Non-targeted analytical comparison of a heated tobacco product aerosol against mainstream cigarette smoke: does heating tobacco produce an inherently different set of aerosol constituents?

Smoking-related diseases remain a significant public health concern, and heated tobacco products (HTPs) have emerged as a potential alternative to cigarettes. While several studies have confirmed that HTP aerosols contain lower levels of harmful and potentially harmful constituents (HPHCs) than cigarette smoke, less is known about constituents that are intrinsically higher in HTP aerosols. This study provides a comprehensive comparative assessment of an HTP aerosol produced with Tobacco Heating System 2.2 (THS) and comparator cigarette (CC) smoke aiming at identifying all unique or increased compounds in THS aerosol by applying a broad set of LC-MS and GC × GC-MS methods. To focus on differences due to heating versus burning tobacco, confounding factors were minimized by using the same tobacco in both test items and not adding flavorants. Of all analytical features, only 3.5%-corresponding to 31 distinctive compounds-were significantly more abundant in THS aerosol than in CC smoke. A notable subset of these compounds was identified as reaction products of glycerol. The only compound unique to THS aerosol was traced back to its presence in a non-tobacco material in the test item and not a direct product of heating tobacco. Our results demonstrate that heating a glycerol-containing tobacco substrate to the temperatures applied in THS does not introduce new compounds in the resulting aerosol compared to CC smoke which are detectable with the method portfolio applied in this study. Overall, this study contributes to a better understanding of the chemical composition of HTP aerosols and their potential impact on human health.

A Multicentre Randomised Controlled Study Evaluating the Effect of a Standardised Education Programme on Quality of Life, Disease Severity, and Disease Knowledge in Patients with Moderate-To-Severe Psoriasis: The EDUPSO Study.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease that has a profound effect on health-related quality of life (HRQoL). Patient education programmes may help patients to gain life-long control over their chronic disease. OBJECTIVE: This multicentre randomised controlled study evaluated whether a standardised multidisciplinary education programme was beneficial to psoriasis patients. METHODS: Adults with moderate-to-severe psoriasis were randomly assigned (1:1) to an intervention group to receive an educational programme or to a control group to receive usual care. Randomization was stratified by previous treatment history. The primary outcome was HRQoL, assessed by scoring the Skindex-29 domains emotion, symptom, and functioning. Psoriasis severity was assessed using the psoriasis area severity index (PASI). Levels of perceived stress, patient knowledge about psoriasis, and patient satisfaction were also assessed. Follow-up evaluations were performed at 3, 6, and 12 months. RESULTS: A total 142 patients formed the intention-to-treat population: 70 in the control group and 72 in the intervention group. Skindex component scores and the PASI were significantly lower at 3, 6, and 12 months as compared to baseline in both groups, but no significant differences were found between the groups. Knowledge about psoriasis improved significantly during follow-up amongst patients from the intervention group compared to controls (68% of correct answers vs. 56%; p < 0.01). Patient satisfaction with psoriasis management and treatment was also better in the intervention group. CONCLUSIONS: The standardised education programme did not improve HRQoL and disease severity in psoriasis, but led to a significant improvement in patient knowledge about the disease and increased patient satisfaction.

Multiple sclerosis: Is there a risk of worsening after yellow fever vaccination?

BACKGROUND: Yellow fever vaccine (YFV) is not advised for multiple sclerosis (MS) patients because of the potential risk of post-vaccine relapses. OBJECTIVE: To assess the risk of relapsing-remitting multiple sclerosis (RR-MS) worsening after YFV. METHODS: Non-interventional observational retrospective, exposed/non-exposed cohort study nested in the French national cohort including MS. RESULTS: 128 RR-MS were included. The 1-year annualized relapse rate (ARR) following YFV did not differ between exposed: 0.219 (0.420) and non-exposed subjects: 0.208 (0.521) (p = 0.92). Time to first relapse was not different between groups (adjusted hazard ratio (HR) = 1.33; 95% confidence interval (CI) = 0.53-3.30, p = 0.54). CONCLUSION: These results suggest that YFV does not worsen the course of RR-MS.

IL-1ß induces thymic stromal lymphopoietin and an atopic dermatitis-like phenotype in reconstructed healthy human epidermis.

