Effects of sarpogrelate hydrochloride on skin ulcers and quality of life in patients with systemic sclerosis

5-Hydroxytryptamine 2A serotonin receptor (5-HT(2A) ) is associated with the contraction of vascular smooth muscle, platelet aggregation and thrombus formation and coronary artery spasms. Sarpogrelate hydrochloride (sarpogrelate) is a selective 5-HT(2A) antagonist and was supposed to be effective for Raynaud's phenomenon with collagen disease. Sarpogrelate has not been investigated regarding the effects, safety and quality of life (QOL) in patient with skin ulcers of collagen disease. Eleven patients with skin ulcers and systemic sclerosis (SSc) were administrated sarpogrelate p.o. three times a day for 3-6 months. The area (mean ± standard error) of skin ulcer at the pretreatment, and after 3 and 6 months of sarpogrelate intake was 2.1 ± 0.8, 0.2 ± 0.1 and 0.1 ± 0.1 mm(2), respectively. The reduction of skin ulcer area was significant after 3 months of sarpogrelate intake. In assessment of QOL, scores of symptoms and emotions but not of functioning were significantly improved after sarpogrelate intake. The global score (mean ± SE) of Skindex-16 at pretreatment, and after 3 and 6 months of sarpogrelate intake was 31.8 ± 8.7, 23.7 ± 8.3 and 10.9 ± 4.6, respectively. The score was significantly improved after 6 months of sarpogrelate intake. There were no obvious side-effects during this study. Sarpogrelate was considered to be a useful drug to improve skin ulcers and QOL in patients with SSc.     

Laser-Doppler measurement of digital blood flow regulation in normals and in patients with Raynaud's phenomenon

Finger blood flow was measured continuously by a laser-Doppler flowmeter in normal subjects and in patients suffering from primary or secondary Raynaud's phenomenon. In normals, skin areas with and without arteriovenous anastomoses could be differentiated. Blood flow in areas with shunt vessels decreased after a deep breath but not during venous stasis or the Valsalva maneuvre, while in other skin areas a decrease in blood flow was observed after all three maneuvres, suggesting a dual innervation of nutritional and shunt vessels. In patients with Raynaud's phenomenon (scleroderma) fingertip blood flow reacted in the same way as normal skin without shunt vessels. During direct and indirect cooling, finger blood flow in patients with secondary Raynaud's phenomenon reacted with the same relative reduction as normals but resting blood flow in the patients was significantly decreased and the rewarming period was greatly prolonged. In patients with primary Raynaud's phenomenon an even more prolonged decrease in blood flow was observed after direct or indirect cooling. Defective function of arteriovenous anastomoses is proposed as an explanation of the deviations from normal. A pathophysiological classification of Raynaud's phenomenon may be possible on the basis of the function tests described.     

Chromosome aberrations in Raynaud's phenomenon

We evaluated the occurrence of spontaneous chromosome damage in cultured peripheral lymphocytes of subjects with idiopathic and pre-scleroderma Raynaud's phenomenon, by means of molecular cytogenetic analysis. Using the micronucleus assay as a marker of chromosome alteration, we studied 30 patients with pre-scleroderma Raynaud's phenomenon, 30 patients with idiopathic Raynaud's phenomenon and 30 healthy subjects. All subjects were classified as ANA-, ACA+ or Scl 70+. To identify the mechanism of micronucleus formation, fluorescence in situ hybridisation analysis was also performed. Pre-scleroderma Raynaud's phenomenon subjects showed significantly higher micronucleus frequencies than idiopathic Raynaud's phenomenon subjects and controls (37.0 +/- 11.5 vs. 11.1 +/- 3.2 and 10.7 +/- 2.7 respectively p < 0.0001). Interestingly, subjects with idiopathic Raynaud's phenomenon displayed micronucleus frequency comparable to that of healthy controls. Furthermore, ACA+ subjects showed the highest micronucleus frequencies (41.0 +/- 7.6) as compared to subjects with Scl 70+ antibody (25.0 +/- 3.5). Our results show that circulating lymphocytes of only pre-scleroderma Raynaud's phenomenon subjects undergo chromosomal damage, as detected by the micronucleus assay, at a higher rate than expected. No prevalence of aneuploidogenic or clastogenic events in micronucleus formation is revealed by fluorescence in situ hybridisation analysis.     

