Vitamin E gel reduces time of healing of digital ulcers in systemic sclerosis.

BACKGROUND: In systemic sclerosis (SSc), digital ulcers (DU) are painful, difficult to heal and frequently infected, thus greatly affecting quality of life and increasing SSc-related disability. Vitamin E has been previously used in cutaneous lesions for its antioxidant and anti-inflammatory effects. OBJECTIVES: To study the healing effect of D-alpha-tocopheryl acetate (acetic ester of alpha-tocopherol) (VE) gel on DU of SSc patients. METHODS: 27 SSc patients with a total of 86 DU were enrolled in an open pilot study. The patients were randomly assigned to two groups: 15 patients were treated until DU healing with the local standard ulcer care protocol with the application of vitamin E gel (experimental group), while 12 patients were treated with standard ulcer care protocol only (control group). In both groups, DU were treated twice a week and pain was scored by a NRS (numeric rating scale). In both groups the cost of medications was analysed. RESULTS: VE induced a faster healing of DU in respect to controls (13.22+/-2.72 weeks, versus 20.94+/-3.65; p<0.0001) with a lower number of medications (26.18+/-5.63 vs. 41.88+/-7.31; p<0.0001). Resolution of pain was faster in experimental (17.82+/-4,59 medications) than in controls (26.26+/-19.16 medications) (p=0.0022). In the experimental group, the cost of medications was significantly lower (6,919.15 euros/patient) than in the control group (11,056.32 euros/patient). CONCLUSION: The application of VE reduces time of healing and has a faster resolution of pain, with a significant reduction of costs. Topical VE may improve the management of DU in SSc.

Angiotensin-converting enzyme I/D polymorphism and macrovascular disease in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by microvascular and macrovascular alterations. The D allele of the ACE I/D polymorphism is known to be associated with an increased incidence of atherosclerosis and has been recently proposed as associated with increased risk of SSc. This study evaluates the relationship between intima-media thickness (IMT), ankle-brachial pressure measurements (ABPI) and ACE I/D polymorphism in SSc patients. METHODS: According to the presence of ACE D allele (analysed by PCR), 53 SSc patients (47 females and 6 males; median age was 60.4 +/- 10.68 yrs; range 40-75 yrs) were divided in carriers of the D allele (DD + ID) (n = 46) and carriers of the I allele (II) (n = 7). In these patients, IMT and ABPI [calculated as the posterior tibial artery pressure (mmHg) divided by the brachial pressure] were obtained. Forty-three healthy controls (40 women and 13 men; median age 56.3 +/- 10.23; range 40-70 yrs) of the same ethnicity were recruited. RESULTS: SSc patients had IMT significantly higher than controls (0.85 +/- 0.03 vs 0. 68 +/- 0.01; P < 0.03). No significant differences (P > 0.3) in ABPI values between patients (1.018 +/- 0.10) and controls (1.091 +/- 0.11) were found. SSc patients with ACE DD and ID genotype showed an IMT significantly greater (0.89 +/- 0.03) than those carrying the II genotype (0.61 +/- 0.01) (P < 0.04). ABPI was not different among ACE gene genotypes. CONCLUSION: Our findings confirm an increased prevalence of macrovascular disease in SSc patients and show that IMT is greater in patients carrying the ACE DD and ID genotype in comparison with II homozygotes. This suggests that, in SSc, the presence of ACE D allele may predispose to an involvement of the macrovascular system.

Circulating levels of Nepsilon-(carboxymethyl)lysine are increased in systemic sclerosis.

OBJECTIVE: Advanced glycation endproducts (AGEs), including Nepsilon-(carboxymethyl)lysine-protein adducts (CML) are involved in micro/macrovascular changes and are co-localized with adhesion molecules in inflamed tissues. Serum levels of CML were investigated in systemic sclerosis (SSc) characterized by microvascular modifications and correlated with indices of micro/macrovascular damage. METHODS: In 66 SSc patients (limited SSc, n = 55; diffuse SSc, n = 11) and 20 controls, CML serum levels were measured by enzyme-linked immunosorbent assay. Nailfold capillaroscopy, intima-media thickness (IMT) and the ankle-brachial index (ABI) were also recorded, to characterize micro/macrovascular involvement. RESULTS: CML levels were significantly higher in SSc (79.2 +/- 39 mg/ml vs 49.6 +/- 26.1 mg/ml, mean +/- s.d.; P<0.01), without significant differences between SSc subsets. CML levels were significantly higher in all capillaroscopic patterns: the 'early' pattern showed higher levels than 'active' and 'late' patterns. IMT was significantly higher in SSc (P<0.01) than in controls, whilst ABI was no different from controls. CONCLUSIONS: These data indicate that although both CML formation and macrovascular involvement are increased in SSc, there is no correlation between these two parameters. However, the characteristic early nailfold capillaroscopy changes of SSc are associated with proportionally greater CML formation, suggesting that AGEs are involved in SSc microangiopathy.

