MEDICAL POSITION PAPER Management Guidelines of Eosinophilic Esophagitis A. Papadopoulou, yS. Koletzko, zR. Heuschkel, J.A. Dias, jjK.J. Allen, S.H. Murch, S. Chong, F. Gottrand, yyS. Husby, zzP. Lionetti, M.L. Mearin, jjjjF.M. Ruemmele, M.G. Scha¨ppi, A. Staiano, M. Wilschanski, and yyyY. Vandenplas, for the ESPGHAN Eosinophilic Esophagitis Working Group and the Gastroenterology Committee
Munnskold.noOral Diseases (2005) 11, 374–378. doi:10.1111/j.1601-0825.2005.01133.x Ó 2005 Blackwell Munksgaard All rights reserved Norwegian LongoVitalÒ and recurrent aphthousulceration: a randomized, double-blind, placebo-controlledstudy I Kolseth1, BB Herlofson1, A Pedersen2 1Department of Oral Surgery and Oral Medicine, University of Oslo, Norway; 2The Oral Medicine Clinic, Jyllinge, Denmark OBJECTIVE: LongoVitalÒ (LV) is a herbal-based tabletenriched with the recommended daily doses of vitamins.
The present study was undertaken to investigate possible prevention of recurrent aphthous ulceration (RAU) dur- Recurrent aphthous ulceration (RAU) is the most ing 4 months daily intake of the Norwegian LV.
common oral mucosal disease aﬀecting about 20% of DESIGN: The study was a placebo-controlled, double- the general population with a prevalence of about 2% blind, randomized, clinical trial.
(Axell, 1976). The etiology of RAU remains unknown, SUBJECTS: Sixty otherwise healthy patients with at least and the spectrum of suggested symptomatic therapies one attack of minor RAU per 2 months were included in is broad. However, the superiority of one to the other is dubious. LongoVitalÒ (LV) (DK. Reg. No. 5178/75) is METHODS: After an introduction period (IP) of 60 days, the ﬁrst harmless systemic therapy which has shown to the patients were randomly divided into three groups and be of beneﬁt in the prevention of RAU (Pedersen et al, given either LV, the herbs of LV only, or placebo. Three 1990a). LV has been sold as a food supplement in the test tablets were taken every day together with breakfast Scandinavian countries since 1975. The tablet is based for 4 months [tablet period (TP)] and the patients fol- on dried and ground herbs supplemented with the lowed up for another 4 months (F-UP). The number of new recommended doses of vitamins (Table 1). The herbal ulcers (NU) and ulcer-free days (UFD) were observed.
component of the tablets, however, varies slightly RESULTS: Fifty-two patients completed the study. Nei- between the countries due to diﬀerent regulations for ther NU nor UFD showed any statistical significant dif- food supplements. The previous study with LV on RAU ferences between any of the groups in any of the periods.
was performed with the Danish LV which at that time All three groups, however, showed a significant increase contained arnica (Pedersen et al, 1990a). The only in UFD during the first 2 months of TP compared to IP.
diﬀerence between the Danish and the Norwegian LV Within the LV group only, there was a further increase in is that the Norwegian LV does not contain arnica. The UFD after 2 months intake of the tablets. The number of present study was undertaken to investigate possible NU and UFD decreased significantly in both the LV and prevention of RAU during 4 months daily intake of the the herbal group in F-UP compared with TP.
Norwegian LV or the herbal component alone and to CONCLUSION: Neither the Norwegian LV nor the elucidate to what extent the possible eﬀect could be herbal component alone was superior to placebo in the ascribed to the herbal component alone or if there was a prevention of RAU. The results, however, indicate that synergistic eﬀect of herbs and vitamins. The null neither the LV nor the herbal group benefited from the hypothesis was that there was no diﬀerent eﬀect of Norwegian LV or the herbal component alone as Oral Diseases (2005) 11, 374–378 compared to placebo in the prevention of RAU.