Atopic dermatitis (AD) is a common skin inflammatory disease characterized by the production of thymic stromal lymphopoietin (TSLP) and marked TH 2 polarization. Recent studies suggest that IL-1ß contributes to the development of AD skin inflammation. Here, we have investigated the impact of IL-1ß signalling on the epidermal homeostasis of both healthy subjects and AD patients [with functional filaggrin (FLG) alleles], with particular attention to TSLP production and keratinocyte differentiation. In healthy reconstructed human epidermis (RHE), IL-1ß promoted (i) robust secretion of TSLP in an NF-κB-dependent manner and (ii) a significant decrease in the expression of filaggrin and other proteins of the epidermal differentiation complex. These effects were prevented by treatment of RHE with the anti-IL-1ß mAb canakinumab and by the IL-1 receptor antagonist anakinra. Interestingly, RHE generated from AD donors behaved like that of healthy individuals and showed comparable responses to IL-1ß signals. Collectively, our results suggest that IL-1ß may be an early key mediator for the acquisition of an AD phenotype through induction of TSLP and alteration of the epidermal homeostasis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

High Rate of Acquisition but Short Duration of Carriage of Multidrug-Resistant Enterobacteriaceae After Travel to the Tropics.

BACKGROUND: Multidrug-resistant Enterobacteriaceae (MRE) are widespread in the community, especially in tropical regions. Travelers are at risk of acquiring MRE in these regions, but the precise extent of the problem is not known. METHODS: From February 2012 to April 2013, travelers attending 6 international vaccination centers in the Paris area prior to traveling to tropical regions were asked to provide a fecal sample before and after their trip. Those found to have acquired MRE were asked to send fecal samples 1, 2, 3, 6, and 12 months after their return, or until MRE was no longer detected. The fecal relative abundance of MRE among all Enterobacteriaceae was determined in each carrier. RESULTS: Among 824 participating travelers, 574 provided fecal samples before and after travel and were not MRE carriers before departure. Of these, 292 (50.9%) acquired an average of 1.8 MRE. Three travelers (0.5%) acquired carbapenemase-producing Enterobacteriaceae. The acquisition rate was higher in Asia (142/196 [72.4%]) than in sub-Saharan Africa (93/195 [47.7%]) or Latin America (57/183 [31.1%]). MRE acquisition was associated with the type of travel, diarrhea, and exposure to ß-lactams during the travel. Three months after return, 4.7% of the travelers carried MRE. Carriage lasted longer in travelers returning from Asia and in travelers with a high relative abundance of MRE at return. CONCLUSIONS: MRE acquisition is very frequent among travelers to tropical regions. Travel to these regions should be considered a risk factor of MRE carriage during the first 3 months after return, but not beyond. CLINICAL TRIALS REGISTRATION: NCT01526187.

[Current immunizations for travelers]. / Actualité des vaccinations du voyageur.

The recommendations on travelers' immunizations are regularly evolving in accordance with the data of clinical studies and the epidemiological situation in the world. The recent changes concern the schedule of injections: primovaccination DTCaPolio of children and boosters for adults, accelerated schedule of Japanese encephalitis and hepatitis B immunization, preexposure rabies immunization and vaccination against yellow fever; and the indications of poliomyelitis vaccine, immunization of children against Japanese encephalitis and conjugated vaccines against meningococcal meningitis.

Treatment of Severe Palmoplantar Pustular Psoriasis With Bimekizumab.