The fibrinolytic system components are increased in systemic sclerosis and modulated by Alprostadil (alpha1 ciclodestryn).

OBJECTIVES: To evaluate urokinase plasminogen activator (u-PA), urokinase plasminogen activator soluble receptor (su-PAR), plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA) plasma levels in SSc patients (pts) versus healthy controls and their modulation by intravenous alphacyclodestrine (Alprostadil). METHODS: Plasma levels of u-PA, su-PAR, PAI-1 and t-PA were measured in 40 SSc (34 lSSc and 6 dSSc) pts and in 30 healthy controls. In SSc, blood was drawn before and after 3 consecutive daily of Alprostadil infusion (60 mg in 250 cc NaCl 0.9%). RESULTS: In SSc su-PAR basal levels were higher than controls (7.48 +/- 2.5 vs 4.69 +/- 0.4 ng/ml; p = 0.001) and were significantly reduced by Alprostadil (5.93 +/- 1.7; p = 0.002), but remain higher than controls (p = 0.03). u-PA basal levels were higher than controls (3.78 +/- 1.5 vs 1.29 +/- 0.3 ng/ml; p < 0.001) and were reduced by Alprostadil (2.39 +/- 1.7; p < 0.001) to control levels. SSc PAI-1 basal levels were lower than controls (31.60 +/- 7.7 vs 48.30 +/- 6.8 ng/ml; p < 0.001) and increased by Alprostadil (34.66 +/- 5.4; p = 0.04), but lower than controls (p < 0.001). SSc t-PA basal levels were higher in respect to controls (1645.81 +/- 792.7 vs 571.95 +/- 75.5 pg/ml; p < 0.0001) and reduced by Alprostadil (1318.06 +/- 603.5; p = 0.04), but still higher than controls (p = 0.001). CONCLUSION: Fibrinolysis were increased in SSc. Infusions of Alprostadil modulate u-PA, su-PAR, PAI-1 and t-PA, restoring near normal levels. In SSc, fibrinolysis system may become a potential target for new therapies.

Increased circulating levels of tissue kallikrein in systemic sclerosis correlate with microvascular involvement.

BACKGROUND: In systemic sclerosis (SSc) the lack of an angiogenic response to hypoxia may be due to inappropriate synthesis of angiogenic and angiostatic factors. Tissue kallikrein (t-kallikrein), regulating the kallikrein-kinin system and acting on the microcirculation, is a potent angiogenic agent, and kallistatin is its natural inhibitor. OBJECTIVE: To evaluate, in patients with SSc, t-kallikrein and kallistatin levels and their correlation with clinical features and measures of microvascular involvement. PATIENTS AND METHODS: Serum levels of t-kallikrein and kallistatin (ELISA) and t-kallikrein skin expression (immunohistochemistry) were studied in patients with SSc, and evaluated for subset (dSSc or lSSc), clinical and immunological features, and microvascular involvement (ulcers, telangiectasias, nailfold videocapillaroscopy). RESULTS: Circulating levels of t-kallikrein were higher in SSc than in controls (p<0.001). T-kallikrein did not differ between lSSc and dSSc, although it was higher in lSSc than in controls (p<0.001).T-kallikrein levels were higher in patients with early and active capillaroscopic pattern than in those with late pattern (p = 0.019 and 0.023). Patients with giant capillaries and capillary microhaemorrhages had higher t-kallikrein concentrations than patients with architectural derangement (p = 0.04). No differences in kallistatin levels were detected between patients with SSc and controls, or between lSSc and dSSc. In early SSc skin, the presence of t-kallikrein was found in endothelial and in perivascular inflammatory cells, while no staining in skin of advanced SSc was detected. CONCLUSION: T-kallikrein levels are increased in patients with SSc, particularly in lSSc, and are associated with early and active capillaroscopic patterns. T-kallikrein may play a part in SSc microvascular changes.

