar area (r=0.55; P<0.001), but not at the level of the anterior tibial tuberosity (r=-0.09; P=0.45). The repeatability and the intra- and inter-observer reproducibility of this PI index were 15%, 18% and 21% respectively of the mean of the observed difference at the malleolar level. The chromameter also provided an erythema index, which appears to be less relevant and more variable than the PI, but which might add potentially useful information regarding the characterization of skin inflammation related to the venous disease. CONCLUSION: This study shows that chromametry can be used in clinical research studies to quantify skin changes associated with CVD. Whether it can also be useful for early detection and follow-up of patients with venous trophic changes remains to be investigated.

[Minimal work-up for Raynaud syndrome: a consensus report. Microcirculation Working Group of the French Vascular Medicine Society]. / Bilan étiologique minimal du phénomène de Raynaud : un consensus d'experts.

About ten to fifteen percent of the French population suffer from Raynaud's phenomenon. Most of the time, it is considered as primary Raynaud's phenomenon, without underlying disease. The aim of this expert consensus from the "microcirculation group" for the French Society of Vascular Medicine and the French Society for Microcirculation, was to define clinical guidelines in patients consulting for Raynaud's phenomenon. The recommended minimal screening includes clinical examination, nailfold capillaroscopy and antinuclear antibodies. In particular, the aim of this screening is to identify patients with a significant risk for scleroderma, who would need a careful follow up.

Acceptability and practicability of elastic compression stockings in the elderly: a randomized controlled evaluation.

BACKGROUND: Compression stockings are the cornerstone of the treatment of chronic venous disorders, but practical acceptability is an important limitation in the elderly. OBJECTIVE: To evaluate the practicability of compression stockings in elderly patients. METHODS: Twenty women aged 68-85 years without major disability were asked to put on, wear for three hours and take off Solegg® and Solegg® Fine compressive stockings (15-20 mmHg) in random order on different days, and to rate through questionnaires the difficulties and discomfort they experienced in comparison with their usual non-compressive stockings (controls). RESULTS: Foot and heel insertions of the compression stockings, as well as their removal, were found significantly more difficult, whereas comfort when they were on was higher. In the whole, the compression stockings were found to be more agreeable than the controls. CONCLUSION: Difficulties regarding putting on and removal of the compression stockings remain significant but are counterbalanced by a better comfort when they are on.

NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis.

BACKGROUND: Recent evidence has highlighted a potential role of interleukin 1ß (IL-1ß) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1ß. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders. OBJECTIVE: /st> To study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population. METHODS: NLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin. RESULTS: Conditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA. CONCLUSIONS: Our results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.

Treatment of low-flow vascular malformations by ultrasound-guided sclerotherapy with polidocanol foam: 24 cases and literature review.

OBJECTIVES: Treatment by sclerotherapy has been suggested as a first-line treatment of low-flow vascular malformations. This study reports our experience in treating low-flow vascular malformations by ultrasound-guided sclerosis with polidocanol foam at the Vascular Medicine Department in Grenoble, France. DESIGN: Retrospective single-centre consecutive series. MATERIALS AND METHODS: Between January 2006 and December 2009, we analysed the complete records of patients with symptomatic low-flow vascular malformations of venous, lymphatic or complex type (Klippel-Trenaunay syndrome, KTS) treated by ultrasound-guided sclerosis. The therapeutic indication was always validated by the Consultative Committee for vascular malformations of the University Hospital of Grenoble. All vascular malformations were classified according to the Hamburg Classification. The sclerosing agent was polidocanol used as foam. RESULTS: A total of 24 patients between 7 and 78 years were treated (19 venous malformations, three KTSs and two venous-lymphatic malformations). The concentrations of polidocanol used ranged from 0.25% to 3%. The average number of sessions was 2.3 (1-16). After a median follow-up at 5 months after the last session, 23 out of 24 patients reported a decrease in pain; in nine cases (37.5%), over 50% reduction in size was observed, and in 14 cases (58.3%), a reduction of less than 50% of the original size was obtained. Two minor side effects were reported. CONCLUSIONS: Treatment by ultrasound-guided sclerosis using polidocanol foam seems to be well tolerated and can improve the symptoms of low-flow malformations without the risks of more aggressive sclerosing agents, such as ethanol.

Association of a KCNA5 gene polymorphism with systemic sclerosis-associated pulmonary arterial hypertension in the European Caucasian population.

OBJECTIVE: Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor ß receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. METHODS: Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. RESULTS: The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48-0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13-0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21-0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. CONCLUSION: Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc.

BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects with IRF5 and STAT4.

