Recurrent Digital Ulcers Research Articles

Patients' unmet needs and treatment preferences concerning digital ulcers in systemic sclerosis.

Digital ulcers (DUs) significantly impact on quality of life and function in patients with systemic sclerosis (SSc). The aim of our survey was to explore patients' perspectives and their unmet needs concerning SSc-DUs. SSc patients were invited through international patient associations and social media to participate in an online survey. 358 responses were obtained from 34 countries: US (65.6%), UK (11.5%) and Canada (4.5%). Recurrent DUs are common: >10 DUs (46.1%), 5-10 DUs (21.5%), 1-5 DUs (28.5%), 1 DU (3.9%). Fingertip DUs were most frequent (84.9%), followed by those overlying the interphalangeal joints (50.8%). The impact of DUs in patients is broad, from broad-ranging emotional impacts to impact on activities of daily living, and personal relationships. Half (51.7%) of respondents reported that they received wound/ulcer care, most often provided by non-specialist wound care clinics (63.8%). There was significant variation in local (wound) DU care, in particular the use of debridement and pain management. DU-related education was only provided to one-third of patients. One-quarter (24.6%) were 'very satisfied' or 'satisfied' that the provided DU treatment(s) relieved their DU symptoms. Pain, limited hand function, and ulcer duration/chronicity were the main reasons for patients to consider changing DU treatment. Our data show that there is a large variation in DU treatment between countries. Patient access to specialist wound-care services is limited and only a small proportion of patients had their DU needs met. Moreover, patient education is often neglected. Evidence-based treatment pathways are urgently needed for DU management.

Bosentan Does Not Affect Renal Resistive Index in Scleroderma/Systemic Sclerosis Patients

Introduction: If properly evaluated, chronic kidney disease can be found in up to 50% of patients with systemic sclerosis (SSc). The renal resistive index (RRI) is a marker of intrarenal vascular resistance and can predict SSc-associated vasculopathy. This study aimed to determine the impact of bosentan, a nonselective endothelin-1 receptor antagonist, on RRI and kidney function in SSc patients with recurrent digital ulcers. Methods: Twenty-one patients (age 57 ± 9 years, 19 females) were recruited in a 16-week prospective open-label uncontrolled study. Standardized procedures were used to measure general clinical and laboratory characteristics, systolic, diastolic, and mean arterial pressure (MAP), pulse pressure (PP), diastolic to systolic blood pressure (D/S) ratio, and urinary endothelin-1 levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to calculate kidney function as an estimated glomerular filtration rate (eGFR). RRI was measured by Doppler ultrasound as the average of three samplings of intrarenal blood flow in different kidney regions of both kidneys. Patients with secondary causes of kidney disease or kidney diseases associated with albuminuria were excluded. Results: Bosentan treatment for 16 weeks did not change RRI (0.731 ± 0.049–0.730 ± 0.054, p = 0.925), but increased urine endothelin-1 to creatinine ratio (0.27 ± 0.15–0.49 ± 0.57 pg/mg, p = 0.032) and reduced MAP (123 ± 10–101 ± 11 mm Hg, p < 0.001), PP (76 ± 11–68 ± 10 mm Hg, p = 0.003), D/S ratio (0.563 ± 0.044–0.538 ± 0.031, p = 0.006), and eGFR (92 ± 20–84 ± 24 mL/min/1.73 m2, p = 0.003). Discussion/Conclusion: In conclusion, in patients with SSc complicated by digital ulcers and normal to mildly diminished kidney function, bosentan had no effect on intrarenal hemodynamics, but reduced blood pressure levels and kidney function.

Impaired Fibrinolysis Is Linked With Digital Vasculopathy and Onset of New Digital Ulcers in Systemic Sclerosis.

