Faculty Bibliography

OBJECTIVE: To study the clinical spectrum of Behcet's disease (BD) in childhood, in comparison to adult-onset disease. METHODS: Nineteen children, who fulfilled disease criteria up to the age of 16 yr, were studied. The results were compared to those of 34 adult patients with BD. An activity index and severity score were calculated for both study groups. RESULTS: The mean age of disease onset was 6.9+/-3.9 yr, similar ages of onset were found in males and females. The clinical spectrum of childhood BD resembled that of adult disease; however, the prevalence of certain manifestations was different between children and adults. Children with BD had significantly less genital ulcers, less vascular thromboses and more non-specific gastrointestinal symptoms, as well as central nervous system involvement and arthralgia. A relatively high prevalence of uveitis was found in childhood BD. The activity index and severity score were significantly lower in children than in adults. CONCLUSION: Our results point to a similar systemic expression of BD in children and adults; however, the disease seems to run a less severe course in children.

Behcet's disease (BD) is a multisystem disease, in which recurrent aphthous stomatitis (RAS) is a universal finding. We studied the expression of RAS in patients with BD, and the correlation between major or minor RAS and systemic expression and severity of the disease. Thirty-five patients with BD were studied, of whom 13 (37%) had major, 21 (60%) had minor and one (3%) had herpetiform RAS. The frequency of major RAS was significantly higher compared with a control group of patients with idiopathic RAS (37% vs 9%, P < 0.05). The BD patients with major RAS had significantly more relapses of oral ulceration in a year, higher numbers of oral ulcers per relapse, and longer duration of aphthous episodes, compared with patients with minor RAS. Oral ulcers also appeared at a significantly younger age in patients with major than with minor RAS. However, the systemic expression of the disease, as well as the disease severity score, were similar in patients with major and minor RAS. The results of this study indicate that major RAS is common in patients with BD, and is associated with a more severe, repeated and prolonged oral disease. Nevertheless, the presence of major RAS in BD does not predict a more severe systemic illness.

OBJECTIVE: To explore the main patterns of Behcet's disease (BD) expression, applying factor analysis. METHODS: Sixty-eight BD patients were studied. The following disease manifestations were used for the factor analysis: genital ulcerations, typical skin lesions (erythema nodosum, folliculitis or papulo-pustular rash), uveitis, CNS involvement, joint disease, deep vein and superficial vein thrombosis, and gastrointestinal manifestations. The results were further analyzed according to sex, HLA typing, and childhood vs. adult-onset disease. RESULTS: Five factors were derived, which accounted for 69% of the variance of the matrix. Factor 1 represented the association between folliculitis and genital ulceration. Factor 2 represented the association between papulo-pustular rash and gastrointestinal symptoms. Factor 3 represented the inverse association between superficial vein thrombosis and erythema nodosum. Factor 4 represented the correlation between deep vein thrombosis and neuro-Behcet. Factor 5 represented joint disease. No difference was found between males and females in relation to factors 1, 2 or 5, but factors 3 and 4 had higher scores in male patients (p = 0.1 and p = 0.07, respectively). Factor 3 was significantly higher in patients with HLA-B5, compared to HLA-B5-negative BD patients (p < 0.001). Factors 1 and 3 were higher in patients with adult onset of the disease (p = 0.07, and p = 0.003, respectively), while factor 2 was higher in patients with childhood-onset BD (p = 0.07). CONCLUSIONS: The application of factor analysis revealed possible associations between distinct types of skin lesions, or venous thrombosis, and other disease manifestations of Behcet's syndrome, some of which were sex, age at onset, or HLA-related.

OBJECTIVE: To evaluate the correlation between the age at onset of Behcet's disease (BD) and sex distribution, mode of disease appearance, and number of organs involved during the disease. METHODS: BD was defined according to the International Study Group criteria. Data from medical files and from patient interviews were collected. Results were analyzed for children and adults, according to age at disease onset. A systemic involvement index was calculated as the sum of visceral organ systems involved. RESULTS: Fifty-nine patients with BD were studied, 26 male and 33 female. The mean age at disease onset was 8.4 +/- 4.5 years in children and 29.8 +/- 7.9 years in adults. The age of onset was significantly lower in male versus female patients. BD presented in children almost entirely as recurrent aphthous stomatitis, while in adults, less than one-third of patients presented first with oral ulcers. The mean age at disease onset of patients who presented first with oral ulcers was significantly lower than the age of patients presenting first with non-oral aphthosis. The mean systemic involvement index was higher in adult onset than in juvenile onset disease. A significant linear correlation was found between age of disease onset and total number of visceral organ systems involved. CONCLUSION: BD was observed to occur earlier in males than in females. The first manifestation of BD in children is almost exclusively in the form of oral ulcers, while older patients have a large proportion of non-oral aphthosis as their first disease manifestation. Disease onset at an older age is positively correlated with increased disease spectrum.