OBJECTIVE: To determine whether the functional BANK1 variants rs3733197 and rs10516487 are associated with systemic sclerosis (SSc) in 2 European Caucasian populations and to investigate the putative gene-gene interactions between BANK1 and IRF5 as well as STAT4. METHODS: BANK1 single-nucleotide polymorphisms were genotyped in a total population of 2,432 individuals. The French cohort consisted of 874 SSc patients and 955 controls (previously genotyped for both IRF5 rs2004640 and STAT4 rs7574865). The German cohort consisted of 421 SSc patients and 182 controls. RESULTS: The BANK1 variants were found to be associated with diffuse cutaneous SSc (dcSSc) in both cohorts, providing an odds ratio (OR) of 0.77 for the rs10516487 T rare allele in the combined populations of dcSSc patients as compared with the combined populations of controls (95% confidence interval [95% CI] 0.64-0.93) and an OR of 0.73 (95% CI 0.61-0.87) for the rs3733197 A rare allele. BANK1 haplotype analysis found the A-T haplotype to be protective in dcSSc patients (OR 0.70 [95% CI 0.57-0.86], P = 3.39 x 10(-4)) and the G-C haplotype to be a risk factor (OR 1.25 [95% CI 1.06-1.47], P = 0.008). Significant differences were also observed when the limited cutaneous subset of SSc was compared with the dcSSc subset, both for the rare alleles and for the haplotypes. The BANK1, IRF5, and STAT4 risk alleles displayed a multiplicatively increased risk of dcSSc of 1.43-fold. CONCLUSION: Our results establish BANK1 as a new SSc genetic susceptibility factor and show that BANK1, IRF5, and STAT4 act with additive effects.

Clinical and microcirculatory effects of transcutaneous CO2 therapy in intermittent claudication. Randomized double-blind clinical trial with a parallel design.

BACKGROUND: This randomized, double blind trial determined the short and long-term clinical and hemodynamic vasodilator effects induced by percutaneous applications of natural CO2 gas in patients with moderate Fontaine stage II. PATIENTS AND METHODS: 62 patients with intermittent claudication (100-500 meters) were randomized to 18 consecutive days of CO2 treatment or placebo (air). The gas fluids were applied at a constant temperature of 30 degrees C on pre-humidified skin. The effects of the treatment were evaluated by total distance walked (primary criterion) and hemodynamic and microcirculatory findings. Patients also answered a quality of life questionnaire. RESULTS: The Strandness test showed a significant increase in total distance walked (+ 131 meters, 66%; p = 0.001) and pain-free distance (+ 81 meters, 73%; p = 0.02) after 18 days of CO2 treatment. The improvement was maintained 3 and 12 months later. The systolic pressure index (ABI) increased by 37% (p = 0.001) 1 minute after treadmill walking and ABI recovery time decreased significantly by 38% (p = 0.002). Microcirculatory findings showed an increase in systolic pressure of the great toe (13%; p < 0.0001), in baseline pO2 (20%; p = 0.01) and in vasomotion (78%; p = 0.001) in the treatment group. The improvement in total walking distance was correlated with the increase in ABI and peripheral cutaneous oxygenation. Patients' subjective assessments corroborated the benefits. No significant change was observed in the placebo group. CONCLUSIONS: This study demonstrates that 18 consecutive days of percutaneous CO2 treatment significantly increases walking distance in patients with moderate intermittent claudication. This effect, which was associated with an increase in peripheral systolic pressure and pO2, is evidence of a better ability to withstand effort.

STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis.

OBJECTIVE: Systemic sclerosis (SSc) belongs to the group of connective tissue disorders (CTDs), among which are several disorders characterized by a type I interferon (IFN) signature. The recent identification of an association between IRF5 and SSc further highlights a key role for IFN. STAT4, which encodes STAT-4, contributes to IFN signaling, and its genetic variants were found to be associated with CTDs. The aim of this study was to determine whether the STAT4 rs7574865 single-nucleotide polymorphism is associated with SSc, and whether it interacts with IRF5. METHODS: Both the STAT4 rs7574865 and IRF5 rs2004640 polymorphisms were genotyped in 1,855 individuals of French Caucasian origin comprising a discovery set of 440 patients with SSc and 485 control subjects and a replication set of 445 patients with SSc and an additional 485 control subjects. RESULTS: STAT4 rs7574865 was shown to be associated with SSc (P=0.001, odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.11-1.51). This association was not restricted to a particular phenotype. An additive effect of the STAT4 rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiple increased 1.28-fold risk of SSc. The OR for SSc was 2.72 (95% CI 1.86-3.99) for combinations of genotypes with >or=3 risk alleles. An additive effect was also detected for fibrosing alveolitis: carriage of at least 3 risk alleles appeared to be an independent risk factor (P=2.2x10(-4), OR 1.97, 95% CI 1.28-3.04). CONCLUSION: Our results establish STAT4 rs7574865 as a new SSc genetic susceptibility factor. STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc-related fibrosing alveolitis.