Keywords: aphthous ulcers; herbs; LongoVital; nutritional sup-plementation; vitamins Material and methods PatientsSixty consecutive patients with minor RAU (Lehner,1968) were included in the study. The patients were Correspondence: Anne Pedersen, DDS, PhD, Dr. Odont., 4 Jagtvej, enrolled from the register of patients with RAU at the P.O. Box 27, DK-4040 Jyllinge, Denmark. Tel: 45-46 73 39 88, Faculty of Dentistry, University of Oslo, from col- Fax: 45-46 73 39 87, E-mail: [email protected] leagues, and among patients who contacted the Depart- Received 5 January 2004; revised 2 February 2005; accepted 9February 2005 ment of Oral Surgery and Oral Medicine after reading Norwegian LongoVital and aphthous ulcersI Kolseth et al Table 1 Contents of Norwegian LongoVitalper recommended daily dose – three tablets Vitamin A (retinyl acetate), 3000 IU Vitamin D (cholecalciferol), 400 IU Vitamin E (tocopheryl acetate), 12 IU Vitamin C (ascorbic acid), 60 mg Niacin (niacinamide), 20 mg Pantothenic acid (calcium pantothenate), 10 mg Vitamin B6 (pyridoxine HCL), 2 mg Vitamin B2 (riboﬂavin), 1.8 mg Vitamin B1 (thiamine mononitrate), 1.5 mg about the trial in the national newspaper. A detailed F Nørgaard, A Pedersen, pers. comm.). Therefore, the interview of the patients did not reveal any severe percentage of T-lymphocyte subsets (CD3+, CD4+, physical or psychological illnesses, and oral diseases CD8+) and the CD4:CD8 ratio was also determined day apart from RAU were absent. The RAU diagnosis was 0, day 120 and day 240.
based on disease history and clinical inspection duringan introduction period (IP) of 60 days.
The protocol was reviewed and approved by the local Patients registered data for each day on special forms.
ethics committee and oral consent to participate was The registrations included with or without ulcers, ulcer- obtained after written information about the trial. The free days (UFD), number of ulcers (NU), degree of pain, inclusion criterion was at least one ulcer attack during type and amount of alleviating drugs used. The degree IP. Patients who had used LV or any other continuous of pain was assessed using a numerical scale 1–3, where systemic RAU therapy through the preceding 3 months 1 represented weak pain, 2 moderate pain, and 3 severe were not included in the study.
The investigation was designed as a clinical, pros- At the clinical examinations, patients were asked pective, placebo-controlled double-blind 10-month trial.
about change of general medication, if any illnesses The patients started with an IP in order to survey their had occurred, possible change in lifestyle, and suspec- RAU activity. The patients were asked to ﬁll in a daily ted side eﬀects of the tablets. Patients' period of record of RAU symptoms, and to contact the examiner preference (all-over preference of TP or F-UP when for objective conﬁrmation of the diagnosis of RAU.
considering degree of pain, number and duration of After IP the patients started on the 4 months tablet recurrences, and number of ulcers as a whole) was period (TP) succeeded by a 4-month follow-up period recorded day 240.
(F-UP) in order to evaluate any possible carry-overeﬀect. The patients were randomly divided into three Treatment response groups: 20 patients who received LV, 20 the herbal The treatment response was determined from the component of LV alone, and 20 placebo. The tablets following parameters: were coated to make them indistinguishable from each (1) Number of ulcer-free days (UFD).
other. As the recommended daily dosage of LV is three (2) Number of new ulcers (NU).
tablets in the morning, the patients were instructed to (3) Immunological parameters.
take three tablets every morning together with breakfast (4) Patients' period of preference.
and to keep a diary of recurrences. They were further-more encouraged not to make any changes in lifestyleduring the study. Special emphasis was made on not to Statistical methods change smoking habits, toothpaste brand and the use of food supplements. If changes were made during the applied for statistical analysis of intergroup parameters, study, the patients were asked to report this in the diary.
