Histopathological and clinical evaluation of papulopustular lesions in Behçet's disease.

OBJECTIVES: Behçet's disease (BD) is a chronic inflammatory disorder characterised by aphthous stomatitis, genital ulcerations, erythema nodosum-like manifestations and papulopustular lesions. While a neutrophilic vasculitis accompanies most skin lesions it is usually regarded that the papulopustular lesions in BD are similar to acne vulgaris (AV). The aim of our current study was to further assess the clinical and histopathological features of papulopustular lesions in BD and how these features compared to those of AV. METHODS: To analyse the histopathological features of BD and AV, 89 punch biopsies were taken from 58 BD (52 male, 6 female) and 31 AV patients (26 male, 5 female). Sections were evaluated in a blind manner by two different pathologists. A dermatologist who was blind to the patients' diagnosis counted the number of papules, pustules, comedones, folliculitis, cysts and nodules on the face, chest, back, upper and lower extremities. RESULTS: The number of papules, pustules and comedones was higher on the face in the AV group, whereas in the BD group, both number of papules and folliculitis on the back and that of folliculitis were higher on the lower extremities in the AV group. With the exception of comedone formation, which was more frequent among the AV patients [20/31 (64.5%) vs. 23/58 (39.6%), p=0.025] the presence of suppurative folliculitis/perifolliculitis, intrafollicular abscess formation, leukocytoclastic vasculitis or microorganisms were not useful in differentiating BD from AV. However, the interobserver agreement for histologic assessment was low. Kappa was 0.17 for suppurative foliculitis/perifol¬liculitis; 0.39 for intrafollicular abscess formation; 0.51 for leukocytoclastic vasculitis. CONCLUSIONS: In the BD group, although the inflammatory lesions located on the face were less than those in the AV group inflammatory lesions such as folliculitis on the legs were only seen, again in the BD group. The papulopustular lesions of BD could not be distinguished from AV by histology. Some of this might be due to high interobsever variation in interpretation. Acne is an inherent manifestation of BD.

Intravascular/Intralymphatic Histiocytosis: A Report of 3 Cases.

Intravascular/intralymphatic histiocytosis (IV/ILH) is a rare, reactive cutaneous condition, with uncertain pathogenesis. It may be associated with various inflammatory and neoplastic diseases. Although the clinical presentation is various, the biopsies reveal dilated vessels, mostly lymphatics, containing aggregates of histiocytes within their lumina. We described 3 cases of IV/ILH with different clinical presentations. In the first case, the patient presented with lymphedema in the genital region without any underlying disease. However, the second and third cases had reticular erythematous skin lesions. The second case had common variable immunodeficiency disease, rheumatoid arthritis, inflammatory bowel disease, and a history of a lymphoproliferative lesion. The third case had metal prostheses at both his right and left knees. In all these 3 cases, histopathologic and immunohistochemical findings were similar to each other and to those cases reported in the literature. In addition, the third case was admixed with reactive angioendotheliomatosis. In the second case, the endothelium of the ectatic vessels expressed CD31 and CD34, but not D2-40/podoplanin, pointing out that these vessels were blood vessels rather than lymphatics, differing from the other 2 cases. In conclusion, we believe, the most convincing statement about IV/ILH is that it is not a distinct clinicopathologic entity, but a histopathologic feature found as a part of a constellation of inflammatory changes or many other conditions.

Apremilast for Behçet's syndrome--a phase 2, placebo-controlled study.