The purpose of the present study was to investigate a possible seasonal pattern in various clinical and laboratory manifestations in a group of systemic lupus erythamatosus (SLE) patients. One hundred and five SLE patients were followed up during a 4 yr period. Data on each of the clinical and laboratory variables examined, as well as the results of the disease activity index (SLEDAI), were plotted against the month during which they were obtained. Photosensitivity was the only variable to show a seasonal pattern, having higher scores during the summer months (1.04 +/- 0.16 in July vs 0.58 +/- 0.12 in December). We were unable to show seasonal patterns in any of the other variables examined. As a group, SLE patients do not show any significant seasonal pattern in disease manifestations and activity, except for photosensitivity. However, such a pattern may exist for the individual patient.

Patients with systemic lupus erythematosus (SLE) were evaluated using a telephone questionnaire on the activity of various disease manifestations during the seasons of the past year. The results were compared to those of patients with Behcet's disease (BD), using the same questionnaires, and analyzed in relation to the mean temperature, humidity, barometric pressure, and ultraviolet radiation (UVR) in the patient's location, obtained from the official Israeli Meteorological Service. It was found that SLE patients had a tendency towards winter worsening of clinical manifestations, shown as increased incidence of joint pains, weakness, fatigue, Raynaud's phenomenon, and rash, as well as increased number of hospital admissions, sick leaves, and need to raise the dose of medications. The symptoms of patients with BD were not correlated to seasons of the year, except for increased joint pains in autumn and spring. We suggest that UVR accumulation might cause exacerbations in SLE patients several months after prolonged exposure to sunlight in the summer.

Since colchicine-sensitive microtubules regulate the expression and topography of surface glycoproteins on a variety of cells, we sought evidence that colchicine interferes with neutrophil-endothelial interactions by altering the number and/or distribution of selectins on endothelial cells and neutrophils. Extremely low, prophylactic, concentrations of colchicine (IC50 = 3 nM) eliminated the E-selectin-mediated increment in endothelial adhesiveness for neutrophils in response to IL-1 (P < 0.001) or TNF alpha (P < 0.001) by changing the distribution, but not the number, of E-selectin molecules on the surface of the endothelial cells. Colchicine inhibited stimulated endothelial adhesiveness via its effects on microtubules since vinblastine, an agent which perturbs microtubule function by other mechanisms, diminished adhesiveness whereas the photoinactivated colchicine derivative gamma-lumicolchicine was inactive. Colchicine had no effect on cell viability. At higher, therapeutic, concentrations colchicine (IC50 = 300 nM, P < 0.001) also diminished the expression of L-selectin on the surface of neutrophils (but not lymphocytes) without affecting expression of the beta 2-integrin CD11b/CD18. In confirmation, L-selectin expression was strikingly reduced (relative to CD11b/CD18 expression) on neutrophils from two individuals who had ingested therapeutic doses of colchicine. These results suggest that colchicine may exert its prophylactic effects on cytokine-provoked inflammation by diminishing the qualitative expression of E-selectin on endothelium, and its therapeutic effects by diminishing the quantitative expression of L-selectin on neutrophils