and Friedman and Wilcoxon's matched-pair signed ranktest were used to analyse intragroup parameters. Fre- quencies were analysed by the sign test (binomial theorem). P-values <0.05 were considered statistically The patients were clinically examined at the start of IP, day 0 (start of TP), day 30, 120 and day 240. In order tomonitor for the eﬀect of the tablets on liver function, blood samples were collected three times: day 0, day 120and day 240 for determination of the concentration of Eight patients withdrew within the ﬁrst 4 months of the liver enzymes (alanine transaminase [ALAT], lactate trial leaving 52 patients for data analysis [32 female (F), dehydrogenase [LDT] and alkaline phosphatase). Previ- 20 male (M); mean age 42 year (range 16–75)]. Further ous studies with the Danish LV showed an immunostim- description of the population in Table 2. Eighteen ulating eﬀect of the tablets in diﬀerent patient categories patients had received LV (12F, 6M), 16 the herbal (Pedersen et al, 1990b, 1999; B Klausen, LP Ryder, component alone (8F, 8M), and 18 placebo (12F, 6M).
Norwegian LongoVital and aphthous ulcers Table 2 Clinical data of the population included in the study - 52 patients with recurrent aphthous ulceration (RAU) General Background Predisposing Factors for RAU Previous Treatments Hereditary RAU disposition Mechanical trauma Mild GI complaints Allergic tendencies Adulthood (>20 yr) Often having a cold Tetracycline rinse SLS-free toothpaste 1-2 recurrence/month 1 recurrence/2 months Postmenopausal hormones Number of ulcers/recurrence Duration of ulcers Psychological stress None of the treatment-response parameters showed any 44.5 (17.3–69.1). F-UP medians (95% conﬁdence limit statistically signiﬁcant diﬀerences between any of the of median): LV: 47.0 (1.4–75.0); herbs: 33.0 (7.2–83.7); groups at any of the test periods. However, within the placebo 45.0 (21.5–80.9).
LV and the herbal group some diﬀerences were demon-strated (Figures 1–3).
LV / Herbs alone / Placebo
Number of ulcer-free days Within all 3 groups a signiﬁcant increase in the number of UFD was demonstrated from IP compared to the ﬁrst60 days of TP (TP1) (Figure 1). IP median: LV: 16.5; herbs: 13.0; placebo: 14.0, and median of TP1: LV: 20.0; herbs: 21.5; placebo: 22.0. In the LV group, there was afurther increase in UFD from the ﬁrst 2 months to the later 2 months of TP (TP2). TP2 medians: LV: 31.0; herbs: 24.0; placebo: 16.5.
There were no statistically signiﬁcant diﬀerences between any of the three groups from TP as a whole to F-UP. TP median (95% conﬁdence limit of median): LV: 54.0 (16.9–88.9); herbs: 52.0 (10.3–88.6); placebo: Figure 2 Number of new ulcers (medians) during 4-month dailyintake of LongoVital (LV), the herbal component of LV, or placebo(TP), and during the 4-month tablet-free follow-up period (F-UP) in adouble-blind trial on 52 patients with minor RAU. *P < 0.05; NS, not LV / Herbs alone / Placebo
LV / Herbs alone / Placebo
Day 0–120 Day 121–240 Figure 1 Number of ulcer-free days (medians) during the 2-month introduction period (IP), 4-month daily intake of LongoVital (LV), theherbal component of LV, or placebo (TP), and during the 4-month Figure 3 CD4:CD8 ratio (median) during 4-month daily intake of tablet-free follow-up period (F-UP) in a double-blind trial on 52 LongoVital (LV), the herbal component of LV, or placebo, and during patients with minor RAU. Data from TP split up into periods of the 4-month tablet-free follow-up period in a double-blind trial on 52 2 months are also shown (TP1 and TP2). **P < 0.01; *P < 0.05.
patients with minor RAU. *P < 0.05. Statistically insigniﬁcant Statistically insigniﬁcant diﬀerences are not marked diﬀerences are not marked Norwegian LongoVital and aphthous ulcersI Kolseth et al Number of new ulcers of UFD or reduced the number of NU compared to placebo. This is in contrast to the former study with the between any of the three groups from TP to F-UP. TP Danish LV where the number of recurrences was medians (95% conﬁdence limit of median): LV: 12.0 signiﬁcantly reduced after 2 months of intake of LV (8.0–28.9); herbs: 23.0 (8.1–28.8); placebo: 13.5 (8.0– compared with placebo (Pedersen et al, 1990a). The 22.2). F-UP median (95% conﬁdence limit of median): divergent results of the two studies may be explained by LV: 9.0 (6.5–14.0); herbs: 15.0 (5.7–24.2); placebo 13.0 the lack of arnica in the Norwegian LV as this is the (5.9–23.8). Within both the LV and the herbal group, only major diﬀerence between the Danish and the the number of NU was signiﬁcantly reduced from TP to Norwegian LV.