Systemic sclerosis-related Raynaud's phenomenon: effects of iloprost infusion therapy on serum cytokine, growth factor and soluble adhesion molecule levels.

Microvascular damage occurs in systemic sclerosis and is associated with increased serum levels of endothelial adhesion molecules and endothelium-associated cytokines, including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, endothelin-1 and vascular endothelial growth factor (VEGF). Iloprost, a prostacyclin analogue, induces clinical benefit in patients suffering from scleroderma-related Raynaud's phenomenon. This study was performed to investigate the effect of iloprost infusions on endothelium activation. Serum samples from 12 patients with systemic sclerosis were examined using specific enzyme-linked immunoassays. The serum levels of sICAM-1, sVCAM-1 and soluble E-selectin were initially elevated and significantly reduced after iloprost infusions. The serum concentrations of VEGF and endothelin-1 revealed decreased levels after therapy too. These results indicate that the well-known clinical benefit of iloprost infusions on Raynaud's phenomenon is serologically detectable by a reduction of serum levels of endothelium-associated adhesion molecules, cytokines and growth factors reflecting an improvement in endothelial function.     

Ketanserin in the treatment of Raynaud''s phenomenon associated with generalized scleroderma

The efficacy of the 5-HT-2-receptor antagonist, ketanserin, in the treatment of Raynaud's phenomenon was assessed in a double-blind, placebo-controlled, crossover trial in nine patients with generalized scleroderma (GS). Each patient received ketanserin 20 mg or placebo three times a day in the 1st week and 40 mg ketanserin or placebo three times a day for the remaining 4 weeks, and was then crossed over for 5 weeks. Measurements were made of finger blood pressure and flow during a cold challenge test and patients recorded numbers of Raynaud's attacks. No significant improvement was found in reactions to cold provocation or in numbers of Raynaud's attacks during ketanserin treatment, but intolerable side-effects were common. Interactions with concomitant medication might be a possible explanation for this. We conclude that ketanserin in the dose given, is not effective in the treatment of Raynaud's phenomenon in GS.     

Migraine and systemic scleroderma

Scleroderma with typical migraine headaches occurred in 16 well-documented cases observed over a 25-year period. Although the number of cases is within the expected range of coincidence of both diseases, in 13 of the 16 patients the scleroderma developed after 15 years or more of therapy with ergot or methysergide preparations. Eleven of the 13 patients had Raynaud's vasospastic phenomenon as part of their systemic scleroderma. The vascular pathology of scleroderma, Raynaud's phenomenon, and ergotism is similar enough to suggest caution in the administration of these drugs to patients with migraine and extra caution in observing for signs of Raynaud's phenomenon or early vascular scleroderma.     

Longitudinal study of patients with anticentromere antibody

As has previously been reported by many investigators, the anticentromere antibody is considered to be a useful serologic marker for the CREST (calcinosis, Raynaud's phenomenon, esophageal involvement, sclerodactyly and telangiectasia) variant of systemic sclerosis. However, this antibody also appears in other conditions. By screening antinuclear antibody tests using HEp-2 cells as substrate, 39 patients were shown to have the anticentromere antibody. These patients were divided into 4 groups: group 1 = 17 patients with systemic sclerosis; group 2 = 9 patients with Raynaud's phenomenon alone; group 3 = 7 patients with other connective-tissue diseases, and group 4 = 6 patients with conditions other than those present in groups 1-3. Follow-up over years revealed that some patients suffering solely from Raynaud's phenomenon (group 2) developed the symptoms of systemic sclerosis. In contrast, of the patients who did not have Raynaud's phenomenon (group 4), none developed any symptom suggesting systemic sclerosis. We suggest that the simultaneous presence of Raynaud's phenomenon and the anticentromere antibody predicts the occurrence of systemic sclerosis. In contrast, the presence of the anticentromere antibody alone cannot necessarily be used to predict the development of systemic sclerosis.     