Previous studies have shown that neutrophils in the circulation of patients with active systemic lupus erythematosus (SLE) are activated as judged by their increased surface expression of the beta 2-integrin CD11b/CD18. Since activation of neutrophils leads to altered expression of another adhesion molecule, L-selectin (LS), we examined neutrophils from patients with SLE for changes in the expression of CD11b/CD18 and LS by cytofluorographic analysis of immunofluorescent-labeled cells. Overall there was no difference between surface expression of CD11b/CD18 on neutrophils from SLE patients or controls [mean fluorescence 225 +/- 26 vs 225 +/- 13 relative fluorescence units (RFU), respectively]. However, as previously reported, neutrophils from patients with more active disease (activity score > or = 3, UCH Middlesex activity score) expressed greater CD11b/CD18 than neutrophils from controls (319 +/- 40 RFU, P < 0.03, n = 9) or from patients with less active disease (193 +/- 10 RFU, P < 0.006). Indeed, CD11b/CD18 expression correlated directly with disease activity (r = 0.54, P < 0.02). Stimulation of neutrophils ex vivo with the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (100 nM) induced up-regulation of CD11b/CD18 in cells from both SLE patients and controls (205 +/- 12% vs 239 +/- 15% of basal, respectively), but neutrophils from the most active patients (score > or = 3) increased CD11b/CD18 expression less than controls (175 +/- 12% of basal, P < 0.003, n = 9). The magnitude of the stimulated increment in expression of CD11b/CD18 on neutrophils correlated inversely with SLE activity (r = -0.64, P < 0.003, n = 20). Surprisingly, we observed no change in LS expression on neutrophils from SLE patients compared to controls (143 +/- 14 vs 141 +/- 16 RFU, respectively) even in patients with the highest activity indices (154 +/- 21 RFU). In contrast to CD11b/CD18, there was no correlation between LS expression and disease activity (r = 0.12, P = NS). Stimulation of neutrophils reduced the expression of LS similarly in both controls and SLE patients (67 +/- 3% vs 58 +/- 4% reduction, respectively) and did not correlate with disease activity (r = 0.07, P = NS, n = 20). These results show, for the first time, that changes in CD11b/CD18 expression do not correlate with LS expression on neutrophils from patients with active SLE.(ABSTRACT TRUNCATED AT 400 WORDS)

Neutrophils express receptors for numerous phlogistons which, when occupied, trigger distinct signal-transduction pathways. Previous studies have shown that stimulation of neutrophils with chemoattractants induces shedding of the adhesive molecule L-selectin and increased expression of the beta 2-integrin CD11b/CD18. We determined the effect of ligation of classic, G-protein-linked chemoattractant receptors [C5a, interleukin-8 (IL-8), formylmethionyl-leucylphenylalanine (FMLP) and substance P], receptors for the Fc portion of IgG (Fc gamma receptors) and receptors for transforming growth factor beta (TGF beta) on expression of adhesive molecules by neutrophils and the stimulus-transduction mechanisms thought to mediate these changes. We were surprised to observe that occupancy of Fc gamma receptors by immunocomplexes (BSA-anti-BSA) stimulated increased expression by neutrophils of CD11b/CD18 at concentrations which did not affect L-selectin expression (EC50 9 micrograms/ml versus 350 micrograms/ml respectively, P < 0.00001, n = 5). In contrast, similar to previous studies, recombinant C5a, recombinant IL-8 and FMLP all stimulated increased expression of CD11b/CD18 (170-260% of basal, P < 0.001, n = 5) and shedding of L-selectin (56-75% reduction from basal, P < 0.001, n = 5) at similar concentrations and with similar potencies (EC50 = 2, 5, and 3 nM respectively). In contrast, neither TGF beta 1 nor, surprisingly, substance P affected expression of CD11b/CD18 or L-selectin. The regulation of expression of CD11b/CD18 or L-selectin in response to FMLP or immunocomplexes was unaffected by cytochalasin B (5 micrograms/ml) or the tyrosine kinase inhibitor tyrphostin-25 (25 microM). Although occupancy of both chemoattractant (FMLP) and Fc gamma receptors stimulated increments in the second messenger diacylglycerol, disruption of actin microfilaments by cytochalasin B enhanced diacylglycerol generation in response to FMLP but not in response to ligation of Fc gamma receptors. Moreover, both FMLP and immune aggregates provoked fluxes of intracellular Ca2+ concentration which differed with respect to both magnitude and kinetics and did not correlate well with regulation of adhesive-molecule expression. As upregulation of CD11b/CD18 is tightly linked to exocytosis of specific granules, these results suggest that shedding of L-selectin by activated neutrophils is not linked to exocytosis. These studies provide further evidence that receptors for chemoattractants and immunocomplexes on the neutrophil are linked to multiple signalling pathways