RESUMEN

The term "rhupus" is traditionally used to describe patients with coexistence of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The aim of the present work was to investigate prevalence, clinical and radiological picture as well as the serological profile of a series of rhupus patients; SLE patients and RA patients from our Unit were used as disease control groups. A total of 103 consecutive SLE patients were screened; among the entire cohort, 10 patients (9.7%) were classified as "rhupus". In our rhupus patients SLE features preceded the onset of arthritis in 5 patients (50%) while in the remaining patients arthritis appeared before or simultaneously (3 and 2 patients respectively). As compared with SLE patients, rhupus patients have significantly less kidney involvement (p=0.01) while no differences were observed between neuropsychiatric, cutaneous, hematological involvement or serositis. At our physical examination, 9 (90%) rhupus patients were presenting active joint involvement; CRP positivity and ESR levels resulted significantly higher than in SLE (p=0.006) patients while no differences were observed with respect to RA patients. In all rhupus patients, at least one pathological finding was revealed by ultrasound (US) examination at wrist and/or hand joints; overall, rhupus patients presented higher scores in all the US parameters with respect to SLE patients, especially at hands; no statistically significant differences have been observed with respect to RA patients. Magnetic resonance (MR) revealed erosions in all rhupus patients with a concomitant bone edema in five patients. The cumulative erosive burden in rhupus patients was significantly higher than in SLE patients and similar to RA patients (SLE vs rhupus p=0.005); bone pathology distribution was also similar between rhupus patients and RA patients. These data suggest the importance of assessing joint involvement in SLE with advanced imaging techniques and of evaluating the presence of prognostic factors for joint disease severity in order to establish adequate disease monitoring and to institute early appropriate therapies to avoid late consequences of unrecognized concomitant rheumatoid arthritis (Amezcua-Guerra et al., 2006 [25]; Zhao et al., 2009 [26]).

Asunto(s)

RESUMEN

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.

Asunto(s)

RESUMEN

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.

Asunto(s)

RESUMEN

Systemic Sclerosis (SSc) is a multisystem disease that affects the skin and internal organs (i.e., gastrointestinal tract, lung, heart, kidney and peripheral nervous system). In the early phase, lung involvement is characterized by interstitial inflammatory alterations that are detected by bronchoalveolar lavage analysis and high resolution computed tomography (ground glass). As the disease progresses, fibrotic changes become evident and the diffusing capacity for carbon monoxide (DLCO) is impaired. Cardiac involvement in SSc can be manifested as myocardial disease, pericardial disease, conduction system disease, or arrhythmias. Cardiac involvement is a poor prognostic factor, but the diagnosis may be late or missing because of the frequent discrepancy between clinical manifestations and the real cardiac involvement. For this reason, resort to all the available diagnostic procedures is recommended to achieve an early diagnosis. The motility disorders are a major feature of gastrointestinal involvement in SSc, striking any part of this system (especially esophagus and anorectal region). Kidney involvement and scleroderma renal crisis are now considered rare because of the introduction of ACE inhibitors. Some patients may develop myositis or erosive arthropathy that complicate enormously the joint retraction induced by skin fibrosis. The peripheral nervous system (PNS) is also targeted by SSc: a distal mononeuropathy of the median nerve is a frequent and early feature; autonomic nerve dysfunction (parasympathetic impairment and marked sympathetic overactivity) seems to be a fundamental etiologic factor linked to the development of microvascular, cardiac and gastrointestinal alterations. The whole approach to the SSc patient is very complex and must consider, at the same time, many organs and systems. Thus, a global vision of SSc patient is needed in order to assure an early diagnosis of specific organ involvement as well as early treatment. Systemic Sclerosis (SSc) is a multisystem disease, that affects the skin, the gastrointestinal tract, the lung, the heart and the kidney. The extent and severity of internal organ involvement are the more important factors influencing the disease outcome and prognosis in SSc. In recent years, it has become evident that early diagnosis and accurate staging of visceral involvement are fundamental for appropriate management and therapeutic approach to the disease. Diagnostic procedures for specific organ and system involvement are now more sensitive because of the continuous technological improvement and, mostly, because they take advantage of the studies carried out in other diseases by other medical branches. This review will consider briefly the most frequent and important organ involvement in SSc.