Damage of cutaneous peripheral nervous system evolves differently according to the disease phase and subset of systemic sclerosis.

OBJECTIVE: Evidence shows that peripheral nervous system (PNS) is involved in systemic sclerosis (SSc), but few morphological studies have assessed the ultrastructural pathological modifications. The aim was to study ultrastructural modifications of skin PNS fibres in SSc according to subsets [limited SSc (lSSc) and diffuse SSc (dSSc)] and phases (early and advanced) of the disease. METHODS: Skin biopsies were taken from the forearms of 23 SSc patients (11 lSSc and 12 dSSc) and 10 controls. Each biopsy was processed for transmission electron microscopy (TEM). RESULTS: At TEM, observation in skin from early lSSc, signs of inflammation were evident, while PNS fibres were not damaged. The microvascular wall showed hypertrophic endothelial cells bulging into the lumen. In advanced lSSc, fibrosis prevailed on inflammation and slight ultrastructural alterations of PNS fibres were evident in the papillary derma. In early dSSc, ultrastructural alterations of PNS fibres, similar to those observed in the advanced phase of lSSc, were found together with signs of inflammation and fibrosis. In advanced dSSc, in the papillary and reticular dermis PNS fibres were reduced and showed relevant ultrastructural alterations. CONCLUSIONS: In SSc, PNS ultrastructure damage is linked to the progression and severity of skin involvement. The alterations evolve from the early to the advanced phase mainly in the diffuse subset. In particular, the severe PNS lesions found in advanced lSSc are already present and widely diffuse in early dSSc and the microvascular involvement in early lSSc seems to precede the modification of the PNS in the skin. Thus, an early therapeutic approach can be useful to reduce the progression of PNS and skin damage in SSc patients.

Topical application of nerve growth factor in human diabetic foot ulcers. A study of three cases.

Three diabetic patients with leg or foot ulcers unresponsive to conventional therapies were treated with topical application of Nerve Growth Factor (NGF). The results showed that NGF promotes healing after 5-14 weeks of treatment. This study suggests that the use of topical application of NGF may represent a new useful tool for the management of difficult diabetic ulcers.

Infliximab in spondyloarthropathy associated with Crohn's disease: an open study on the efficacy of inducing and maintaining remission of musculoskeletal and gut manifestations.

OBJECTIVE: To evaluate the efficacy and tolerability of anti-tumour necrosis factor alpha (TNFalpha) monoclonal antibody (infliximab) in the treatment of spondyloarthropathy (SpA) associated with active and inactive Crohn's disease (CD). METHODS: Twenty four patients with SpA associated with active or inactive CD (16 active, 8 quiescent) were treated with anti-TNFalpha monoclonal antibody (infliximab) with repeated infusions for a period of 12-18 months. The treatment aimed at ameliorating the general musculoskeletal and spinal pain, controlling peripheral arthritis and enthesitis, decreasing the BASDAI score, modifying acute phase reactants, and reducing CD activity. RESULTS: Infliximab improved both gastrointestinal (p<0.01) and overall articular symptoms (BASDAI, p<0.01; general musculoskeletal and spinal pain, p<0.01; peripheral arthritis, p<0.01) in patients with active CD. Additionally, infliximab effectively controlled not only axial involvement and peripheral arthritis but also enthesitis (p<0.01) and prevented inflammatory bowel disease reactivation in patients with inactive CD and low inflammatory markers. Amelioration of gut and musculoskeletal involvement persisted for up to 12 months. CONCLUSION: Infliximab may act on the inflammation of entheses and of periarticular structures, which usually does not cause a change in the haematological markers that are the main indicators of pain and joint ankylosis in SpA. Infliximab induces and maintains remission of CD while at the same time treating active and severe SpA, suggesting that it should be the preferred drug for the treatment of active and severe SpA associated with active or quiescent CD.

[Peripheral nervous system in limited systemic sclerosis]. / Il sistema nervoso periferico nella sclerosi sistemica limitata.