To assess thrombin generation, fibrin formation, and structure together with the fibrinolytic status in patients with systemic sclerosis (SSc) in relation to the occurrence of digital ulcers (DUs) during the course of disease. We studied variables of endothelial dysfunction, thrombin generation, overall hemostatic potential, and fibrin clot turbidity in plasma from 58 patients with SSc (39 with DU history and 19 DU-naïve) and 46 matched healthy controls (HCs). Fibrin structure was visualized using scanning electron microscopy (SEM). Finally, 39 patients with a history of DUs were followed for 1.5 years and the predictive value of all investigated markers for new DU onset was explored. Significantly enhanced endogenous thrombin potential (ETP) and prolonged clot lysis time (CLT) were found in patients with DUs compared to HCs. CLT was prolonged in patients with DUs compared to those without, showing good validity in identifying DUs with an area under the curve of 0.7 (95% CI 0.6-0.8). The levels of ETP and intercellular adhesion molecule 1 were independently associated with CLT. Over the follow-up period, 20 patients developed new DUs. CLT was prolonged (P < 0.001) in patients with new DU episodes, especially those with recurrent DUs. Regression analysis showed that the Raynaud phenomenon visual analog scale and CLT were predictors of new DUs (OR 1.1, 95% CI 1.0-1.1 and OR 1.2, 95% CI 1.1-1.3, respectively). SEM confirmed denser fibrin clots in patients with new DUs. Our results suggest that impaired fibrinolysis might have an emerging role in underlying digital vasculopathy and its progression in SSc.

Nondigital skin ulcers in systemic sclerosis: A neglected entity

Background: Skin ulcers (SUs) are a common and difficult to manage problem in systemic sclerosis (SSc) and can be broadly classified into two types: digital ulcers (DUs) and non-DUs.Objective: The objective of this study was to analyze prevalence, associated factors, and response to therapy for non-DU.Patients and Methods: All patients with SSc who fulfilled the 2013 ACR/EULAR criteria were included in the study. SUs were divided into DU and various types of non-DU (SU on bony prominences, SU on calcinosis, SU on lower limbs, and SU with gangrene).Results: We included 146 patients with SSc (83.6' females) with a median follow-up of 20.5 months (interquartile range: 52). Eighty-four patients (57.5') had at least one episode of DU. Recurrent DUs despite vasodilators were seen in 36 (24.7') patients. Thirty-four patients (23.3') had non-DU. The most common type of non-DU was SU of lower limbs (23), followed by SU on bony prominences (19). The most common ulcer site was on the malleoli in the lower limbs and elbow in the upper limbs. Most of the ulcers healed in 3–6 months. Three patients developed osteomyelitis. The presence of non-DU was associated with longer duration of disease (P = 0.0009), occurrence of DU (P = 0.011), presence of gangrene (P < 0.001), or calcinosis (P < 0.001), and higher modified Rodnan skin score (P = 0.0013).Conclusion: Non-DUs were found in a quarter of patients with SSc. They are associated with advanced disease and vasculopathy. There is an unmet need to incorporate non-DU in clinical trial outcomes and address them in patient management guidelines.

EP04 Is this scleroderma lung or COVID-19 lung?