Raynaud's phenomenon with oral manifestation in systemic lupus erythematosus

A 24-year-old woman with discoid lupus erythematosus developed systemic lupus erythematosus after 6 years. One of the clinical features was Raynaud's phenomenon in the fingers and toes, and furthermore Raynaud's phenomenon appeared in the tongue when exposed to cold and windy weather.     

Antinuclear antibodies as immunologic markers for a benign subset and different clinical characteristics of scleroderma

Antinuclear antibody (ANA) test results were correlated with the clinical status of 56 patients with systemic scleroderma. Three groups were identified. (1) The speckled pattern represented a benign clinical subset. Acrosclerosis, Raynaud's phenomenon, calcinosis, and esophageal dysmotility characterized this group. None of these patients had pulmonary, renal, or cardiac disease. (2) Two patterns and ANA-negative test results were associated with a different incidence of certain clinical characteristics. The thready pattern was associated with pulmonary involvement. Diffuse skin involvement and Raynaud's phenomenon were found with the nucleolar pattern. Patients with ANA-negative test results had the most severe disease, including renal failure. (3) Two patterns were not associated with different clinical characteristics. These were the small speckle-like thready pattern and the homogeneous pattern. This study supports the theory that ANA patterns may be used as immunologic markers for different clinical characteristics of patients with scleroderma as they have already been used in lupus erythematosus.     

Measuring the activity of the disease in patients with cutaneous lupus erythematosus

The Systemic Lupus Activity Measure (SLAM) is a system proposed by rheumatologists to measure disease activity in their patients with systemic lupus erythematosus (LE). It involves scoring a group of clinical symptoms and laboratory findings, the maximum possible score being 84. In systemic LE, the mid-point is between 9 and 12. We applied SLAM to 176 patients with cutaneous LE. Ninety-seven had localized discoid LE (L-DLE), 59 had disseminated discoid LE (D-DLE) and 20 had subacute cutaneous LE (SCLE). Eighty-five patients had low activity disease (0-4 points), 72 mildly active disease (5-9 points), 15 moderately active disease (10-14 points) and only four had very active disease (>/= 15 points). The most frequent lesions in patients who scored more than 10 points were photosensitivity, cicatricial alopecia, Raynaud's phenomenon and oral ulcers. Fifty patients were followed up for more than 5 years (mean follow-up 9 years). Nine of these had an increased SLAM score. Seven had L-DLE, one D-DLE and one SCLE. Seven of the 50 patients had photosensitivity, five cicatricial alopecia, five non-cicatricial alopecia, two Raynaud's phenomenon and two oral ulcers. Three patients who started with L-DLE evolved to D-DLE. The SLAM system is useful in the monitoring of disease activity in patients with cutaneous LE. Over time, even L-DLE patients may develop active disease. Photosensitivity, alopecia, oral ulcers and Raynaud's phenomenon seem to herald a worse prognosis.     

Treatment of peripheral gangrene due to systemic sclerosis with intravenous pentoxifylline

Vascular problems are very common in systemic sclerosis with 95% of patients suffering with Raynaud's phenomenon at some stage in their illness. Acute ischaemic lesions are much less common, but when they occur are a serious complication, and are often difficult to treat. Many drugs have been used in this situation, including both oral and intravenous vaso-dilators and low molecular weight dextran, each with varying degrees of success. The phospho-diesterase inhibitor, pentoxifylline, is reported to be useful in peripheral vascular disease, and in Raynaud's phenomenon, and the intravenous form is indicated for acute peripheral ischaemia, though its use in the context of connective tissue disease has not so far been reported. We now report the use of intravenous pentoxifylline in two patients with acute peripheral gangrene due to systemic sclerosis.     