OBJECTIVES: PNS is involved in Systemic Sclerosis (SSc) since the earliest phases. Our aim is to perform an ultrastructural study on skin PNS fibers in SSc. METHODS: Skin biopsies were taken from forearms of 8 patients affected by limited SSc (lSSc) and 3 controls and processed for transmission electron microscopy (TEM). The semithin sections (2 mm) were observed at light microscope and optical fields were chosen for ultrathin sections (1 mm) preparation and TEM examination. RESULTS: In lSSc skin, in the semithin sections, damaged areas are close to apparently spared areas. At TEM, in early lSSc patients, signs of inflammation and damaged microvessels are visible in derma. PNS fibers are no damaged. In advanced lSSc, fibrosis prevails on inflammation, and slight ultrastructural alterations of PNS fibers are evident in papillar derma. CONCLUSIONS: PNS lesions are different in severity in lSSc according to the disease duration, resulting more severe in advanced than in early phase.

Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis.

OBJECTIVE: To evaluate the coagulative/fibrinolytic cascade and the circulating markers of the endothelial injury in systemic sclerosis (SSc). METHOD: Plasma was obtained from 29 patients with SSc and tested for thrombin-antithrombin (TAT), fragments 1+2 (F1+2), dermatansulphate (DS), thrombomodulin (TM), lipoprotein (a) [Lp(a)], von Willebrand factor (vWF), tissue type plasminogen activator (tPA), plasminogen activator inhibitor (PAI), D-dimers, intercellular adhesion molecole-1 (ICAM-1), vascular cell adhesion molecule (VCAM), and E-selectin. The data were correlated with lung (forced vital capacity, diffusing lung capacity for carbon monoxide, vital capacity) and skin (skin score) involvement. RESULTS: Coagulation was significantly activated (increase in F1+2, P <.001; TAT, P <.01; and Lp(a), P <.05). TM was not significantly different from controls. vWF was significantly increased (P <.01), and its supranormal multimers increased in more than 50% of patients. DS was significantly increased in diffuse cutaneous SSc (P <.01). Fibrinolysis was impaired as shown by reduced D-dimers (P <.01) and decreased levels of PAI (P < 0.01). The markers of endothelial injury were also significantly elevated. DS correlated significantly with forced vital capacity (P <.01) and forced vital capacity ratio (P <.01). CONCLUSION: Injury to the endothelium reduces endothelial function, as suggested by impairment of fibrinolysis and activation of the coagulative pathway. The loss of the balance between fibrinolysis and coagulation contributes to vessel engulfment with fibrin and breakdown of vessel patency. The increase of circulating DS suggests that this factor may be a new marker of endothelial injury.

Therapy of spondylarthropathy in inflammatory bowel disease.

Musculoskeletal manifestations represent the most common extra-intestinal complication of inflammatory bowel diseases (IBD) and are usually included in the clinical spectrum of the spondyloarthropathies (SpA). Although control of intestinal inflammation often ameliorates articular symptoms, sometimes arthropathy is independent of the gut disease course and may require the same therapeutic options which apply to primary SpA diseases, but with caution so as not aggravate the IBD. At the moment, salicylates (sulphasalazine and mesalazine) and selective COX-2 inhibitors (which are preferable to traditional NSAIDs although they cannot be assumed to be safe for the gastrointestinal tract) are the first choice treatment. Several immunosuppressive and biological agents including methotrexate, thalidomide and TNFalpha antagonists have efficacy for both articular and intestinal inflammation and are currently in use for the induction of remission and for maintenance in more severe cases. New combination therapies and novel biologically-driven treatments, targeted to specific pathophysiological processes, might offer less toxicity and the potential for better treatment outcomes.

Renal functional reserve is impaired in patients with systemic sclerosis without clinical signs of kidney involvement.

OBJECTIVE: To evaluate the functional response of the kidney to an amino acid challenge (the so called renal functional reserve (RFR)) in patients with systemic sclerosis (SSc) with no clinical sign of renal involvement. METHODS: Before and after an intravenous amino acid load (Freamine III Baxter, 8.5% solution, 4.16 ml/min for two hours), glomerular filtration rate (GFR, as creatinine clearance), effective renal plasma flow (ERPF, as para-aminohyppurate clearance), and calculated total renal vascular resistance (TRVR) were measured in 21 patients with SSc with apparently normal renal function and 10 normal controls. RESULTS: In basal conditions, patients had lower ERPF (403.5 (SD 43.8) v 496.4 (SD 71.3) ml/min, p<0.0002) and higher TRVR (10 822 (SD 2044) v 8874 (SD 1639) dyne/sxcm(-5), p<0.014) than controls. The RFR, evaluated as the percentage increase of GFR after the amino acid load, was significantly reduced in patients with SSc (SSc +1.9 (SD18.6)%, controls +34.8 (SD 13.9)%; p<0.0002). However, the response of patients was not uniform. Multiple regression analysis showed that the RFR was inversely dependent on the patients' mean arterial pressure at admission and basal GFR (R(2)=65%, p<0.0001). CONCLUSIONS: Most patients with SSc cannot increase renal filtration under the challenge of a protein overload. This defective renal response to the amino acid load test sustains the concept of the prevalence of vasoconstrictor over vasodilating factors in the kidney of these patients.