Asunto(s)

RESUMEN

In 63 patients affected by Systemic Sclerosis (SSc) (limited subset: 40; diffuse subset: 23; early: 30; advanced: 33) the peroxidation product diene-conjugates (DC) and antibodies against oxidised low density lipoproteins (Ab oxLDL) were tested in serum by a spectrophotometer (absorbance 234 mn) and by a standard ELISA respectively. The data were compared with those obtained by 21 healthy subjects. DC was significantly higher in patients (73.3 +/- 37.2 microM/l; p < 0.0001) than in controls (48.4 +/- 16.7) as well as in the limited (80 +/- 48.8; p < 0.05) than in the diffuse subset (64.5 +/- 36.4); and in early (84.1 +/- 31.4; p < 0.05) than in advanced stage of the disease (67.9 +/- 42.5). The levels of Ab oxLDL were significantly higher in SSc patients (309.5 +/- 367.2 mU/ml; p < 0.0001) in all its subsets (limited: 351.9 +/- 351.1, p < 0.0001; diffuse: 207.7 +/- 316.1, p < 0.05; early: 428.9 +/- 417.1, p < 0.001; advanced: 302.7 +/- 89.9, p < 0.0001) than in controls (89.3 +/- 29.1). These antibodies levels were higher in limited subset than in diffuse (p < 0.05) and in early SSc than in advanced SSc (p < 0.05). The highest values of parameters of oxidative stress are found in the early stages, when the episodes of reperfusion after ischemic episodes (Raynaud's phenomenon) are very frequent. Moreover, the damage is higher in the early stages of SSc, with intact microvessels, than in late stages, when microvessels are very reduced in number, destroyed by the worsening of the disease. These data show that the respiratory burst deduced by the lipoperoxidation is higher in SSc than in controls, and may be an important pathogenetic factors involved in tissue changes in SSc.

Asunto(s)

RESUMEN

OBJECTIVE: Neprilysin (NEP; EC3.4.24.11) is an ectopeptidase mainly produced by fibroblasts and cleaving a large number of neuropeptides. We previously found increased plasma circulating levels of NEP in patients with systemic sclerosis (SSc), but in SSc fibroblasts derived from the diffuse subset NEP was present in lower concentration. We evaluate in vitro fibroblasts of both subsets of the disease, diffuse and limited, the intracellular levels of NEP, and its expression as CD10 on the cellular surface. METHODS: Fibroblasts, derived from biopsies taken from affected skin of 8 patients with the limited subset and 5 with the diffuse subset, were grown in vitro and intracellular levels of NEP activity were measured with a fluorometric method, while CD10 surface expression was evaluated by FACS analysis. Cell proliferation was assessed by 3HThymidine incorporation. RESULTS: Intracellular NEP activity was significantly increased in diffuse (7.02+/-4.8 pg/ml/min 10(6) cells) compared to limited SSc (1.11+/-2.0) and control fibroblasts (1.41+/-0.9). CD10 expression was significantly impaired on diffuse SSc fibroblasts (47.3+/-15%) compared to controls (74.6+/-11%) and the limited subset (82.7+/-11%). Cell proliferation of diffuse SSc fibroblasts was strikingly higher than controls and limited SSc fibroblasts. CONCLUSION: These results confirm that NEP is produced by fibroblasts and indicate that in diffuse SSc fibroblasts NEP is produced in higher quantities, while the expression of the enzyme on the cell surface is significantly reduced. This condition may affect the proliferation rate of fibroblasts as well as the metabolism of various peptides.

Asunto(s)