Case report - IntroductionThis is a case of Pakistani female with limited systemic sclerosis and associated mild interstitial lung disease. The lung disease was complicated by SARS-COV-2 related pneumonitis in April 2020 and that led to treatment challenges.She was previously seen in multiple private hospitals and labelled as Rheumatoid arthritis. She was being treated with long term steroids and Methotrexate. After her initial presentation to our Rheumatology services, her diagnosis was correctly revised to Systemic Sclerosis with phenotype of CREST. Her treatment was adjusted to Vasodilators and Mycophenolate due to skin and Lung involvement. Case report - Case descriptionThis is a case of 40-year-old Pakistani female who had been having multiple joint pains since 2010. She also experienced severe Raynaud’s.She presented to our Rheumatology clinic in December 2018. Her symptoms included recurrent digital ulcers, tight and tough skin at fingers and Raynaud’s worse during winter months. Her examination confirmed peripheral cyanosis with multiple digital ulcers with superimposed infection, marked sclerodactyly and calcinosis. She was started on Vasodilator therapy including calcium channel blocker and PDE5 inhibitor due to severity of ulceration. Infection was managed with prolonged course of antimicrobial therapy. Her immunology showed positive anti nRNP/Sm. Anti-centromere and anti Scl 70 were negative. Her condition fit description of CREST (Calcinosis, RP, Oesophageal dysmotility, telangiectasia). Her management included weaning off Methotrexate and reduction in the dose of corticosteroids. In February 2019, Respiratory work up showed normal Chest radiograph, High resolution CT chest showing no significant abnormality and FEV1 82%, FVC 86%, and DLCO 77%. Her PASP was 25mmHg. Overall, her condition remained stable over the course of next year. Her medication included Cellcept, low dose prednisolone, hydroxychloroquine, and Sildenafil. More importantly, Digital ulcers have been well controlled with combined vasodilator therapy. In April 2020, she developed SARS-CoV-2 with mild respiratory symptoms and was admitted to a different hospital. Fortunately, she responded well to ward based supportive and symptomatic treatment with no need for respiratory support. Subsequently, she has seen a different respiratory physician and had repeat imaging of chest which has led to dilemma whether the ground glass opacities in both lungs is due to scleroderma lung or COVID-19 related lung disease. She was given high dose prednisolone by the respiratory physician which has been reduced in rheumatology clinic. The new findings on chest imaging are sequelae of SARS-COV-2.Case report - DiscussionThis case highlights few important points as below: Systemic sclerosis diagnosis was not made for many years even though she has had severe digital ulcers for a long time. She was being managed as Rheumatoid arthritis. Systemic sclerosis remains a difficult disease to diagnose and is still under recognised. SARS-COV-2 related illness has not affected this patient adversely despite the fact of being on long term maintenance prednisolone of 7.5mg daily dose and Cellcept 2gm. Her cellcept was temporarily stopped during acute illness. We know that viral pneumonitis can present with typical ground glass opacities in bilateral areas of lungs and differential diagnosis does include connective tissue related lung disease but this lady had no significant respiratory involvement prior to COVID-19 illness and follow up scan will help to decide if this is disease progression or related to viral cause.Case report - Key learning pointsThere are multiple learning points in this case: Continuity of care under same primary team can avoid confusion related to diagnosis and diagnosis related complications. This lady had none, or mild subclinical lung involvement related to systemic sclerosis prior to contracting COVID-19 illness. Her CT chest findings after the episode of SARS-COV-2 were attributed to systemic sclerosis as she was seen by different respiratory team. This continuity is not always possible, but MDT collaboration needs to be improved across hospitals and across various departments. Systemic sclerosis remains an under diagnosed and under recognized complex rheumatic disorder and more primary care physicians need to be educated so they can appropriately refer these cases to Rheumatology services.Multi-disciplinary collaboration between Rheumatology, Respiratory and other specialties is the key point to manage these complex cases. This case also highlights an interesting observation that presence of significant immune disorder and immunosuppressant medication does not always equate to worse outcome if patient contracts SARS-COV-2. Supportive care, appropriate observation, and temporary suspension of DMARD in such cases can avoid any further complications.

Pharmacotherapy Options in the Management of Raynaud's Phenomenon.

Multiple classes of medications have been studied for the treatment of Raynaud's phenomenon (RP) with or without digital ischemia. The goal of this review is to discuss the outcomes of recent studies and to report on our approach to the management of RP in light of the available evidence. Comparing treatments for RP remains a challenge as efficacy endpoint vary widely among trials. While calcium channel blockers are used first-line in the pharmacologic management of RP, phosphodiesterase 5 inhibitors have also been shown to be beneficial in reducing symptoms. In the setting of digital ischemia, administration of intravenous prostanoids is the standard of care. Bosentan has shown benefit in the prevention of future ulcers in patients with scleroderma. Botulinum toxin therapy was ineffective in a clinical trial involving scleroderma patients; more controlled studies are needed in other subsets of patients. Digital sympathectomy may be beneficial in cases of critical digital ischemia, though recurrence of symptoms is common. Comparative effectiveness studies are needed to determine which therapeutic interventions are most beneficial in patients with RP. Based on the available evidence, we start with CCBs and add a phosphodiesterase inhibitor if symptoms are not controlled, or intravenous prostacyclin in the setting of severe critical digital ischemia. We may additionally add an endothelial receptor antagonist in cases of recurrent digital ulcers. A surgical sympathectomy may be used in refractory cases of digital ischemia. A digital block may also be a less invasive, but temporary, intervention allowing for titration of medical therapy.