Evidence for hyaluronan production in the air pouch model in rats.

OBJECTIVE: The aim of our work was to investigate the presence of hyaluronan (HA) in the rat air pouch and its behaviour in response to inflammatory stimuli. METHODS: HA levels (by a microplate assay) and the leucocyte count were determined in the fluid obtained from air pouches in which acute or subacute inflammation had been induced by the injection of monosodium urate crystals (MSU) or high density polyethylene (HDPE) debris respectively and in relative controls. RESULTS: In control pouches of both groups, remarkable levels of HA were found; these levels were higher in the very first hours (2475 and 1850 micrograms/l at 6 hrs) and then gradually decreased. In pouches injected with MSU, HA moderately increased (p < 0.001) after 6 hrs, reached a peak after 12 hrs (p < 0.001) and began to taper at 24 hrs (p < 0.001). The leucocyte count was also increased at 6 hrs (p < 0.001), became higher at 12 hrs (p < 0.001) and tapered at 24 hrs (p < 0.001). In the HDPE pouches, HA levels were significantly reduced with respect to controls after 6 hours (p < 0.001), increasing later (p < 0.001) to reach a peak at 24 hrs (p < 0.001), and returning to the original levels, or even below, in the following 72 hours. CONCLUSIONS: These data confirm that the pouch lining produces fair amounts of HA and provide evidence that, in this system, HA levels seem to be influenced by the degree of inflammation even if with variable behaviour in relation to the different characteristics and phases of phlogosis. The present data suggest that the air pouch is a useful experimental model for studies on HA metabolism in either acute or chronic inflammation.

Nerve growth factor and neuropeptides circulating levels in systemic sclerosis (scleroderma).

OBJECTIVE: To determine the circulating levels of nerve growth factor (NGF), neuropeptide Y (NPY), and vasoactive intestinal peptide (VIP) in systemic sclerosis (SSc), and to correlate these levels with clinical and laboratory features. METHODS: Forty four patients with SSc were evaluated for circulating NGF (immunoenzymatic assay), NPY and VIP (radioimmunoassay), anticentromere and antitopoisomerase I autoantibodies, lung disease (pulmonary function tests with carbon monoxide transfer factor (TLCO), ventilation scintiscan with 99mTc DTPA radioaerosol, high resolution computed tomography (HRCT), pulmonary pressure (echo colour Doppler)), heart disease (standard and 24 ECG, echocardiography), cutaneous involvement (skin score), joint involvement (evidence of tender or swollen joints, or both), peripheral nervous system (PNS) involvement (electromyography), rheumatoid factor, angiotensin converting enzyme (fluorimetric method), von Willebrand factor (ELISA), and erythrocyte sedimentation rate (ESR) (Westergren). RESULTS: Circulating NGF levels in SSc were significantly increased compared with controls (p<0.00001) and significantly higher in the diffuse than in the limited subset of patients (p<0.01). Patients with articular disease had significantly higher levels of NGF. A significant indirect correlation between NGF levels and TLCO was detected (p<0.01), but no correlation was found between NGF and HRCT, DTPA, skin score, PNS involvement and angiotensin converting enzyme and von Willebrand factor levels, antitopoisomerase or anticentromere antibodies, and ESR. NGF levels increased progressively as the disease worsened. Similarly, VIP circulating levels were significantly increased in patients with SSc (p<0.001), whereas the increase of NPY levels did not reach statistical significance. However, both neuropeptides, following the same trend as NGF, increased as the disease worsened (skin score and lung disease). CONCLUSIONS: The increase of NGF and VIP in patients with SSc, the former in the diffuse subset of the disease, and in patients with prominent articular disease, may suggest a link between neurotransmitters and the disease pathogenesis. Neuropeptide circulating levels seem to increase only in patients with the most severe disease.