Efficacy of a 5-HT1a receptor agonist in atopic dermatitis

Background. Atopic dermatitis (AD) can be aggravated by mental stress. We recently showed that pretreatment with tandospirone citrate (TC), a serotonin (5-HT) agonist for the 5-HT_1A receptor subtype, significantly inhibits stress-induced degranulation of mouse dermal mast cells. Aims. To evaluate the efficacy of TC in treatment of AD. Methods. Changes in anxiety levels, depression symptoms and the clinical severity of AD after administration of TC were examined. Data were collected for 20 patients with AD who received TC 30 mg/day for 4 weeks and 17 patients with AD who did not receive the drug. Profile of Mood States (POMS) scores were used to meaure several types of mental stress. Severity of AD was evaluated using the SCORAD Index, and the patients’ level of stress and sleeping status were evaluated using visual analogue scales. Results. Before TC administration, all scores were markedly different in the 37 patients compared with 37 normal healthy controls matched for age and gender. POMS scores for tension–anxiety (T-A) and the SCORAD Index decreased signficantly in patients who received TC, but did not change significantly in the untreated patients. The two groups had significantly different treatment responses based on changes in T-A scores. There was a significant correlation between changes in the T-A score and SCORAD Index. Conclusion. These data suggest that anxiolytic drugs such as 5-HT_1A agonists are useful in the clinical management of stress-associated aggravation of AD. Inhibition of stress-induced mast cell degranulation may be one of the mechanisms underlying the clinical efficacy.     

Combined pizotiphen and cinnarizine treatment in urticaria factitia

30 patients suffering from urticaria factitia were treated with pizotiphen and cinnarizin for 6 weeks. In 13 patients, the effect of treatment was controlled by means of the dermographism test. Placebo administration failed to affect the subjective and objective symptoms. During treatment with pizotiphen and cinnarizin, the flare significantly decreased within the first week and finally did not differ from that observed in healthy persons after 6 weeks of therapy. 19 out of 30 patients were totally free of symptoms. In 11 cases, treatment resulted in significant reduction of the urticaria, but only 7 patients still complained of itching. After repetition of the therapy, 5 patients were free of symptoms; 2 patients still reported on slight itching one year after treatment.     

Ketanserin in the treatment of systemic sclerosis: a double-blind controlled trial

In a randomized, double-blind study, the selective and specific S2-serotonergic receptor antagonist, ketanserin was compared with placebo in 24 patients with systemic sclerosis. Following a 6-week placebo washout period, patients were randomly allocated to receive ketanserin or placebo for 6 months. Ketanserin failed to produce a greater improvement than placebo in functional and objective clinical signs and symptoms as well as in most subjective assessments. However, in a global rating by the physician ketanserin was superior to placebo. No difference in the frequency or severity of side-effects was found. The results cast doubt on the hypothesis that serotonin may be a major contributing factor in the pathophysiology of systemic sclerosis.     

Differences in red cell behaviour between patients with Raynaud''s phenomenon and systemic sclerosis and patients with Raynaud''s disease

The 'filterability' and electrophoretic mobility of erythrocytes from 42 patients with systemic sclerosis and Raynaud's phenomenon were studied and compared with the findings from 24 patients with Raynaud's disease and 26 normal controls. Red blood cells from patients with systemic sclerosis and Raynaud's phenomenon were less filterable (P less than 0.0001) and had decreased electrophoretic mobility (P less than 0.001) compared with erythrocytes from patients with Raynaud's disease and the controls. There was no significant difference between the values from the patients with Raynaud's disease and the controls. These results indicate that measurement of erythrocyte filterability and electrophoretic mobility may be useful in the differentiation of patients with Raynaud's disease who have no underlying collagen disease from those who have Raynaud's phenomenon in association with systemic sclerosis.     

Raynaud's phenomenon with gangrene of the digits as the revealing sign of an antiphospholipid syndrome

We report the case of a 37-year-old woman who suffered for years of Raynaud's phenomenon associated with gangrene of digits. The patient displayed high levels of circulating antiphospholipid (aPL) antibodies, which on treatment with aspirin decreased significantly along with resolution of both Raynaud's phenomena and distal ischemic necrosis. To our knowledge this is the first report of an aPL syndrome featuring severe Raynaud's phenomenon as the only clinical sign. Possible pathogenetic correlations and the favourable therapeutic effect of aspirin are discussed.     

