Angiotensin receptors in Dupuytren's disease: a target for pharmacological treatment?

BACKGROUND: Attempts at the pharmacological treatment of Dupuytren's disease have so far been unsuccessful, and the disease is not yet fully understood on a cellular level. The Renin-Angiotensin System has long been understood to play a circulating hormonal role. However, there is much evidence showing Angiotensin II to play a local role in wound healing and fibrosis, with ACE inhibitors being widely used as an anti-fibrotic agent in renal and cardiac disease. METHODS: This study was designed to investigate the presence of Angiotensin II receptors 1 (AT1) and 2 (AT2) in Dupuytren's tissue to form a basis for further study into the pharmacological treatment of this condition. Tissue was harvested from 11 patients undergoing surgery for Dupuytren's disease. Each specimen was processed into frozen sections and immunostaining was employed to identify AT1 and AT2 receptors. RESULTS: Immunostaining for AT1 receptors was mildly positive in one patient and negative in all the remaining patients. However, all specimens stained extensively for AT2 receptors. This suggests that the expression of AT2 receptors is more prominent than AT1 receptors in Dupuytren's disease. CONCLUSION: These findings have opened a new avenue for future research involving ACE inhibitors, AT2 agonists, and AT2 antagonists in Dupuytren's disease.

Epidemiology of Dupuytren's disease: clinical, serological, and social assessment. The Reykjavik Study.

Dupuytren's disease or palmar fibromatosis is a common disabling hand disorder, mainly confined to Caucasians of northwestern European origin. The prevalence of Dupuytren's disease and possible risk factors related to the disease were evaluated in a random sample of 1297 males and 868 females, aged 46 to 74 years. Blood samples were collected and biochemical parameters were evaluated. The possible relation between the disease and clinical, social, and biochemical parameters were estimated with age-adjusted univariate logistic regression analysis. Altogether 19.2% of the males and 4.4% of the female participants had clinical signs of Dupuytren's disease. The prevalence increased with age, from 7.2% among males in the age group 45-49 years up to 39.5% in those 70-74 years old. The more severe form of the disease, finger contractures, was found in 5.0% of the men and 1.4% had required operation, while this was rarely seen among women. In men elevated fasting blood glucose (P < 0.04), low body weight, and body mass index were significantly correlated with the presence of the disease (P < 0.001). Dupuytren's disease was common among heavy smokers (P = 0.02) and those having manual labor as occupation (P = 0.018). These results show that Dupuytren's disease is common in the Icelandic population and occupation and lifestyle seem to be related to the disease.

Dupuytren's disease in type I diabetic subjects: investigation of biochemical markers of type III and I collagen.

OBJECTIVE: To clarify whether biochemical markers of collagen type III and I metabolism show alterations in type I diabetic subjects with Dupuytren's disease (DD) compared to those without DD. METHODS: DD was assessed in a total of 28 type I diabetic subjects, mean age 43.4 +/- 9.5 (SD) and duration of diabetes 25.2 +/- 9.7 years. Concentrations of aminoterminal propeptide of type III procollagen (PIIINP), carboxyterminal propeptide of type I procollagen (PICP) and carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in serum and excretion of cross-linked N-telopeptides of type I collagen (NTX) and deoxypyridinoline crosslinks (DPyr) into urine were measured. RESULTS: The prevalence of DD was 32% (9 of 28 diabetic subjects). Average serum ICTP was 2.7 +/- 0.8 micrograms/l in subjects without DD and 3.6 +/- 1.2 micrograms/l with DD (p = 0.0276). No significant association between other collagen markers and DD was found. The reference intervals of PIIINP and ICTP were exceeded only in 1 and 2 subjects, respectively, and they both had DD. CONCLUSION: The degradation of type I collagen might be increased in diabetic subjects with DD. The overall implication was that synthesis or degradation of type III and I collagen in diabetic subjects with DD did not differ enough from those without DD to reflect changes in the biochemical markers of type III and I collagen.

Lipids and Dupuytren's disease.

We studied prospectively the relationship between serum lipids and Dupuytren's disease of the hand in 85 patients, 65 men and 20 women. The Dupuytren patients had significantly higher fasting serum cholesterol and triglyceride levels than did the controls (p < 0.001). The raised levels of serum lipids appeared to be associated with the pathogenesis of Dupuytren's disease, and this may help to explain the high incidence of Dupuytren's disease in alcoholic, diabetic and epileptic patients, since these conditions are also associated with raised serum lipid levels.