Review: Defining a Unified Vascular Phenotype in Systemic Sclerosis.

Microcirculation impairment and related vasculopathy are hallmarks of systemic sclerosis (SSc). Digital ulceration is second only to Raynaud's phenomenon as a vascular complication occurring in patients with SSc. Digital ulcers are painful and generate disability. Furthermore, patients may develop recurrent digital ulcers, and it is reasonable to question whether the outcomes of such patients might be different from those of patients who are not affected. Recently, several registries have provided relevant information about digital ulcers. Male sex and severe skin disease appear to be the main associated factors observed in several registries. However, limitations of those studies are the differences in the definitions of digital ulcers and organ involvement. Few longitudinal studies are available, and the more robust data from the European League Against Rheumatism Scleroderma Trial and Research cohort suggested worse outcomes in patients with a history of digital ulcers but could not demonstrate that a history of digital ulcers can predict additional vascular complications such as pulmonary arterial hypertension, heart failure, or renal crisis. Nevertheless, the autopsy studies published many years ago and the more recent longitudinal biomarker studies support the concept of generalized vasculopathy and apotential association between various cardiovascular complications. It is expected that with the availability of several structured registries, identification of a vascular profile or vascular phenotype will be addressed using more robust data in the near future.

Raynaud and digital ulcers in patients with juvenile systemic sclerosis: ambulatory iloprost protocol. A single center experience

Results: Since 2007 we treated three patients with jSSc and active digital ulcers: two girls, 12 and 13 years, and a boy of 18 months old at time of first treatment. A total of 19 treatments of iv. iloprost were done, 15 of these in ambulatory basis with the elastomeric pump. Outcomes were good with a reduced number and severity of RP attacks in all patients, and reduced pain associated with RP and DU. No disabling or severe side effects were observed. Two patients, the girls, had no more active digital ulcers after the second treatment with a follow-up of 2 and 3 years respectively. One patient, male, has recurrent digital ulcers, but number has decreased from 4 to 1 not interfering with daily activities. Conclusion: Iloprost iv. perfusion with the elastomeric pump at ambulatory is a safe and effective treatment for patients with refractory RP to calcium channel blockers and in patients with digital ulcers. The authors suggest two treatments in the winter season with reduction of number and severity of R and ulcer healing.

Ischemic digital ulcers affect hand disability and pain in systemic sclerosis.

Ischemic digital ulcers (DU) are frequent and severe complications of systemic sclerosis (SSc). The purpose of our study was to assess the effect of DU on hand disability and pain in patients with SSc. The Evaluation of the Impact of Recurrent Ischemic DU on Hand Disability in Patients with SSc (ECLIPSE) is a prospective, multicenter, noninterventional study with a 2-year followup. Patients with SSc who experienced at least 1 DU in the previous year and received bosentan therapy were included between October 2009 and March 2011. This cohort is described at the time of inclusion. There were 190 patients (132 females) from 53 centers. Mean age ± SD was 43 ± 15 years at SSc diagnosis and 53 ± 15 years at inclusion. In 105 patients (56.2%), DU were the first non-Raynaud symptoms of SSc. The mean time interval between the occurrence of Raynaud phenomenon and the first DU episode was 6.6 ± 9.1 years. The mean numbers of active DU and fingers affected per patient for both hands were 2.3 ± 1.8 and 2.2 ± 1.6, respectively. Presence of active DU at inclusion was significantly associated with pain and impaired hand function: Visual Analog Scale for pain (0 to 10) was 6.2 ± 2.6 versus 2.5 ± 2.4 (p < 0.0001) and Cochin Hand Function Scale for hand disability (0 to 90) was 38 ± 20 versus 25 ± 19 (p < 0.0001), respectively. DU represent a major sign of SSc, often affecting multiple fingers and both hands. They are significantly associated with pain and hand disability.