BACKGROUND: Oral ulcers, the hallmark of Behçet's syndrome, can be resistant to conventional treatment; therefore, alternative agents are needed. Apremilast is an oral phosphodiesterase-4 inhibitor that modulates several inflammatory pathways. METHODS: We conducted a phase 2, multicenter, placebo-controlled study in which 111 patients with Behçet's syndrome who had two or more oral ulcers were randomly assigned to receive 30 mg of apremilast twice daily or placebo for 12 weeks. This regimen was followed by a 12-week extension phase in which the placebo group was switched to apremilast and a 28-day post-treatment observational follow-up phase. The patients and clinicians were unaware of the study assignments throughout the trial. The primary end point was the number of oral ulcers at week 12. Secondary outcomes included pain from these ulcers (measured on a 100-mm visual-analogue scale, with higher scores indicating worse pain), the number of genital ulcers, overall disease activity, and quality of life. RESULTS: The mean (±SD) number of oral ulcers per patient at week 12 was significantly lower in the apremilast group than in the placebo group (0.5±1.0 vs. 2.1±2.6) (P<0.001). The mean decline in pain from oral ulcers from baseline to week 12 was greater with apremilast than with placebo (-44.7±24.3 mm vs. -16.0±32.5 mm) (P<0.001). Nausea, vomiting, and diarrhea were more common in the apremilast group (with 22, 9, and 12 incidents, respectively, among 55 patients) than in the placebo group (with 10, 1, and 2 incidents, respectively, among 56 patients), findings that were similar to those in previous studies of apremilast. There were two serious adverse events in patients receiving apremilast. CONCLUSIONS: Apremilast was effective in treating oral ulcers, which are the cardinal manifestation of Behçet's syndrome. This preliminary study was neither large enough nor long enough to assess long-term efficacy, the effect on other manifestations of Behçet's syndrome, or the risk of uncommon serious adverse events. (Funded by Celgene; ClinicalTrials.gov number, NCT00866359.).

Colchicine in Behçet syndrome: a longterm survey of patients in a controlled trial.

OBJECTIVE: To test the hypothesis that colchicine use during early disease decreases immunosuppressive use in Behçet syndrome (BS) in the long term. METHODS: Patients with BS who participated in a double-blind, placebo-controlled trial of colchicine 16.6±1.1 years ago were evaluated for immunosuppressive use during the posttrial period. RESULTS: We could contact 90/116 patients; 28 (31%) received immunosuppressives during the posttrial period, 14 being from the colchicine arm. Posttrial colchicine use and cumulative duration were similar between patients who received immunosuppressives and those who did not. CONCLUSION: Continuous use of colchicine, even when initiated at an early disease stage, does not seem to decrease the use of immunosuppressives in the long term.

Behçet's syndrome: facts and controversies.

Behçet's syndrome is a systemic vasculitis of small and large vessels affecting both veins and arteries. Almost all patients with Behçet's syndrome have recurrent oral aphthae, followed by genital ulcers, variable skin lesions, such as erythema nodosum and papulopustuler lesions, arthritis, uveitis, thrombophlebitis, and gastrointestinal and central nervous system involvement. Recent epidemiologic works suggest that genetic factors are more important than environmental factors in its pathogenesis. European League Against Rheumatism guidelines were recently published for the treatment of Behçet's syndrome. Although these are quite useful for the management of mucocutaneous, eye, and joint involvement, treatment of vascular, neurological, and gastrointestinal involvement are still problematic as there are no controlled studies for these manifestations. This contribution addresses the epidemiology, mucocutaneous manifestations, diagnostic criteria, and evidence-based therapies, including biologic agents.

Prognosis of Behcet's syndrome among men with mucocutaneous involvement at disease onset: long-term outcome of patients enrolled in a controlled trial.

OBJECTIVE: To assess the influence of being free of major organ involvement during the early years of the disease on the prognosis of men with Behçet's syndrome (BS). METHODS: Ninety-six men with BS, who had only active mucocutaneous manifestations when entering a controlled trial of thalidomide mean (s.d.) 11.7 (0.8) years ago, were re-evaluated for the use of immunosuppressives as an indication of major organ involvement during the post-trial period. RESULTS: Outcome information was obtained in 91 (95%) patients. Thirty-nine (43%) patients had to use immunosuppressives during the post-trial period. Immunosuppressive use was significantly more frequent among patients developing BS at younger age (76%; or=25 years). Developing BS at young age (OR = 6.3; 95% CI 2.09, 19.04) and not using colchicine during the post-trial period (OR = 3.860; 95% CI 1.484, 10.034) were risk factors for immunosuppressive use. However, 82% of the patients using colchicine had onset during old age. Colchicine showed a significant effect in decreasing the use of immunosuppressives only among patients of old age at onset (Fisher's exact test = 5.026; P = 0.031) in the subgroup analysis. Eye disease (18 patients) and vascular involvement (14 patients) were the most frequent indications for immunosuppressive use. CONCLUSIONS: Being free of major organ involvement during the early years of BS does not indicate a mild prognosis for men developing BS at young age. Whether colchicine will reduce the need for immunosuppressive use among men developing BS at old age awaits formal studies.