RESUMEN

OBJECTIVE: To assess the frequency of antiendothelial cell autoantibodies (AECAs) in a group of patients with systemic sclerosis (SSc) and possible associations with clinical and serologic features of the disease. METHODS: Sera from 50 patients with SSc (38 with the limited and 12 with the diffuse form) were screened for AECA (ELISA). The reference limits were were 56.6% for the IgM isotype and 3.3.5% for the IgG isotype. AECA results were analyzed in relation to lung involvement (chest x-ray, high resolution computed tomography (HRCT), ventilation scintiscan with radioaereosol (DTPA), pulmonary pressure (echodoppler technique): heart involvement (EKG, 24 hr ambulatory EKG, echocardiography), cutaneous involvement (skin score), capillaroscopic characteristics and digital ulcers. AECA were also correlated with the erythrocyte sedimentation rate (ESR), anticentromere (ACA) and antitopoisomerase I (ATA) autoantibodies, and angiotensin converting enzyme plasma levels (ACE). RESULTS: The AECA IgG prevalence was 40% (22/50) for the SSc group as a whole, without significant differences between subsets. A significant negative correlation was shown between the AECA and ACE plasma levels in both subsets. In the diffuse form, a significant positive correlation was found between AECA and ESR and significant associations were found between AECA and the parameters reflecting alveolo-capillary involvement (DLco, DTPA), the pulmonary artery pressures, digital ulcers and capillaroscopic abnormalities. No statistically significant correlations were found between AECA and heart involvement, the skin score or pulmonary interstitial fibrosis. CONCLUSIONS: These data suggest that in SSc the anti-endothelial cell antibodies are directly linked to vascular injury and could reflect endothelial damage. Further studies are needed to verify whether AECA might identify a subgroup of patients at higher risk for the development of vascular crises and whether they might therefore be considered a predictor of outcome in SSc patients.

Asunto(s)

RESUMEN

OBJECTIVE: An increased percentage of Vdelta1+/gamma/delta T cells has been detected both in the peripheral blood and bronchoalveolar lavage fluid of patients with systemic sclerosis (SSc). This study evaluated the subset distribution, activation status, and expression of cellular adhesion molecules, such as intercellular adhesion molecule 1 (CD54), very late activation antigen alpha4 (CD49d), and lymphocyte function-associated antigen 1alpha (CD11a), on circulating gamma/delta T cells, as well as their presence in the skin of SSc patients. METHODS: We studied 12 patients with SSc and 16 healthy volunteer donors. The distribution, activation status, and expression of cellular adhesion molecules were studied by flow cytometry; their presence in SSc patient skin was evaluated by immunohistochemistry. RESULTS: We found that the percentages and absolute numbers of peripheral blood gamma/delta T cells, CD16, CD8, CD45RO, CD25, HLA-DR, CD54, and CD11a coexpression did not differ significantly from those of the controls. CD49d gamma/delta T cells were significantly increased in SSc patients (2.3%) compared with controls (0.5%). A marked increase in the ratio of Vdelta1+ cells to gamma/delta cells was observed in the patients (72%) compared with the controls (31%). The Vdelta1+ subset showed a significant expression of both HLA-DR (83% of total Vdelta1+ cells) and CD49d (90% of total Vdelta1+ cells) compared with the controls (20.5% and 60%, respectively). In the skin, the absolute numbers of gamma/delta T cells were found in striking amounts in perivascular areas, particularly in the early edematous phase of SSc (22.58 in patients and 0 in controls); the majority of gamma/delta T cells were Vdelta1+ (19 in patients and 0 in controls). In the advanced phase of SSc, Vdelta1+ T cells were also increased compared with controls (3.5 versus 0). CONCLUSION: Our results show that Vdelta1+ T cells express both adhesion molecules and activation markers, and strongly support gamma/delta T cell homing to sites of inflammation. The increase in the Vdelta1 subset suggests a selective V gene subset expansion.

Asunto(s)

Asunto(s)

RESUMEN

OBJECTIVES: To investigate the frequency and the main electrophysiological characteristics of the canalicolar passage nerve involvement in patients with systemic sclerosis (SSc). METHODS: Thirty-two SSc patients were enrolled in the study, classified according to the type (diffuse or limited) and the duration (> / < 5 years) of the disease. Sensory-motor nerve conduction studies (NCS) of the upper and lower limbs, in particular at the critical canalicolar points, were conducted by recording the Compound Muscular Action Potential (CMAP) and the Sensory Action Potential (sNAP). The following parameters were evaluated: Motor Nerve Conduction Velocity (MNCV) and Sensory Nerve Conduction Velocity; distal and proximal latency of the CMAP and the onset and peak latency of the sNAP; peak-peak amplitude and negative-peak area of the CMAP and sNAP; and the Terminal Latency Index (TLI) (Terminal Distance/MCNV x Distal latency). RESULTS: Four (12.5%) patients had a distal neuropathy of the upper limbs (one with monolateral and two with bilateral involvement of the median nerve and one bilateral involvement of the ulnar nerve). Fourteen (43.7%) patients showed a decrement of the median nerve TLI and seven (21.8%) of either the median or the ulnar nerve (Table I). Motor and sensitive conduction velocity and latency studies did not show a statistical difference between SSc patients and controls. The amplitude and area of the CMAP (distal and proximal), sNAP and of the median nerve TLI were significantly decreased in patients with respect to controls. CONCLUSION: Distal mononeuropathy of the median nerve was the most frequent result in our patients. The involvement of the peripheral nervous system seems to be strictly topographical, following the modifications of the tissues and vascular tone (Raynaud's phenomenon) at the upper acral level. The neurophysiological alterations detected in our study at the wrist level may not be linked merely to a compressive event but also to microvascular involvement. Nerve involvement closely connected with the pathogenesis and distribution of SSc should be considered when peripheral nervous system involvement is the initial symptom of the disease.