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in sera and tissue of patients with Dupuytren's disease.

Dupuytren's contracture is a fibroproliferative disorder characterized by progressive deposition of mature collagen fibers. In other fibrotic diseases affecting organs such as the liver, lung, heart, and skin, matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), play an important role. In this study, serum concentrations of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined in 22 patients (five women and 17 men; average age, 67 +/- 11 years) with Dupuytren's disease using an enzyme-linked immunosorbent assay. Tissue samples were obtained for standard histological and immunohistochemical analyses. Sera and samples of palmar fascia from 20 patients (13 women and seven men; average age, 60 +/- 15 years) who had undergone hand surgery for carpal tunnel syndrome were used as the control group. Statistical analysis was performed using the Mann-Whitney test. Patients with Dupuytren's contracture presented with a TIMP-1 concentration of 437 +/- 160 ng/ml, a significantly higher TIMP-1 concentration than that seen in the control patients, who had a concentration of 321 +/- 70 ng/ml (p < 0.05). Patients with a proliferative active disease (n = 14) had a significantly higher TIMP-1 concentration (525 +/- 136 ng/ml) than patients (n = 8) with a contracture in the late involutional and residual phase (286 +/- 41 ng/ml; p < 0.05). There were no significant differences in the TIMP-2, MMP-1, MMP-2, and MMP-9 serum concentrations between patients with palmar fibromatosis and the control group. Patients with Dupuytren's disease had a significantly lower MMP-to-TIMP ratio (1.1 +/- 0.3; p < 0.05) than the control group (1.5 +/- 0.35). Patients with an active palmar fibromatosis presented a significantly (p < 0.05) reduced ratio (1 +/- 0.2) compared with those in later phases (1.4 +/- 0.3). TIMP-1 and TIMP-2 could be detected in tissue of patients with Dupuytren's contracture, with an accumulation in proliferative areas. MMPs could be detected locally in Dupuytren's tissue in a few patients, with less positive staining than for TIMPs. In the control group, there was just little or no staining for TIMPs and MMPs. The data indicate that the physiological balance between MMPs and their natural inhibitors is disturbed in patients with a proliferative active Dupuytren's disease. The decrease in the systemic MMP-to-TIMP ratio can cause increased synthesis and deposition of collagen, leading to palmar fibromatosis.

The incidence of gout in patients with Dupuytren's disease.

In a retrospective study we found that the incidence of gout in patients with Dupuytren's disease is 3.5%. The mean serum uric acid was 330 mumol/l. (5.5 mg./100 ml.) in men and 240 mumol./l. (4.0 mg./100 ml.) in women. The rate of hyperuricaemia was 7%. These are not significantly higher than the expected figures in Britain.

Rationale for the need to employ a conservative method in the treatment of patients with dystrophy of the hand.

Radioimmunoassay determining sexual hormone levels, functional state of the autonomic nervous system and blood supply, were used to study the causes aiding the development of dystrophies of the hand in women. All these conditions were found to be associated with gross disorders of the endocrine system, autonomic dysfunction and changes in the system of blood supply. The results were used to develop a policy for the selection of the therapeutic method and its timing with a favourable effect.

[The factors promoting dystrophic pathology of the hand and duodenal peptic ulcer in women]. / O faktorakh, sposobstvuiushchikh distroficheskoi patologii kisti i iazvennoi bolezni dvenadtsatiperstnoi kishki u zhenshchin.

The authors have made an attempt to make exact the reasons of the frequent association of hand dystrophic pathology and duodenal ulceration disease in women. It is revealed that pointed diseases are to be the late symptoms of equally directed alterations in the organism, including neuro-humoral and immune mechanisms of adaptation, occurring in women even in sexual maturing period and being the favourable background for occurrence of various diseases including hand dystrophic pathology and duodenal ulcerative disease.

First identification of resident and circulating fibrocytes in Dupuytren's disease shown to be inhibited by serum amyloid P and Xiapex.