Low-dose natural human interferon-alpha lozenges in the treatment of Behçet's syndrome.

OBJECTIVES: There had been evidence that low-dose local IFN could be beneficial in the management of recurrent oral ulcers (OUs). We investigated the efficacy and collected initial data on the safety of low-dose natural human IFN-alpha administered by the oral mucosal route in Behçet's syndrome (BS) in a placebo controlled, double blind study. METHODS: Eighty-four (59 males and 25 females) patients with BS with mainly skin mucosa disease and a history of recurrent OU for > or = 1 year were studied. When they had at least two OUs with a total diameter of > or = 4 mm, they were randomly allocated to (i) 2000 IFN-alpha IU/day, (ii) 1000 IFN-alpha IU/day and (iii) placebo groups. Subjects were monitored weekly over an initial 4 weeks and bi-weekly for an additional 8 weeks of treatment. OU were counted and measured at each study visit. The primary efficacy end point was the difference in the total ulcer burden at Week 0 compared with that at Week 12. RESULTS: Out of the 84 patients enrolled, 72 completed the trial. There were no statistically significant differences between the treatment arms in terms of the primary endpoint. CONCLUSIONS: Low-dose natural human IFN-alpha did not have beneficial effects on reducing the total ulcer burden among BS patients from Turkey. The study also showed that counting the number of ulcers rather than measuring the size would be adequate in future studies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00483184, http://www.clinicaltrials.gov/ct2/results?term=NCT00483184.

Comparative study of adhesion molecule expression in nodular lesions of Behçet syndrome and other forms of panniculitis.

Adhesion molecules have a role in many vasculitic disorders. Our aim was to evaluate the status of adhesion molecules in nodular lesions of Behçet syndrome (BS) and compare them with results for the 2 most common types of panniculitis, erythema nodosum (EN) and nodular vasculitis (NV). We included the data for 28 patients with nodular lesions of BS, 24 with EN, and 22 with NV. A panel of monoclonal antibodies against E-selectin, P-selectin, vascular cell adhesion molecule-1, platelet endothelial cell adhesion molecule-1, and intercellular adhesion molecule (ICAM)-1 were applied. The distribution and intensity of adhesion molecules were assessed. There were no statistically significant differences between the BS and control groups in regard to these adhesion molecules except for ICAM-1. The percentage of strongly ICAM-1-stained endothelial cells in subcutaneous fat tissue in relation to the total number of endothelial cells was the lowest in BS (P= .0208). Because many lesions of BS were related to an enhanced inflammatory response, the lower percentage of ICAM-1 expression seems counterintuitive.

Short-term trial of etanercept in Behçet's disease: a double blind, placebo controlled study.

