Pulsed versus continuous wave low-level light therapy on osteoarticular signs and symptoms in limited scleroderma (CREST syndrome): a case report.

Limited cutaneous systemic sclerosis (lcSSc) was formerly known as CREST syndrome in reference to the associated clinical features: calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasias. The transforming growth factor beta has been identified as a major player in the pathogenic process, where low-level light therapy (LLLT) has been shown to modulate this cytokine superfamily. This case study was conducted to assess the efficacy of 940 nm using millisecond pulsing and continuous wave (CW) modes on osteoarticular signs and symptoms associated with lcSSc. The patient was treated two to three times a week for 13 weeks using a sequential pulsing mode on one elbow and a CW mode on the other. Efficacy assessments included inflammation, symptoms, pain, health scales, patient satisfaction, clinical global impression, and adverse effects monitoring. Considerable functional and morphologic improvements were observed after LLLT, with the best results seen with the pulsing mode. No adverse effects were noted. Pulsed LLLT represents a treatment alternative for osteoarticular signs and symptoms in limited scleroderma (CREST syndrome).

Sporadic hemiplegic migraine and CREST syndrome.

Hemiplegic migraines are characterised by attacks of migraine with aura accompanied by transient motor weakness. There are both familial and sporadic subtypes, which are now recognised as separate entities by the International Classification of Headache Disorders, edition II (ICHD-II). The sporadic subtype has been associated with other medical conditions, particularly rheumatological diseases. We report the case of a woman with sporadic hemiplegic migraine associated with CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia). Since there is a close relationship between migraine and Raynaud's phenomenon, it could be speculated that the sporadic hemiplegic migraines in our patient might be secondary to CREST syndrome.

Intracranial aneurysms in patients with CREST syndrome.

CREST syndrome is a variant of scleroderma characterized by calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactyly, and telangiectasia, and is a collagen vascular disease characterized by inflammation and fibrosis of multiple organs/tissues. Neurological and cerebrovascular abnormalities are uncommon in CREST syndrome. Here, we report two patients with CREST syndrome harboring intracranial aneurysms. A 53-year-old woman with a 6-month history of CREST syndrome had multiple intracranial aneurysms that arose from the right middle cerebral artery, the left middle cerebral artery, the choroidal segment of the left internal carotid artery, and the left anterior cerebral artery. A 64-year-old woman with a 2-year history of CREST syndrome had a fusiform aneurysm located on the insular segment of the left middle cerebral artery. These patients were treated surgically and good outcome was achieved in both cases. The pathogenesis of cerebral aneurysms associated with collagen diseases, including CREST syndrome, remains unclear. Early treatment of CREST syndrome and other collagen diseases may prevent arteritis from progressing to affect the intracranial arteries and thus reduce the occurrence of aneurysms. The prognosis for patients with collagen diseases after rupture of cerebral aneurysm seems to be poor because the multiplicity, atypical morphology, and atypical location of their aneurysms make treatment difficult. Thus, early detection and treatment are important to improve the prognosis.

The role of radiology in the management of systemic sclerosis.

Systemic sclerosis is a multisystem connective tissue disorder. Radiology plays an integral part in its management, guiding the clinician concerning the onset and severity of visceral involvement. After skin involvement, the gastrointestinal tract is the most commonly affected system; contrast radiography and magnetic resonance imaging (MRI) play a role in diagnosis. Non-specific interstitial pneumonia is the most frequent respiratory disease and high-resolution computed tomography (CT) is the cornerstone of management. In common with other rheumatic disorders, the role of cardiac MRI is expanding. Radiography remains the main technique in the investigation of skeletal involvement, although MRI is useful as a problem-solving tool. Neurological involvement is increasingly recognized and the major role of radiology is the exclusion of coexistent pathology. We present a thorough review of the role of radiology in the management of systemic sclerosis.

[Pulmonary arterial hypertension in collagenoses: clinical features, epidemiology, pathogenesis, diagnosis and treatment]. / Pulmonale arterielle Hypertonie bei Kollagenosen: Klinik, Epidemiologie, Pathogenese, Diagnostik und Therapie.