Asunto(s)

RESUMEN

OBJECTIVE: We studied the effect of melatonin (MLT) (N-acetyl 5-methoxytryptamine) on the growth rate of normal skin fibroblasts and of fibroblasts from involved and apparently uninvolved skin of patients affected by systemic sclerosis (SSc). METHODS: The growth rate was evaluated on the basis of growth curves and a 3H-thymidine incorporation assay. RESULTS: Our results demonstrate that a dose of 200 micrograms/ml of MLT inhibits (> 80%) both control and SSc fibroblasts. Inhibition was dose-dependent and was greater than 70% for MLT concentrations of 100 micrograms/ml, 200 micrograms/ml and 400 micrograms/ml. 3H-thymidine incorporation was correlated with the effect on the growth curves (81% at 200 micrograms/ml of MLT). In contrast, at a low dosage of 6 micrograms/ml, MLT exerted a stimulatory effect on cell proliferation in all the cell lines analyzed. Cell viability was not affected by MLT at any of the concentrations tested. A recovery study indicated that replacement of MLT-containing medium with MLT-free medium resulted in a re-establishment of cell growth. CONCLUSIONS: These results suggest that MLT, at higher dosages, is a potent inhibitor of the proliferation of fibroblasts derived from the skin of healthy and SSc patients.

Asunto(s)

Asunto(s)

RESUMEN

There is growing evidence that the pineal gland has antineoplastic properties, which include the action of melatonin (MLT) on the immune system through the release of cytokines by activated T-cells and monocytes. Despite these intriguing preliminary findings, only few studies have been undertaken to date on MLT's action in cancer patients. The present study was carried out on 23 patients (15 males and 8 females, range 48-71 years), with advanced solid tumors, who received MLT (10 mg/day orally for a month) after conventional therapy. Blood was assayed for tumor necrosis factor alpha (TNF-alpha), Interleukin-2 (IL-2) and human interferon gamma (IFN-gamma). Blood samples were taken immediately before the start of MLT administration and 30 days after therapy. Plasma was collected in EDTA tubes on ice, centrifuged immediately at 4-degrees-C and stored frozen at -80-degrees-C until assayed. Cytokines were quantified by immunoradiometric assays. Circulating levels of TNF-alpha, IL-2 and IFN-gamma increased by 28%, 51% and 41% respectively after MLT administration. These increments were statistically significant (paired Student's t-test, p<0.01). These findings are consistent with the hypothesis that MLT modulates immune functions in cancer patients by activating the cytokine system.

Asunto(s)

RESUMEN

The aim of our study was to ascertain the prevalence of ventricular late potentials (VLP) in systemic sclerosis (SSc) and their correlation with the immunologic patterns and cutaneous and pulmonary involvement of the disease. Ventricular late potentials, which are low-amplitude high-frequency signals present in the terminal portion of the QRS complex, express the delayed and fragmented depolarization of ventricular myocardial fibers. Observed in myocardial interstitial fibrosis, they are characteristic of the myocardial alterations occurring in SSc. Twenty-six patients with SSc (1 man, 25 women) with a confirmed lack of cardiac involvement (negative history and normal clinical, electrocardiographic, and echocardiographic findings) underwent signal averaged high resolution electrocardiography. Pulmonary involvement was evaluated by pulmonary function tests and high resolution computed tomography. The degree of cutaneous involvement was assessed by skin score. In the patients with SSc, VLP presence with time-domain analysis was 30.8% when a 25-250 Hz pass-band filter was used and 26.9% when a 40-250 Hz pass-band filter was used whereas with frequency domain analysis it was 23.1%. Ventricular late potentials were confirmed in 7.7% of the control subjects, no matter what filter or technique was used. No significant correlations among VLP, pulmonary involvement, skin score and specific antibody patterns were found. Although this technique requires further consolidation, it seems to have the potential for use as an early index of myocardial fibrosis.