OBJECTIVE: To determine the effect of the tumor necrosis factor-alpha blocker etanercept on the pathergy and monosodium urate (MSU) status and on the mucocutaneous and articular manifestations of patients with Behçet's disease (BD). METHODS: Forty male patients with BD, all with positive pathergy and MSU tests and mucocutaneous disease and/or arthritis, were randomized (20 patients to each study arm) to receive either etanercept 25 mg twice a week or placebo for 4 weeks. The pathergy and MSU responses and the frequencies of mucocutaneous and articular manifestations were compared between the 2 groups. RESULTS: There were no decreases in the pathergy and MSU responses in the etanercept group compared to the placebo group at any time. The mean numbers of oral ulcers, nodular lesions, and papulopustular lesions were less in the etanercept group compared to the placebo group at all weekly evaluations, except for the second week for papulopustular lesions. The probability of being free of oral ulcers and nodular lesions was also significantly higher in the former group (log-rank chi-square = 9.83, p = 0.0017; log-rank chi-square = 14.17, p = 0.0002, respectively). CONCLUSION: Etanercept did not affect the pathergy reaction and the cutaneous response to MSU crystals. However, the drug was effective in suppressing most of the mucocutaneous manifestations of BD.

Stiff skin syndrome: a case report.

Stiff skin syndrome (SSS) is a disease similar to scleroderma with an unknown etiology. Stone-hard areas of skin are observed from birth or in early childhood. In this article we describe a 15-year-old girl with skin hardening and limitation of movement. We diagnosed the case as SSS, of which we have not encountered a similar report in the Turkish literature.

The long-term mortality and morbidity of Behçet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center.

We surveyed the 20-year outcome of a cohort of patients with Behçet syndrome with emphasis on both mortality and morbidity. During 1999 and 2000, we collected outcome information on 387/428 (90.4%) of a cohort of patients (262 male, 125 female) who had registered in a dedicated outpatient clinic between July 1977 and December 1983. In 245/345 (71.0%) patients, outcome information was based on a formal hospital reevaluation, and in the remaining patients, on detailed telephone interviews. Forty-two patients (9.8%) (39 male, 3 female) had died, mainly due to major vessel disease and neurologic involvement. Mortality, as measured by standardized mortality ratios (SMR), was specifically increased among young males, among whom morbidity was also the highest. However, the SMR tended to decrease significantly with the passage of time. The same was also true for all mucocutaneous and articular manifestations. Both the onset of eye disease and its greatest damage were also usually within the first few years of disease onset. These suggest that the "disease burden" of Behçet syndrome is usually confined to the early years of its course, and in many patients the syndrome "burns out." However, central nervous system involvement and major vessel disease are exceptions. They can have their onset late (5-10 yr) during the disease course. As reflected in the mortality figures, the disease was less severe among the females for almost each disease manifestation. There were no female patients with arterial aneurysms. Severely impaired vision did not always mean an eventual loss of useful vision, and those patients with a late onset of eye disease had a better visual prognosis.

Interferon alfa combined with azathioprine for the uveitis of Behçet's disease: an open study.

BACKGROUND: Eye involvement is the main cause of morbidity in Behçet's syndrome. The efficacy of the combined use of azathioprine and interferon alfa in treating this condition has not been studied. METHODS: Ten male BD patients with retinal involvement but no irreversible structural changes were treated with azathioprine 2.5 mg/kg/day and IFN alpha 2b three times weekly for 24 weeks in an open trial. At week 24, IFN alpha was stopped and the patients continued to use azathioprine or received other immunosuppressives as indicated. Clinical response was assessed by visual acuity changes of either eye under the combination treatment and during the follow-up after stopping interferon. RESULTS: As compared to the study entry, the mean visual acuities of either eye increased significantly at the end of the combination treatment (right eye 5.8 +/- 1.26 vs. 8.3 1.14; P = 0.043; left eye 6.3 1.15 SEM vs. 9.1 +/- 0.9 SEM; P = 0.027). The improvement in visual acuity persisted in the nine patients who were followed for 7.2 +/- 1.6 SEM months after stopping interferon. Reversible hematologic toxicity, mostly in the form of leukopenia, was detected in six patients during the combination treatment. CONCLUSIONS: The combination of IFN alpha and azathioprine appears to be effective for eye involvement of BD. However, the frequent occurrence of myelosuppression mandates close monitoring.

Photodynamic therapy with verteporfin for choroidal neovascularization in patients with angioid streaks.