Pulmonary arterial hypertension (PAH) is a severe vasculopathy, which is characterised by progressive narrowing and obliteration of the pulmonary arterioles and increased endothelin-1 levels. The increase of vascular resistance in the lung vessels leads to chronic pressure overload and to right heart failure, if untreated. PAH often occurs in association with rheumatic-inflammatory diseases (e.g., in 15% of patients with systemic sclerosis (SSc), especially in the limited form or in CREST patients) and determines their prognosis: in advanced stages, untreated patients die within a short period. Therefore all SSc patients, particularly the newly diagnosed ones, should be screened for PAH with echocardiography. If PAH is suspected, a right heart catheter should be performed, and if PAH is confirmed, adequate treatment should be initiated. While few years ago lung transplantation was the only option for patients with severe PAH, in recent years enormous progress was seen in drug treatment. Today prostanoids (Ventavis) and the endothelin receptor antagonist bosentan (Tracleer) are available for patients with PAH in WHO/NYHA stage III: they have substantially improved the prognosis of PAH in the last years. Since few months, also the phosphodiesterase inhibitor sildenafil (Revatio) is available. The combination of drugs with different mode of action will likely further improve the prognosis of PAH patients.

Abnormal pulmonary vascular responses in patients registered with a systemic autoimmunity database: Pulmonary Hypertension Assessment and Screening Evaluation using stress echocardiography (PHASE-I).

UNLABELLED: Patients with autoimmune disease, and in particular limited systemic sclerosis (CREST syndrome), are at risk of developing pulmonary artery hypertension (PAH) which is associated with a poor prognosis. With improvements in therapy offering improved survival and functional capacity, there has been an emphasis on screening to identify patients at risk. Assessment of patients during exercise may enable early identification of patients with this condition. AIMS AND METHODS: We aimed to assess the ability of exercise stress echocardiography to evaluate the change in pulmonary artery pressure in 51 patients with autoimmune disease (systemic lupus erythamatosus (SLE), limited systemic sclerosis (LSS or "CREST") and diffuse systemic sclerosis (DSS)). Systolic pulmonary artery pressure (sPAP) was estimated using interrogation of the tricuspid incompetence jet before and after exercise. PAH was classified as normal, mild, moderate or severe using echocardiographic assessment of sPAP. RESULTS: We were able to estimate pre-exercise and post-exercise sPAP in 92% and 90% of patients, respectively. Pulmonary pressures rose or remained unchanged in all screened individuals, with a mean rise during stress of 14.1mmHg (+/-1.1). Pulmonary artery pressure rose significantly in each of three subgroups (p<0.05). Stress echocardiography demonstrated PAH (using a cut-off of >35mmHg) in 59% of all individuals with systemic autoimmunity. CONCLUSION: Stress echocardiography is a useful tool in identifying individuals with autoimmune disease who may have underlying pulmonary arterial disease that may be amenable to therapy. We noted a consistent elevation in sPAP across all autoimmune subtypes, suggesting an abnormal pulmonary vascular response to exercise exists in these patients.

[Pulmonary hypertension in patients with systemic scleroderma with CREST-syndrome and without it]. / Legochnaia gipertoniia u bol'nykh sistemnoi sklerodermiei s CREST-sindromom i bez takovogo.

AIM: To study incidence rate and characteristics of pulmonary hypertension development in patients with systemic sclerosis (SS). MATERIAL AND METHODS: The study included 31 SS patients (30 females, 1 male, age 33-75 years, mean age 47.7 +/- 1.7 years). RESULTS: Pulmonary hypertension occurred more frequently in SS patients with CREST-syndrome than in SS patients free of this syndrome. SS patients with CREST-syndrome had also more severe ventricular hypertrophy than ventricular dilation. CONCLUSION: Echocardiography proved to be a highly informative method for detection of pulmonary hypertension in patients with SS. The necessity of hemodynamical study in SS patients is emphasized.

Human ninein is a centrosomal autoantigen recognized by CREST patient sera and plays a regulatory role in microtubule nucleation.

Centrosome is the major microtubule organizing center in mammalian cells that plays a critical role in a variety of cellular events by the microtubule arrays emanating from it. Despite its significance, the molecular mechanisms underlying the structure and function of the centrosome are still not clear. Herein we describe the identification of three isotypes of human ninein by expression library screening with autoimmune sera from CREST patients. All three ninein isotypes exhibit centrosomal localization throughout the cell cycle when GFP-tagged fusion proteins are expressed transiently in mammalian cells. Construction of serial deletions of GFP-tagged ninein reveals that a stretch of three leucine zippers with a flanking sequence is required and sufficient for centrosomal targeting. Overexpression of ninein results in mislocalization of gamma-tubulin, recruiting it to ectopic (noncentrosomal) ninein-containing sites which are not active in nucleating microtubules. In these cells, nucleation of microtubules from the centrosome is also inhibited. These results thus suggest a regulatory role for ninein in microtubule nucleation.