F-UP (Figure 2).
Both within the LV and the herbal group there was a signiﬁcant reduction in number of NU from the TP compared to F-UP. This supports the previously dem- Liver enzyme values were all within or close to the onstrated carry-over eﬀect of LV (Pedersen et al, normal ranges at all three times of determination in all 1990a). Considering that the number of NU decreased three groups. There was no correlation between the type in F-UP, it is somewhat surprising that the number of of tablets and liver enzyme values.
UFD decreased in the F-UP.
In the present study, one group received the herbal Immunological parameters component alone in order to establish whether the Neither CD3+, CD4+ nor CD8+ counts showed any previously demonstrated beneﬁcial eﬀect of LV on RAU signiﬁcant diﬀerences between or within groups at any was to be ascribed to the herbs alone, or to the time. Within the LV group, however, the CD4:CD8 combination of vitamins and herbs. No signiﬁcant ratio increased signiﬁcantly from day 0 to day 120 – LV diﬀerences were demonstrated between LV and the medians (95% conﬁdence limit of median): day 0: 1.06 herbal group at any time, suggesting that the beneﬁt of (0.76–1.96); day 120: 1.17 (0.89–1.98) (Figure 3).
LV on RAU may mainly be assigned to the herbalcomponent.
Subjective evaluation of all-over period of preference Several studies with the Danish LV have shown an There were no signiﬁcant diﬀerences in all-over period immunostimulating eﬀect of the tablets in patients of preference between any of the groups.
with RAU (Pedersen et al, 1990b), in patients withSjo¨gren's syndrome (Pedersen et al, 1999), and in Reasons for withdrawal from the study periodontal patients (Klausen B, Ryder LP, Nørgaard Eight patients withdrew within the ﬁrst 4 months of the F, Pedersen A, pers. comm.). In the present study, the trial – four patients because of problems with indiges- CD4:CD8 ratio increased signiﬁcantly within the LV tion (diarrhoea and/or constipation), one because of group only, during the tablet intake. This seems to pregnancy, one because of an allergic reaction, and two indicate an immunostimulating eﬀect of the Nor- because of lack of time to keep the schedule. Three of wegian LV although not to the same extent as the the four patients who withdrew because of problems Danish LV. No changes in any of the evaluated with indigestion withdrew while on herbal tablets and 1 immunological parameters were demonstrated in the while on LV tablets.
herbal group. Thus, the inﬂuence of LV on theimmune system is possibly caused by a synergism between vitamins and the various trace elements in the Nine of the 52 patients in the study reported mild herbs (Chandra and Newberne, 1977).
indigestion problems at the very beginning of the tablet In contrast to the former study with the Danish LV in period and they were evenly distributed among the three the treatment of RAU (Pedersen et al, 1990a) there were no signiﬁcant diﬀerences in all-over period of preferencebetween any of the groups in the present study.
Use of alleviating drugs As in the previous study with LV on RAU (Pedersen Alleviating drugs used were mainly topical corticoster- et al, 1990a), liver enzyme values did not indicate any oid preparations and diﬀerent kind of antiseptic mouth- negative eﬀect on the liver of any of the three diﬀerent washes. Only one patient had used systemic cortisone twice for a period of 5 days. In the tablet period, The use of toothpaste without the anionic detergent, alleviating drugs had been used by four patients while sodium lauryl sulphate (SLS), has been reported to be of on LV, by seven patients while on herbal tablets, and by beneﬁt in controlling RAU (Herlofson and Barkvoll, ﬁve while on placebo. In the follow-up period, allevi- 1994, 1996; Chahine et al, 1997). In the present study ating drugs had been by two patients in the LV group there was an even distribution of patients using SLS-free and by six patients in both the herbal group and the toothpaste among the three groups, and the patients placebo group.
were told not to change toothpaste brand during thestudy periods. Hence, this parameter does not appear tohave had any inﬂuence on the test results.