PURPOSE: To evaluate safety and efficacy of photodynamic therapy with verteporfin for subfoveal choroidal neovascularization associated with angioid streaks. DESIGN: Prospective interventional case series. METHODS: Eight patients (eight eyes) with subfoveal choroidal neovascularization secondary to angioid streaks were reviewed. Standardized protocol refraction, visual acuity testing, ophthalmologic examinations, color photographs, fluorescein angiograms and indocyanine angiograms were used to evaluate the results of photodynamic therapy with verteporfin. Follow up ranged from 6 to 12 months with a mean (+/- SD) of 8.75 (+/- 2.37) months. RESULTS: Photodynamic therapy with verteporfin was well tolerated in patients with choroidal neovascularization related to angioid streaks. No deterioration in visual acuity was observed. Increase in median best-corrected visual acuity was 1.37 lines (SD +/- 1.59 lines, range 1-5 lines) at the last follow up. Two (25%) patients had no improvement of visual acuity. At the last follow up three (37.5%) patients showed no leakage and three (37.5%) patients had minimal leakage from choroidal neovascularization. Photodynamic therapy related ocular complications were not reported in any case. CONCLUSIONS: Photodynamic therapy with verteporfin generally achieved short-term cessation of or decrease of fluorescein leakage from subfoveal choroidal neovascularization without loss of vision in patients with angioid streaks. Further studies with longer follow up are necessary to confirm whether verteporfin therapy is beneficial for subfoveal choroidal neovascularization related to angioid streaks.

Comparison of two surgical approaches for treating vitiligo: a preliminary study.

BACKGROUND: Surgical techniques have recently been introduced for patients with vitiligo. Randomized controlled trials have not been performed. AIM: To compare the efficacy and side-effects of two surgical methods (suction blister vs. thin split-thickness graft technique) for the treatment of vitiligo. METHODS: Three suction blisters, approximately 0.8 cm in diameter, made with a special tool attached to a vacuum extractor, which were converted to erosions by removal of the roofs of the bullae, and one round erosion of approximately the same diameter, made using a silver knife, were created. One roof of a blister and two cutaneous thin split-thickness grafts taken from the gluteal region were transferred onto recipient vitiliginous areas; one was left alone. The results were evaluated by one non-blind and two blind observers bimonthly during the 3-month follow-up period. RESULTS: Repigmentation rates were 25-65% in the suction blister technique and 90% in the thin split-thickness graft technique (P < 0.001). CONCLUSIONS: The thin split-thickness graft technique is superior to the suction blister technique in treating vitiligo.

Comparación entre dos procedimientosquirúrgicos para tratar el vitíligo: estudiopreliminar / Comparison of two surgical approaches for treating vitiligo: a preliminary study

Antecedentes: Recientemente se han introducido varias técnicas quirúrgicas para tratar a los pacientes con vitíligo. No se han realizado hasta ahora ensayos controlados y aleatorios. Objetivo: Comparar la eficacia y los efectos secundarios de dos métodos quirúrgicos (técnica de injerto de ampollas de succión frente a técnicas de injerto de capas finas de piel) para el tratamiento del vitíligo. Métodos: Se elaboraron tres ampollas de succión de 0,8 cm de diámetro, aproximadamente, con un instrumento especial unido a un extractor de vacío, que se convirtieron en erosiones al extraer las cúpulas de las ampollas, y una erosión redonda de aproximadamente el mismo diámetro, con un bisturí de plata. La cúpula de una ampolla y dos injertos de capas finas de piel extraídos de la región glútea se trasladaron a las zonas de vitíligo receptoras; una se dejó sin tocar. Los resultados se evaluaron por un observador no ciego y dos ciegos, dos veces al mes, durante el período de seguimiento de tres meses. Resultados: Se observaron tasas de repigmentación del 25-65 por ciento con la técnica de ampollas de succión y del 90 por ciento con la técnica de injerto de capas finas de piel (p<0,001).Conclusiones: La técnica de injerto de capas finas de piel es mejor que la técnica de ampollas de succión para tratar el vitíligo (AU)