Association between the IRF5 rs2004640 functional polymorphism and systemic sclerosis: a new perspective for pulmonary fibrosis.

OBJECTIVE: There is now growing evidence that connective tissue diseases, including systemic sclerosis (SSc), share a common genetic background. Microarray studies support a pivotal role of type I interferon (IFN) in the pathophysiology of connective tissue diseases. Interferon regulatory factors coordinate the expression of type I IFNs, and the IRF5 gene has been identified as a susceptibility gene of systemic lupus and Sjögren's syndrome. The aim of this study was to determine whether the IRF5 rs2004640 single-nucleotide polymorphism is associated with SSc. METHODS: The IRF5 rs2004640 (GT) functional polymorphism was genotyped in 1,641 subjects of French European Caucasian origin: a discovery set comprising 427 patients with SSc and 380 control subjects and a replication set comprising 454 patients with SSc and 380 control subjects. RESULTS: In both the discovery set and the replication set, the TT genotype was significantly more common in patients with SSc than in control subjects, with an odds ratio (OR) for the combined populations of 1.58 (95% confidence interval [95% CI] 1.18-2.11 [P for trend 0.002]). Analyses of the whole SSc population showed a significant association between homozygosity for the T allele and the presence of antinuclear antibodies (corrected P [Pcorr]=0.04, OR 1.59, 95% CI 1.16-2.17) and fibrosing alveolitis (Pcorr=0.001, OR 2.07, 95% CI 1.38-3.11). In a multivariate analysis model including the diffuse cutaneous subtype of SSc and positivity for anti-topoisomerase I antibodies, the IRF5 rs2004640 TT genotype remained associated with fibrosing alveolitis (P=0.029, OR 1.92, 95% CI 1.07-3.44). CONCLUSION: The IRF5 rs2004640 GT substitution is associated with susceptibility to SSc. These data provide new insight into the pathogenesis of SSc, including clues to the mechanisms leading to fibrosing alveolitis.

[A rare cause of embolic ischemia of the hand: an isolated aneurism of a branch of the axillary artery]. / Une cause rare d'ischémie embolique de la main: un anévrisme isolé d'une branche de l'artère axillaire.

A 48-year-old man was admitted for subacute ischemia of the right hand of sudden onset. The patient, who participated in amateur sports, had an uneventful medical history. Duplex ultrasonography revealed thrombosis of the right radial and ulnar arteries. On heparin, the clinical course was favorable and investigations to search for an embolic source revealed an aneurism of the posterior circumflex artery (arteriography). The etiological work-up was negative as was the search for other aneurismal locations. Surgical excision was carried out. Pathology examination of the surgical specimen revealed a thrombosed aneurism that had developed on an atherosclerotic plaque. Aneurisms of the posterior circumflex artery have been described in professional baseball and volleyball players, but all sports that involve repetitive movements of the arm at extension, external rotation and forced abduction can complicate such damage. Compression of the aneurismal artery by the humeral head leads to extrusion of the thrombus under pressure and to retrograde embolisation towards the leg arteries. Thus, in the same way as for hypothenar hammer syndrome, signs of distal ischemia in an athlete should lead to a search for this type of injury.

Interstitial granulomatous dermatitis: a misdiagnosed cutaneous form of systemic lupus erythematosus?

Interstitial granulomatous dermatitis (IGD) is a recently described, rare dermatological entity. The clinical features are diverse and the precise aetiology is unknown. We present a rare and atypical case of IGD in a patient with systemic lupus erythematosus (SLE). A 26-year-old woman had been diagnosed with SLE when she was 15 years old. The diagnosis was based on cutaneous, articular, pulmonary, haematological and immunological features. The patient presented with a cutaneous diffuse macular eruption on the limbs, appearing in a cockade (rosette) pattern with a violaceous centre and erythematous surround. The face and trunk were spared. The cutaneous histological features led us to consider a diagnosis of IGD. The lesions disappeared after 15 days of systemic steroid therapy. This case is a new clinical form of IGD with an atypical location and clinical presentation. IGD has usually been associated with drug-related adverse reactions and autoimmune diseases. Reports in the literature of IGD in patients with SLE are rare.