Dupuytren's disease (DD) is a common progressive fibroproliferative disorder causing permanent digital contracture. Proliferative myofibroblasts are thought to be the cells responsible for DD initiation and recurrence, although their source remains unknown. DD tissue has also been shown to harbor mesenchymal and hematopoietic stem cells. Fibrocytes are circulating cells that show characteristics of fibroblasts and they express surface markers for both hematopoietic and mesenchymal stromal cells. Fibrocytes differentiate from peripheral CD14+ mononuclear cells, which can be inhibited by serum amyloid P (SAP). In this study we have demonstrated the presence of fibrocytes in DD blood and tissue, moreover we have evaluated the effects of SAP and Xiapex (Collagenase Clostridium histolyticum) on fibrocytes derived from DD. H&E staining showed typical Spindle shaped morphology of fibrocytes. FACS analysis based on a unique combination of 3 markers, revealed the increased presence of fibrocytes in blood and tissue of DD patients. Additionally, immunohistology of DD nodule and cord tissue showed the presence of collagen 1+/CD34+ cells. No difference in plasma SAP levels was observed between DD and control. Higher concentrations of SAP significantly inhibited fibrocytes differentiated from DD derived monocytes compared to control. DD fascia derived fibrocytes showed resistance to growth inhibition by SAP, particularly nodule derived fibrocytes showed robust growth even at higher SAP concentrations compared to control. DD derived fibrocytes were positive for typical fibrocyte dual markers, i.e. Collagen 1/LSP-1 and collagen 1/CD34. Xiapex was more effective in inhibiting the growth of nodule derived cells compared to commercially available collagenase A. Our results show for the first time the increased presence of fibrocytes in DD patient's blood and disease tissue compared to control tissue. Additionally, we evaluate the response of these fibrocytes to SAP and Xiapex therapy.

[Collagenase Clostridum histolyticum in the management of Dupuytren's contracture]. / Kollagenase Clostridium histolyticum im Management der Dupuytrenschen Kontraktur.

Dupuytren's contracture is a fibroproliferate disease of the palmar aponeurosis with a formation of nodules and cords. Surgical treatment is the gold standard for Dupuytren's contracture at the moment. A short while ago Collagenase clostridium histolyticum was licensed as a non-surgical method to treat Dupuytren's contracture. Collagenase clostridium histolyticum is injected directly into the Dupuytren's cord and after 24 h the contracture is distended by manual rupturing. Collagenase clostridium histolyticum causes a depletion of collagen, however neurovascular structures are spared. 2 clinical phase III studies showed that contractures could be effectively reduced when using Collagenase clostridium histolyticum. However, there are no long-term results regarding effectiveness and side effects, or comparative studies using surgical methods. This paper presents a review of Collagenase clostridium histolyticum and its role in the management of Dupuytren's contracture. Indication, technical procedure, treatment results and complications are described.

Blood group mythology: present status.

There are still many myths, incorrect beliefs, in medicine; some pertaining to the field of blood grouping are discussed. Certain fallacious statements are dealt with in detail such as the dependence on the A-B-O blood group of the shape of the retracted clot; the patients with Dupuytren contracture all being type Rh1Rh2; the assumption of an association with the blood groups of a number of diseases and even of temperament; the belief in the existence of ant-M-lectin and of little d and thus of anti-d sera; and also of the alleged LW (Landsteiner--Wiener) factor. Finally, Race and Sanger's system of symbols is condemned and the advantages of the author's own nomenclature are pointed out.

Dupuytren's contracture and alcohol.

Reported alcohol consumption was quantified and scored by a validated questionnaire administered by an interviewer to 64 patients (10 female) with Dupuytren's contracture (DC) before hand surgery and to 89 controls (44 female) admitted for other hand or foot surgery. Serum urate (SUA), gamma-glutamyl transferase (GGT), and mean red cell volume (MCV) were measured on admission. Thirteen of 54 men with DC reported current daily alcohol intake of 40 g or more compared with one of 45 male controls (p = 0.0001). Two of 10 women with DC (but none of 44 controls) admitted consuming at least 40 g alcohol daily (p = 0.03). MCV was higher in men (but not women) with DC than in controls (p less than 0.0005). Current alcohol consumption score of patients with DC correlated with SUA (r = 0.308, p less than 0.05), MCV (r = 0.44, p less than 0.01), and GGT (r = 0.54, p much less than 0.001) on admission. DC among men is strongly associated with heavy drinking, reflected both in self reporting and haematological data.