Asunto(s)

RESUMEN

Calcipotriol is demonstrably efficacious for the treatment of psoriasis by virtue of its effects on the skin's immune system and on epidermal growth. We performed this study to emphasize the difference in the expression of certain cell adhesion molecules (CAMs) (ICAM-1, ELAM-1, LFA-1, VLA-3, VLA-6) in lesional and perilesional skin of 10 patients with psoriasis, before and after treatment with topical Calcipotriol. We took two biopsies of lesional and perilesional skin from each patient before and after treatment and then performed an immunohistochemical study to observe the expression of these CAMs, utilizing monoclonal antibodies against these adhesion molecules. We noticed reduced levels of infiltrating cells along with the expression of ICAM-1, LFA-1, ELAM-1 and of CAMs VLA-3, VLA-6 in basal and suprabasal keratinocytes. On the basis of these data we hypothesize that, besides epidermal keratinocytes, another target for Calcipotriol may be the skin's own immune system, suggesting that Calcipotriol can modify T lymphocyte activity (IL-1 dependent) through a down-regulation of CAMs.

Asunto(s)

Asunto(s)

RESUMEN

The real utility of high resolution computed tomography (HRCT) for early detection of lung involvement was investigated in eighteen patients affected with systemic sclerosis (SSc). The results obtained from HRCT have been compared with traditional (chest radiographs, pulmonary function tests (PFT)) and nontraditional (ventilation and perfusion scintiscan) modalities of lung investigation. A significant statistical correlation (p < 0.001) between HRCT scans and chest radiographs was observed. Moreover, HRCT was more sensitive in the detection of early pulmonary interstitial involvement and more accurate in the assessment of interstitial fibrosis in cases with severe lung involvement. A statistical correlation (P < 0.001) between HRCT and the modalities of investigation of alveolo-capillary membrane--as PFT and ventilation scintiscan--was also observed. These results indicate that in SSc HRCT may be a useful technique for assessing early pulmonary involvement and for complementing other methodologies of investigation of lung function.

Asunto(s)

RESUMEN

The presence of autoantibodies against factor VIII is an unusual but serious complication in rheumatoid arthritis. We describe the case of a patient who developed this kind of complication, with spontaneous bleeding and marked changes in the haematological parameters, that was unsuccessfully treated with a high dose of intravenous gammaglobulin. Subsequently, combined therapy with porcine factor VIII concentrate, cyclophosphamide and steroids led to the disappearance of the anti-factor VIII autoantibodies.

Asunto(s)

RESUMEN

Pachydermoperiostosis (PDP) is characterized by finger clubbing, periostosis and peculiar skin involvement (pachydermia, seborrhea and folliculitis). The aim of our work was to determine the occurrence of dermatological symptoms in patients with PDP and their relatives, and to study ultrastructural skin changes in the complete and incomplete forms of the disease. A genetic and cytogenetic study was performed in order to identify the mechanism of transmission, to discover possible links to other genetic and non-genetic diseases and to determine the chromosomal complement and eventual chromosomal anomalies. Pachydermia was the most frequent skin alteration together with seborrhea; folliculitis was present in five patients. In the relatives mild pachydermia was detected in 2 out of 26, while seborrhea was present in 6 subjects. Light microscopic observation showed acanthotic epidermis and endothelial hyperplasia in the dermis with partial occlusion of the lumen, lymphohistiocytic infiltrate, and thickening and packing of collagen fibers. Electron microscopy showed fibroblast activation with increased fibrillogenic activity as shown by hypertrophic Golgi complexes and rough endoplasmatic reticulum with cisternae filled with microfibrils. Endothelial cells partially or completely occluded the capillary lumen and presented an increased amount of Weibel Palade bodies. These data show that skin involvement in PDP is a prominent feature, that sometimes these symptoms may also be present in their relatives, and that endothelial and fibroblast activation is present in the skin. Unfortunately the cytogenetic study did not provide any information about possible karyotype abnormalities.

Asunto(s)