Open label trial of tamoxifen in scleroderma.

BACKGROUND: Previous reports have suggested that treatment with the selective estrogen antagonist tamoxifen may be effective in diminishing primary and secondary Raynaud's vasospasm, including cases occurring in the setting of scleroderma. Tamoxifen treatment has also been associated with improvement of retroperitoneal fibrosis and desmoid tumors, conditions also associated with abnormal fibroblast proliferation. Tamoxifen increases production of the immunosuppressive cytokine TGF beta which modulates fibroblast activity. The potential effect of tamoxifen on vascular reactivity and fibrotic lesions raised questions about its utility as a therapeutic agent in scleroderma. OBJECTIVE: To determine the utility of tamoxifen therapy in scleroderma. METHODS: Open label preliminary, prospective, proof of concept study of tamoxifen. RESULTS: Fifteen patients (3 male, 12 female) with scleroderma were enrolled (10 diffuse disease, 5 CREST). Mean age was 55 (34-75) years. Mean duration of scleroderma was 9.3 (1-25) years. Two patients were excluded. For 13 patients, mean duration of treatment was 7 (1.5-32) months. Two of 13 patients treated with tamoxifen experienced transient improvement. They did not appear to have clinical features that identified them as a unique subset. Both patients subsequently relapsed, in one case 12 months, and in the other 24 months after treatment. CONCLUSION: Based on these results, we would not recommend tamoxifen for further large scale studies in scleroderma.

Systemic sclerosis sine scleroderma: is it always the same disease? Report of three patients and discussion.

The recent description of a large cohort of patients with the diagnosis of systemic sclerosis sine scleroderma (ssSSc) provided significant progress in our understanding of this entity. The prognosis of patients with ssSSc is, however, very variable, from benign in most cases to rapidly disabling in others. By reporting three new cases and analyzing previously published data, we discuss possible subsets and variants of the disease form.

Enhanced expression of the receptor for granulocyte macrophage colony stimulating factor on dermal fibroblasts from scleroderma patients.

OBJECTIVE: To elucidate events that initiate the involvement and stimulation of fibroblasts in systemic sclerosis (SSc). METHODS: We examined 15 patients with SSc diffuse form, 15 with CREST syndrome, and 5 healthy subjects. Cultured fibroblasts obtained from skin biopsies in SSc involved and non-involved areas and norrmal skin fibroblasts were cultured with different doses of granulocyte macrophage colony stimulating factor (GM-CSF) to study the effects of this factor on the expression of GM-CSF receptor (GM-CSFR) on fibroblast proliferation and cellular adhesion structures. RESULTS: Cultured fibroblasts obtained from biopsies of normal and SSc skin areas express GM-CSFR and such expression is increased in SSc fibroblasts. GM-CSF stimulation in vitro did not increase SSc fibroblast growth, in spite of a strongly increased expression of the GM-CSFR. The adhesion structures are always more abundant in SSc fibroblasts as compared to healthy cells and GM-CSF seems able to increase cell adhesion plaques. CONCLUSION: We suggest that shift of fibroblasts toward a more adhesive differentiated pattern, due to or accompanied by an increased expression of GM-CSFR, may be an important event in the pathogenesis of SSc.

[Pulmonary hypertension screening in systemic scleroderma: a cohort study of 67 patients]. / Dépistage de l'hypertension artérielle pulmonaire au cours de la sclérodermie systémique: étude d'une cohorte de 67 patients.