FRI0375 Clinical features of systemic sclerosis in patients with and without recurrent digital ulcers: findings from the duo registry

BackgroundDigital ulcers (DU) are painful and frequent in patients with systemic sclerosis (SSc), with ~30% of patients experiencing DU at least once a year.ObjectivesThis analysis describes SSc clinical features in...

THU0237 Impact of recurrent ischemic digital ulcers on hand disability in systemic sclerosis –

BackgroundIschemic digital ulcers (DU) are a common complication of systemic sclerosis (SSc).ObjectivesTo evaluate the impact of recurrent DU on hand disability in a prospective, longitudinal, observational study of 24 months.MethodsPatients...

Ulnar artery occlusion is predictive of digital ulcers in SSc: a duplex sonography study

To assess the prevalence and risk factors of ulnar artery occlusion (UAO) in an unselected SSc patient cohort and to determine whether UAO is associated with digital ulcers (DUs). A total of 79 SSc patients and 40 'healthy' controls underwent colour duplex sonography of the radial and ulnar artery to compare blood flow velocity, resistive indices (RIs) and presence of occlusion and were followed for a mean of 53 months. In both, radial and ulnar arteries, peak systolic velocity (PSV) and end-diastolic velocity (EDV) were significantly lower and RI higher in SSc patients compared with controls (PSVrad: 40.1 vs 48.6 cm/s; PSVuln 38.2 vs 56.6 cm/s; EDVrad 3.8 vs 10.4 cm/s; EDVuln 3.0 vs 13.0 cm/s; RIrad 0.91 vs 0.82; RIuln 0.92 vs 0.80; all P < 0.01). Seventeen (21.5%) SSc patients had UAO (11 patients bilateral) compared with none in the control subjects. Patients with UAO had a significantly longer disease duration (170 vs 66 months, P < 0.001). At baseline, the prevalence of DU was not different in upper extremities with UAO [8/28 (28.6%)] compared with upper extremities without UAO [36/129 (27.9%)]. However, during follow-up new or recurrent DU occurred more often in upper extremities with UAO than in those without UAO [14/28 (50%) vs 24/113 (21.2%); relative risk (RR) = 2.4; 95% CI 1.4, 3.7; P = 0.002]. Blood flow is significantly decreased in radial and ulnar arteries in SSc. UAO is frequent and an important risk factor for the development of DUs in patients with SSc.

Bosentan for digital ulcers in patients with systemic sclerosis

Recurrent digital ulcers are manifestations of vascular disease in patients with systemic sclerosis (SSc). We report six patients with severe digital ulcers who were treated with bosentan administered p.o., 62.5-125 mg daily. The mean duration from the diagnosis of SSc to the initiation of bosentan was 9.5 years, and the observation period after bosentan administration was from 7 months to 4.5 years. In case 1, neither new digital ulcers nor Raynaud's phenomenon developed for 4.5 years. In case 2, digital ulcers recurred after the discontinuation of bosentan; however, re-administration of bosentan lead to the improvement. In cases 3-5 with recurrent digital ulcers, no new lesions have developed. In these five patients, pain evaluated by visual analog scale was significantly reduced. In three patients, bosentan was discontinued because of severe liver dysfunction. These results suggest that bosentan is an effective treatment for refractory digital ulcers associated with SSc; however, liver function should be carefully monitored. Compared to the doses of bosentan used to treat pulmonary hypertension, relatively lower doses may effectively control painful digital ulcer/gangrene in patients with SSc.