In the present study, four patients on LV or the herbal In the present study, neither LV nor the herbal component withdrew from the trial due to indigestion component of LV signiﬁcantly increased the number problems. Withdrawals because of side eﬀects have not Norwegian LongoVital and aphthous ulcers been reported in any of the former studies with LV Chahine L, Sempson N, Wagoner C (1997). The eﬀect of (Pedersen et al, 1990a, 1999c; Pedersen, 2001; Klausen sodium lauryl sulphate on recurrent aphthous ulcers: a B, Ryder LP, Nørgaard F, Pedersen A, pers. comm.).
clinical study. Compend Contin Educ Dent 18: 1238–1240.
This may indicate that the herbal composition of the Chandra RK, Newberne PM, eds. (1977). Nutrition, immunity Norwegian LV may aﬀect digestion more severely than and infection. Mechanisms of interaction. Plenum Press: NewYork.
the Danish LV, or be due to diﬀerences in the study Herlofson BB, Barkvoll P (1994). Sodium lauryl sulphate and recurrent aphthous ulcers. A preliminary study. Acta Odon- In conclusion, neither the Norwegian LV nor the tol Scand 52: 257–259.
herbal component alone was superior to placebo in the Herlofson BB, Barkvoll P (1996). The eﬀect of two toothpaste prevention of RAU. The results, however, indicated that detergents on the frequency of recurrent aphthous ulcers.
there was a trend favouring LV and the herbs to Acta Odontol Scand 54: 150–153.
placebo. Therefore, the Norwegian LV could be recom- Lehner T (1968). Autoimmunity in oral diseases with special mended as an adjunct to other conventional therapies as reference to recurrent oral ulceration. Proc R Soc Med 61: a preventive measure in RAU patients.
Arnica was part of the Danish LV when the ﬁrst study Pedersen A (2001). LongoVitalÒ and herpes labialis: a rand- omised, double-blind, placebo-controlled study. Oral Dis 7: on RAU was done and it is known for its immunostim- ulating properties (Wagner et al, 1985; Wagner and Pedersen A, Hougen HP, Klausen B, Winther K (1990a).
Juric, 1991) which could explain the diﬀerent clinical LongoVitalÒ in the prevention of recurrent aphthous and immunological ﬁndings in the Danish and the ulceration. J Oral Pathol Med 19: 371–375.
present RAU study. Thus, in order to establish the Pedersen A, Klausen B, Hougen HP, Ryder L, Winther K importance of arnica in RAU prevention, future studies (1990b). Immunomodulation by LongoVitalÒ in patients with arnica containing food supplements are awaited with recurrent aphthous ulceration. J Oral Pathol Med 19: with great interest.
Pedersen A, Gerner N, Palmvang I, Høier-Madsen M (1999).
LongoVitalÒ in the treatment of Sjo¨gren's syndrome. Clin Exp Rheumatol 17: 533–538.
Wagner H, Juric K (1991). Immunologic studies of plant The study was supported by Paramedical A/S, Denmark.
combination preparations. In- vitro and in-vivo studies onthe stimulation of phagocytosis. Arzneimittelforsch 41: Wagner H, Proksch A, Riess-Maurer I et al (1985). Immuno- Axell T (1976). A prevalence study of oral mucosal lesions in stimulating action of polysaccharides (heteroglycan from an adult Swedish population. Odont Revy 27 (suppl 36): 103.
higher plants). Arzneimittelforsch 35: 1069–1075.
Evolutionarily conserved gene family importantfor fat storageBert Kadereit*, Pradeep Kumar*, Wen-Jun Wang*, Diego Miranda*, Erik L. Snapp†, Nadia Severina‡, Ingrid Torregroza‡,Todd Evans‡, and David L. Silver*§ *Department of Biochemistry and the Marion Bessin Liver Research Center and Departments of ‡Developmental and Molecular Biology and †Anatomyand Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461