Evidence for immune activation against oxidized lipoproteins in inactive phases of juvenile chronic arthritis.

OBJECTIVE: Oxidative stress contributes to joint inflammation and damage in rheumatoid arthritis. In a mobile inflamed joint, exercise induced multiple cycles of hypoxia-reperfusion injury may lead to the creation of a redox environment in which oxido-reductase systems, by NADPH mechanisms, produce highly reactive chemical species (i.e., oxygen free radicals). We investigated 2 endproducts of lipid peroxidation, malonildialdehyde (MDA) and diene conjugates (DC), and the formation of antibodies against oxidized low density lipoproteins (Ab oxLDL) in juvenile chronic arthritis (JCA), and assessed the role of oxidative phenomena in different phases and subsets of this disease. METHODS: To assess the role of oxidative stress in JCA, we measured the endproducts of lipid peroxidation, MDA and DC, by the increase of absorbance at 586 nm and 234 nm, respectively, and the levels of Ab oxLDL by ELISA in the sera of 58 patients with JCA and 21 healthy controls. Due to crossreactivity between Ab oxLDL and anticardiolipin antibodies (aCL), the sera were also tested by a standard ELISA for IgG-aCL. The patients were divided into 3 subsets: 29 with pauciarticular (pauci), 15 with polyarticular (poly), and 14 with systemic (sys) onset disease, and then were subdivided, according to different variables appropriate to each subset, reflecting active and inactive disease, into 30 active (14 pauci, 8 poly, 8 sys) and 28 inactive (15 pauci, 7 poly, 6 sys). RESULTS: Levels of Ab oxLDL were significantly increased in the whole group of patients (566.6 +/- 263.0 vs 206.6 +/- 136.3 mU/ml; p < 0.001) and in each of the type of onset (pauci 660.8 +/- 272.1, p < 0.001; poly 341.3 +/- 134.7, p < 0.01; sys 497.8 +/- 114.8, p < 0.001) compared to controls. Ab oxLDL were higher in the inactive than in the active group (743.5 +/- 231.9 and 404.4 +/- 169.9; p < 0.001). MDA and DC levels were not increased significantly in patients' sera. No patient was positive for IgG-aCL. CONCLUSION: These findings suggest that MDA and DC cannot be considered major markers of oxidative stress in JCA and that the Ab oxLDL may represent a delayed sign of oxidative stress previously induced by the inflammatory process in patients with JCA.

Bcl-2, p53 and c-myc expression in juvenile dermatomyositis.

OBJECTIVE: To investigate p53, bcl-2 and c-myc expression in muscle biopsies from children affected with juvenile dermatomyositis (JDM) and to verify a possible dysregulation of programmed cell death in this autoimmune disease. METHODS: Ten muscle biopsies of children affected with JDM were formalin fixed and paraffin embedded. After haematoxylin and eosin staining, immunohistochemistry was performed employing monoclonal antibodies, anti-p53, anti-bcl-2 and anti-myc. Two normal muscle biopsies were studied as controls. RESULTS: In the biopsies of JDM, two different patterns of myofibers damage were observed: the first, with zones characterised by necrosis; and the second, with zones where an apoptotic process was dominant. Immunoreactivity for bcl-2 was positive in 8 out of 10 biopsies. P53 and c-myc expression were not present in any case. No relationship between the degree of bcl-2 immunostaining and the disease course or outcome was observed. CONCLUSIONS: The over-expression of bcl-2 protein in JDM may suggest a dysregulation of apoptosis in myofibers. Further studies are required in order to better understand the role of our data in the pathogenetic pathways of the disease.

NGF, a useful tool in the treatment of chronic vasculitic ulcers in rheumatoid arthritis.

Vasculitic necrosis and ulceration of the skin are frequent complications of connective tissue diseases and are very difficult to heal. We treated chronic vasculitic leg ulcers in rheumatoid arthritis and systemic sclerosis by topical application of nerve growth factor (NGF). In all patients with rheumatoid arthritis, NGF led to rapid healing, whereas less striking results were obtained in patients with systemic sclerosis. The efficacy of NGF could be due to its promoting activity on keratinocytes proliferation and vascular neoangiogenesis. We suggest that topical application of NGF could represent a powerful pharmacological tool for the treatment of vasculitic ulcers.