Treatment of digital ulcers in systemtic sclerosis with endothelin-1 receptor antagonist (bosentan)

In systemic sclerosis (SSc) occurrence of recurrent digital ulcers (DU) is cause of pain and functional disability of hands. Treatment with vasodilator agents, such as calcium channel blockers, ACE inhibitors, prostanoids, has not shown to be an effective therapy. There is evidence that endotelin-1 (ET-1) is a key mediator in regulation of vascular tone and its enhanced production in SSc is believed to lead to vasoconstriction, vessel remodelling, local ischemia and ulcers of fingertips. Recently, an oral endothelin receptor antagonist, bosentan, has been proved to be effective in the treatment of SSc associated pulmonar arterial hypertension (PAH) and to decrease the development of new DU in patients with SSc. In this study, we assessed the occurrence of new DU in eight patients with SSc associated PAH and one SSc patient with recurrent DU refractory to standard vasodilatation therapy. All patients received bosentan at dosage of 62.5 mg bid for 4 weeks and 125 mg bid thereafter for one year. All patients had 3-4 DU of hands at baseline and one patients had also ulcers at lower limbs. In seven out of nine patients we did not record the occurrence of new DU and we also observed a 50% reduction of existing DU, whereas new DU occurred only in two patients. These data suggest that ET-1 plays a key role in DU induction in SSc patients and that ET-1 inhibition by bosentan can be an effective therapeutic strategy.

Gastric Antral Vascular Ectasia Unmasked by Alprostadil for Digital Ulceration in Scleroderma: Figure 1.

To the Editor: We describe a 54-year-old woman with systemic sclerosis (scleroderma, SSc) of the limited subtype. Diagnosis in 1994 was based on tightness of the skin distal to the metacarpophalangeal joints, calcinosis, telangiectasia, esophageal dysmotility, and severe Raynaud’s phenomenon (RP) complicated by recurrent digital ulcers, gangrene and autoamputation. Her serology is significant for positive antinuclear antibody, and anticentromere antibody. During her disease course, she received different regimens of vasodilators including nifedipine, losartan, and topical nitroglycerin in addition to aspirin, with inadequate response. In May 2010 she presented with a refractory ulcer in the right third digit. Despite increase in her vasodilator therapy and addition of pentoxifylline, it progressed to diffuse ulceration of the digit, extending proximal to the distal interphalageal joint. Magnetic resonance imaging revealed no evidence of osteomyelitis. It was decided to admit her to hospital for intravenous (IV) prostaglandin. After she received a 3-day course of continuous IV alprostadil, the ulcer … [↵][1]Address correspondence to Dr. S. Johnson, Division of Rheumatology, Ground Floor, East Wing, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario M5T 2S8. E-mail: Sindhu.Johnson{at}uhn.on.ca [1]: #xref-corresp-1-1

Plaintes et besoins des patients atteints de sclérodermie systémique : une meilleure connaissance afin d’améliorer le suivi

PurposeSystemic sclerosis (ScS) is very heterogeneous in its clinical presentation and its therapeutic care is not codified. A better knowledge of the patients’ needs and complaints could improve the patient educational strategies and their global care. MethodsA self-administered questionnaire aimed to the ScS patient was developed by subspecialty physicians and nurses involved in patient education. It was a cross-sectional study that also included several validated scales: the health control locus scale, the Mactar, HAD and sHAQ scales. ResultsOne hundred and eight patients (91 women; 18 limited ScS, 71 limited cutaneous ScS, 19 diffuse ScS) filled in the questionnaires. Fatigue was the main complaint in all types of ScS, independently of the ScS type. The aesthetic discomfort mentioned by the patients suffering from cutaneous sclerosis or from telangectasia was important and reached 52±33mm on a 100-mm visual scale. It was more common in the patients presenting a diffuse form of the illness but the difference did not reach a statistical significance (P=0.06). Twenty-seven percent of the patients said they were very or extremely worried because of the degradation of their physical appearance. The functional discomfort linked to the cutaneous sclerosis was rated 50±32mm on a 100-mm visual scale. The intensity of the pain, the importance of the functional discomfort linked to the sclerosis and the intensity of the dyspnea were correlated to the sHAQ (P<0.001). Patients having more frequent recurrent digital ulcers had higher sHAQ scores (P=0.04). The repercussions on the professional life were linked to fatigue first, to the Raynaud's syndrome and to arthralgia. The repercussions on the personal life were mainly linked to the fatigue, the pain and the dyspnea. The patients’ compliance was good. ConclusionFatigue, pain, dyspnea and discomfort linked to sclerosis are major chronic symptoms of the patients with ScS. Identifying the needs and complaints of the patients with ScS should help to improve their care by implementation of an educational program.

Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial

ObjectivesIschaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin receptor...

Successful treatment with bosentan of non-digital skin ulcers in severe scleroderma

Recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis leading to severe pain, impaired function and tissue loss. Treatment with the endothelin receptor antagonist, bosentan,...

Macrophage migration inhibitory factor may contribute to vasculopathy in systemic sclerosis

Increasing evidence supports the concept of macrophage migration inhibitory factor (MIF) as a central proinflammatory cytokine in autoimmune diseases. To further evaluate its role in systemic sclerosis (SSc), serum levels of MIF were determined by enzyme-linked immunoassay, and correlations to clinical manifestations were analyzed in 43 patients. MIF levels were significantly increased in patients (median, 18.8; range, <0.015-189 ng/ml) in comparison to healthy controls (n=43, 8.0, <0.015-36.5 ng/ml; P<0.0005). MIF values were higher in diffuse than in limited cutaneous SSc (P<0.005). Patients with pulmonary hypertension and recurrent digital ulcers showed higher MIF levels than patients without these manifestations (P<0.005). This association was also observed in limited cutaneous SSc. Sequential studies revealed decreased MIF levels after initiation of immunosuppressive therapy. MIF levels were not significantly different in patients with and without macrovascular disease of the peripheral arteries. The results suggest that MIF might contribute to inflammation and vasculopathy in SSc.

Effect of Clonazepam on Raynaud's Phenomenon and Fingertip Ulcers in Scleroderma

To report the novel finding of a significant improvement in Raynaud's phenomenon symptoms with clonazepam in a patient with systemic sclerosis. A 45-year-old female with limited scleroderma and chronic renal failure was admitted to our hospital due to hyponatremia (sodium 103 mEq/L). Her hyponatremia was treated by intravenous infusion of NaCl 3%. Clonazepam, which had been prescribed previously for anxiety and insomnia, was discontinued. Three weeks after she was discharged from the hospital, the patient presented with the complaint of increased severity of Raynaud's phenomenon and digital ulcers. She told us that her fingertip ulcers had been healed while she was taking clonazepam and that episodes of Raynaud's phenomenon had increased after discontinuation of the drug. Clonazepam 1 mg twice daily was restarted, and Raynaud's phenomenon and fingertip ulcers resolved within a month. On 2 occasions after that time, we discontinued clonazepam and replaced it with alprazolam, as the patient believed alprazolam was more beneficial in alleviating anxiety. Episodes of Raynaud's phenomenon and new digital ulcers recurred on both of these occasions, and clonazepam was restarted. At the time of writing, no severe episodes of Raynaud's phenomenon or fingertip ulcers have occurred with clonazepam treatment. Raynaud's phenomenon and recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis and lead to pain, impaired function, and tissue loss. Few drugs have previously been shown to affect digital ulcers in the setting of scleroderma. Our patient experienced a significant and sustained improvement in Raynaud's phenomenon and digital ulcers following the initiation of clonazepam. To our knowledge, as of March 2007, this is the first reported use of clonazepam in Raynaud's phenomenon and digital ulcer. While its therapeutic mechanism remains unclear, clonazepam may offer some advantages compared with current agents. We report a case of Raynaud's phenomenon and digital ulcers responding to clonazepam. Further research is warranted to test the robustness of this preliminary finding.