Massimo Vanoli

Post-Menopause is the Main Risk Factor for Developing Isolated Pulmonary Hypertension in Systemic Sclerosis

Abstract: In scleroderma patients, isolated pulmonary hypertension (PHT) has been associated with selected HLA haplotypes, severe impairment of the diffusing capacity for carbon monoxide and the diagnosis of CREST. Most patients with CREST have a late‐age onset of the disease, corresponding to the perimenopausal or postmenopausal period. We conducted a retrospective cohort study to determine the role of post‐menopause and of the other known clinical and biological markers in the development of isolated pulmonary hypertension in Italian patients with systemic sclerosis. 189 female patients with scleroderma who had no ecographic signs of pulmonary hypertension (PHT) and radiographic signs of lung fibrosis at the first visit and did not develop significant pulmonary fibrosis during the observation time were included. Sixty‐three out of 189 patients (33.3%) presented isolated pulmonary hypertension. A severe impairment of diffusing capacity for carbon monoxide at admission was found to be an early predictive element for its development. An increased risk was associated with postmenopausal condition (RR= 5.2, p= 0.000), CREST syndrome (RR= 2.8, p= 0.001) and haplotype HLA‐B35 (RR= 2.8; p= 0.002). A significant positive interaction between postmenopausal condition and either HLA‐B35 (RR= 15.2; p= 0.000) or the diagnosis of CREST (RR= 14.1; p= 0.000) was found. Postmenopausal condition alone or in combination with HLA‐B35 and CREST syndrome is the main risk‐factor for developing primary pulmonary hypertension in scleroderma patients. This suggests that hormonal replacement therapy could play a role in preventing isolated PHT in patients with systemic sclerosis.

HLA class II antigens associated with lupus nephritis in Italian SLE patients

Human leukocyte antigen DR2 (HLA-DR2), namely the allelic variant HLA-DR15, have been associated with lupus nephritis (LN) in Caucasians. The study investigated the relationships between HLA class II alleles and lupus nephritis in Italian patients. Two hundred forty-four patients fulfilling the American Rheumatism Association criteria for systemic lupus erythematosus (SLE) were typed for HLA-DRB1*, -DQA1*, -DQB1*, and -DPB1* alleles by polymerase chain reaction-sequence-specific oligonucleotide and polymears chain reaction-single-strand polymorphism; 71 patients had renal damage assessed by renal biopsy. Glomerulonephritis was classified using WHO criteria. Significance was tested by X(2) on 2x2 tables. HLA-DQA1*0101 was strongly associated with LN (OR = 2.72 [1.43-5.19]; p = 0.002), whereas HLA-DRB1*1501 was only marginally associated (OR = 1.94 [0.88-4.26]; p = not significant). HLA-DQA1*0102 demonstrated a significant protective effect (OR = 0.31 [0.14-0.86]; p = 0.002). On analyzing the distribution of HLA-DRB1*1501 bearing haplotypes in our SLE patients we found that the HLA-DRB1*1501 greatly enhanced the risk of developing LN conferred by the DQA1*0101 allele (OR = 65.96 [9.35-1326.25]), whereas DQA1*0102 suppressed the nephritogenic effect of DRB1*1501. At renal biopsy, 80% of DRB1*15 positive patients were classified as having class IV LN with the remaining 20% having class III LN. The figures were 19% and 21%, respectively, among the HLA-DR15 negative patients. In the Italian population HLA-DQA and HLA-DR alleles interact in conferring susceptibility to or protection against lupus nephritis, the diffuse proliferative glomerulonephritis (i.e., the most severe form of nephritis) is associated with the HLA-DR15 bearing haplotypes.

Anorectal dysfunction and delayed colonic transit in patients with progressive systemic sclerosis

We studied 14 unselected patients with progressive systemic sclerosis (PSS), six with constipation, and eight with normal bowel habits. A control group, matched for age and sex, comprised six patients with idiopathic constipation and seven healthy subjects. Anorectal manometry was performed with perfused catheters and segmental colonic transit was measured by a radiopaque marker technique. The resting pressure of the anal canal was significantly reduced in PSS with constipation (P<0.05). The rectoanal inhibitory reflex was detected in only one PSS patient with constipation, but was present in seven of eight PSS patients with normal bowel habits and in all controls (P<0.01). Total and right colonic transit times were significantly delayed in PSS with constipation and in patients with idiopathic constipation (P<0.05). In patients with PSS, colonic transit was delayed and anal sphincter function was impaired in constipated patients, suggesting involvement of both the colon and the anorectum by the disease.

Acid clearance and oesophageal sensitivity in patients with progressive systemic sclerosis.

This study examined the hypothesis that impaired oesophageal peristalsis was associated with delayed oesophageal clearance of acid in patients with progressive systemic sclerosis (PSS), some of whom are thought to have impaired oesophageal sensitivity to acid. Sixteen patients with PSS had: (a) oesophageal manometry and endoscopy; (b) acid perfusion of the oesophagus with simultaneous measurement of intraoesophageal pH during perfusion and for the next 10 minutes; (c) 22 hour monitoring of intraoesophageal pH; and (d) an evaluation of reflux symptoms during and after perfusion and during overnight pH monitoring. By oesophageal manometry, eight patients had normal peristalsis and eight patients had impaired peristalsis. Oesophageal endoscopy was unremarkable in patients with normal peristalsis, whereas all patients with impaired peristalsis had oesophagitis. The time needed to clear the oesophagus of perfused acid was shorter (p < 0.01) in patients with normal peristalsis and acid clearance time was significantly correlated (p < 0.01) with acid exposure time during overnight pH monitoring. During and after oesophageal perfusion, the nature, duration, and severity of symptoms did not differ between the groups, but overnight symptoms lasted longer (p < 0.05) in patients with impaired peristalsis. It is concluded that in PSS: (1) Impaired oesophageal motility delayed the clearance of acid and increased the exposure time to acid. (2) Acid clearance time is a useful parameter of impaired oesophageal motor function. The assessment of acid clearance time can be used as an alternative to overnight pH monitoring, to assess the impairment of oesophageal acid clearance. (3) Oesophageal sensitivity to acid was preserved in patients with impaired peristalsis and oesophagitis. (4) Reflux symptoms lasted longer in patients with prolonged oesophageal acid exposure but were still reported for a small fraction of the total acid exposure time. Thus, reflux symptoms reflect poorly prolonged exposure of the oesophagus to acid and are not a reliable guide to acid injury of the oesophagus in PSS.

Oesophageal acid clearance in patients with systemic sclerosis: Effect of body position

Objective: To test the effect of body position on oesophageal acid clearance time in patients with systemic sclerosis. Design and methods: Fifteen consecutive patients with systemic sclerosis and six healthy subjects underwent oesophageal manometry and an acid clearance test in three body positions (supine, recumbent at 30° and seated at 90°) in randomized order. Results: In healthy subjects the body position did not affect acid clearance time, whereas in patients the oesophagus cleared mainly by gravity. In patients the acid clearance time was significantly longer in the supine than in the seated position (P<0.05). Nine patients did not have a detectable peristaltic wave in the distal oesophagus. In the other six oesophageal peristalsis was still detectable but contractions had reduced amplitude and often had double and triple peaks; also in this subgroup the acid clearance time recorded in the supine position was prolonged. Conclusions: In systemic sclerosis gravity plays a major role in oesophageal acid clearance time. The finding of delayed acid clearance in a supine patient may suggest initial oesophageal involvement in the disease.