PURPOSE: Pulmonary hypertension is a severe complication of systemic sclerosis and has emerged as a major cause of morbidity and mortality in this condition. Treatment is all the more efficient as pulmonary hypertension is early diagnosed. A good knowledge of the clinical, biological and functional features of pulmonary hypertension in systemic sclerosis is therefore necessary to suspect and to diagnose pulmonary hypertension as early as possible. METHODS: Sixty seven patients with systemic sclerosis were retrospectively studied. We compared clinical, immunological, functional (spirometry) and morphological (pulmonary fibrosis) features according to the presence (n = 25) and the characteristic of pulmonary hypertension (isolated or secondary) or the absence (n = 42) of pulmonary hypertension, assessed by Doppler echocardiography. RESULTS: CREST syndrome (calcinosis, Raynaud's phenomenon, oesophageal involvement, sclerodactyly and telangiectasia) was more frequent in patients with isolated pulmonary hypertension than in patients without PH (72.7% vs 28.5%, P < 0.05; odds-ratio [OR] = 6.6) and dyspnea was more severe (P < 0.001; OR = 11.4). The age at time of pulmonary hypertension diagnosis was higher in patients with secondary pulmonary hypertension than in patients with isolated from (median: 62.5 years (range: 32-35) vs 53 years (range: 37-85), P < 0.05). Patients with isolated pulmonary hypertension had anticardiolipin antibodies more frequently than patients without pulmonary hypertension (72.7% vs 35.7%, P < 0.05). Isolated reduction of diffusing capacity was preferentially observed among patients with isolated pulmonary hypertension than among those without pulmonary hypertension. A linear relation between systolic pulmonary artery pressure values and diffusing capacity values (r = 0.72, P < 0.01) was found. Isolated reduction of diffusing capacity was more frequent in patients with isolated pulmonary hypertension than in patients without pulmonary hypertension (63.6% vs 14.3%, P < 0.001; OR = 10.5). CONCLUSION: The severity of pulmonary hypertension in systemic sclerosis justifies a systematic screening by Doppler echocardiography and diffusing capacity measurement. Our results allow us to better define the characteristics of sclerodermic patients with isolated or secondary pulmonary hypertension. The search for pulmonary hypertension should be repeated with time and clinicians should be particularly vigilant in the case of a patient presenting these characteristics.

Motor activity of the gallbladder in systemic sclerosis.

OBJECTIVE: We sought to measure gallbladder emptying in scleroderma patients, when stimulated by exogenous cholecystokinin. METHODS: Twenty-eight consecutive scleroderma patients were evaluated. Ten were excluded for the presence of gallstones. Gallbladder motor function was studied in 18 patients and 18 controls, using specific parameters for the quantification of gallbladder emptying dynamics. Resting gallbladder volumes were compared using the Dodds method with real-time ultrasound. Cholecystokinin (CCK)-stimulated gallbladder function (0.02 microg/kg CCK intravenous infusion/30 min) was assessed by a scintigraphic technique using 99mTc-DISIDA. Five patients presented with CREST syndrome, 13 with the diffuse form of scleroderma. Four were men, 14 women (average age = 46.6+/-15.4 yr). Patients and controls were paired by gender, age, and weight. RESULTS: Resting gallbladder volumes were larger in the four men with scleroderma than in the women with this disease (p < 0.03, Mann-Whitney). The mean gallbladder resting volume in scleroderma patients was not different from the mean volume detected among controls (p = 0.25), even when controlling for gender (p = 0.78 for women, p = 0.08 for men), scleroderma disease subtype (p = 0.50), or disease duration (p = 0.48). Latency period, ejection period, ejection rate, or ejection fraction as measured during cholecystokinin-stimulated scintigraphic studies were not significantly different between patients and controls. A trend was detected for reduction of the ejection period in scleroderma women (p = 0.70) when compared with scleroderma men. More than 35% of the scleroderma patients presented biliary lithiasis. CONCLUSIONS: There was no significant difference in gallbladder dynamics measured by a scintigraphic technique in scleroderma patients, compared with controls, when gallbladder motor function was evaluated by intravenous CCK.

A case-control and nerve biopsy study of CREST multiple mononeuropathy.

From 536 patients with the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasis), seven were identified as having peripheral neuropathy not attributable to another cause. Peripheral neuropathy developed 0 to 25 years after their first symptoms of scleroderma. Unexplained neuropathy in CREST patients (seven patients) was more frequent than in control subjects (two patients) matched for age, sex, time of evaluation, and geographic referral region. Multiple mononeuropathy occurred significantly more frequently in the CREST group (six patients) than in the control group (0 patients). Four sural nerve biopsy specimens from the CREST patients demonstrated multifocal fiber loss and perivascular inflammation; one was diagnostic for necrotizing vasculitis and two others were highly suggestive for necrotizing vasculitis. The density of myelinated fibers in three nerves from CREST patients was significantly decreased, whereas the index of dispersion (a measure of multifocal fiber loss) was increased, and the frequency of axonal degeneration was significantly increased. Based on these clinical and pathologic findings, we conclude that in the CREST syndrome multiple mononeuropathy, although occurring infrequently, occurs more frequently than by chance and necrotizing vasculitis is the cause of this multiple mononeuropathy.