Vital microscopy of nailfold capillaries in progressive scleroderma in relation to the clinical picture

Capillary microscopic investigations of the nailfold were performed in 38 patients presenting Raynaud's phenomenon (systemic sclerosis: diffuse type n = 6; systemic sclerosis: CREST syndrome n = 21; Raynaud's disease n = 7; mixed connective tissue disease (MCTD) n = 4). A control group of 15 healthy persons was investigated for comparison. 3 stages of capillary alteration were established in patients with systemic sclerosis by recording number (per 2 mm microscopic field diameter), morphology, colour and size of nailfold capillaries. Additional criteria like pericapillary microhemorrhages and disordered capillary blood flow were considered as well. Significant correlations of capillary microscopie findings to different subsets of systemic sclerosis including MCTD could not be proven. Cases provisionally classified as Raynaud's disease could not be assigned to systemic sclerosis on account of capillary microscopy. A clear correlation was found, however, between the grade of capillary alteration and both severity of clinical features and duration of the disease. All cases with capillary changes of stage 3 showed clinical correlation to esophageal dysmotility , also proven in 7 out of 13 patients with stage 2 capillary alteration.     

Anticentromere-protein-B-DNA complex activities in anticentromere antibody-positive patients

Centromere protein B (CENP-B), which is an alphoid DNA binding protein, is the target antigen in autoimmune disease patients (often those with scleroderma). In this study, we analysed activities of anti-CENP-B-DNA complex in anticentromere antibody (ACA)-positive patients using DNA immunoprecipitation with purified CENP-B. The activities correlated with ACA titres and were closely associated with Raynaud's phenomenon. Patients with CREST symptoms (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) showed higher activities than those with no symptoms. Our results suggest that autoimmune responses to native CENP-B may have an important role in the pathogenesis of scleroderma.     

Digital ulcers and necroses: novel manifestations of angiocentric lymphoma

We describe a patient with angiocentric lymphoma whose presenting features were multiple areas of digital ulceration and necrosis, including deep ulcers on both great toes. He lacked the lateral halves of both earlobes because of multiple ulcers. Skin biopsy revealed a patchy and diffuse infiltrate of lymphoid cells with nuclear atypia in the dermis and subcutaneous tissue. Angiocentric and angiodestructive features of the lymphoid cells, a prominent histiocytic infiltrate and some epithelioid cell granulomas were found. The results of immunohistochemical staining showed a T-cell phenotype, and showed positive staining for apoptosis. He died in July 1999. Peripheral vascular disturbances including Raynaud's phenomenon, digital skin ulcers and necroses are novel clinical symptoms in patients with angiocentric lymphoma, which should be added to the differential diagnosis in patients with peripheral vascular disturbances.     

The antipruritic effect of a 5-HT3 receptor antagonist (tropisetron) is dependent on mast cell depletion – an experimental study

The background of this study is that 5-HT3 receptor antagonists are reported to have an antipruritic effect in uremic and cholestatic pruritus. Recently, we could not confirm such an effect in healthy subjects under experimental conditions. Therefore, it was the aim of the present study to further evaluate a possible antipruritic effect of a 5-HT3 receptor antagonist (tropisetron) on serotonin- and histamine-induced itch before and after skin mast cell depletion in 10 healthy subjects. The results were compared to serotonin and histamine iontophoresis in non-pretreated and pretreated skin with an orally applied antihistamine (cetirizine). Skin mast cell depletion was performed by iontophoretical application of compound 48/80. Wheals and flares were planimetrically evaluated. Itching and burning sensations were rated on an analog scale over a 24-min period. The test protocol also comprised alloknesis, defined as induction of perifocal itch sensations by a mechanical stimulus. When serotonin was iontophoretically applied after mast cells had been depleted before, oral tropisetron resulted not only in significantly lower whealing, itching and alloknesis but also reduced flares. In contrast, after oral pretreatment with tropisetron histamine-induced reactions before and after mast cell depletion did not significantly change. Our study demonstrates that in this model, tropisetron as a 5-HT3 receptor antagonist does not effect histamine-induced itch but has a measurable effect in serotonin-induced reactions when mast cells were depleted before. From these data evidence now exists why tropisetron is to some extent effective in certain types of pruritus such as uremic pruritus, known for increased histamine liberation and increased serotonin levels as well as degranulated and diffusely spread mast cells in the skin.