Importance: Palmoplantar pustulosis (PPP) and palmoplantar plaque psoriasis with pustules remain challenging to treat. Studies suggest that an interleukin 17 or interleukin 36 loop acts synergistically in these diseases to induce palmoplantar pustules. Objective: To assess the effectiveness of bimekizumab in treating PPP and palmoplantar plaque psoriasis with pustules. Design, Setting, and Participants: This case series involved 21 adults with PPP (11 patients) or palmoplantar plaque psoriasis with pustules (10 patients) treated at 1 of 7 tertiary dermatological centers in France from September 2022 through June 2023. All patients treated with bimekizumab for at least 3 months were included in the analyses. Main Outcomes and Measures: The main outcome was the posttreatment Investigator Global Assessment (IGA), scored as 0 (complete clearance), 1 (almost clear), 2 (mild), 3 (moderate), or 4 (severe). When relevant, evolution of joint pain and nail involvement was reported. Tolerance and potential adverse events were noted. Results: A total of 21 patients (mean [range] age, 46 [24-68] years; 19 females) were included. Eleven patients had isolated PPP, and 10 had palmoplantar plaque psoriasis with pustules. All of them, except 2 who received bimekizumab as first systemic therapy, had not responded to at least 1 systemic treatment (median [range], 3 [1-7] treatments), and/or had adverse events leading to the discontinuation of the treatment. Complete clearance (IGA score, 0) was achieved by 17 patients in 1 to 4 months. Three patients achieved an IGA score of 1, and 1 achieved an IGA score of 2. Three patients with PPP also presented with acrodermatitis continua of Hallopeau. Nail involvement showed 50% to 70% improvement after 4 to 6 months of bimekizumab treatment for these 3 patients. Two patients had SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome; both had complete clearance of skin lesions associated with joint pain improvement. Four patients (19%) with candidiasis were successfully treated with oral antifungal agents. None of the patients had to stop bimekizumab treatment due to adverse events. Conclusions and Relevance: The findings of this case series suggest that bimekizumab could be an appealing approach for treating PPP, palmoplantar plaque psoriasis with pustules, and SAPHO syndrome. Prospective randomized placebo-controlled clinical trials are needed to confirm these encouraging initial results.

International eDelphi Study to Reach Consensus on the Methotrexate Dosing Regimen in Patients With Psoriasis.

Importance: A clear dosing regimen for methotrexate in psoriasis is lacking, and this might lead to a suboptimal treatment. Because methotrexate is affordable and globally available, a uniform dosing regimen could potentially optimize the treatment of patients with psoriasis worldwide. Objective: To reach international consensus among psoriasis experts on a uniform dosing regimen for treatment with methotrexate in adult and pediatric patients with psoriasis and identify potential future research topics. Design, Setting, and Participants: Between September 2020 and March 2021, a survey study with a modified eDelphi procedure that was developed and distributed by the Amsterdam University Medical Center and completed by 180 participants worldwide (55 [30.6%] resided in non-Western countries) was conducted in 3 rounds. The proposals on which no consensus was reached were discussed in a conference meeting (June 2021). Participants voted on 21 proposals with a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree) and were recruited through the Skin Inflammation and Psoriasis International Network and European Academy of Dermatology and Venereology in June 2020. Apart from being a dermatologist/dermatology resident, there were no specific criteria for participation in the survey. The participants worked mainly at a university hospital (97 [53.9%]) and were experienced in treating patients with psoriasis with methotrexate (163 [91.6%] had more than 10 years of experience). Main Outcomes and Measures: In a survey with eDelphi procedure, we tried to reach consensus on 21 proposals. Consensus was defined as less than 15% voting disagree (1-3). For the consensus meeting, consensus was defined as less than 30% voting disagree. Results: Of 251 participants, 180 (71.7%) completed all 3 survey rounds, and 58 participants (23.1%) joined the conference meeting. Consensus was achieved on 11 proposals in round 1, 3 proposals in round 2, and 2 proposals in round 3. In the consensus meeting, consensus was achieved on 4 proposals. More research is needed, especially for the proposals on folic acid and the dosing of methotrexate for treating subpopulations such as children and vulnerable patients. Conclusions and Relevance: In this eDelphi consensus study, consensus was reached on 20 of 21 proposals involving methotrexate dosing in patients with psoriasis. This consensus may potentially be used to harmonize the treatment with methotrexate in patients with psoriasis.

Psoriasis is a disease of the entire skin: non-lesional skin displays a prepsoriasis phenotype.

Psoriasis is a multifactorial skin pathology resulting from genetic susceptibility and environmental triggers that lead to epidermal and immune dysfunction. There is now strong evidence that non-lesional (NL) psoriatic skin, despite its normal appearance, represents an intermediate state between healthy and lesional skin. Changes observed in NL skin mainly affect the skin barrier, keratinocytes, innate and adaptive immune responses, the microbiota and neurogenic tissue innervation. Several epidermal barrier defects are commonly observed in NL skin compared to healthy skin, including an elevated pH, delayed barrier function repair after injury and lower expression of epidermal differentiation complex proteins. NL keratinocytes also show a predisposition for activation and proliferation, and an increased sensitivity to cytokine or microbial triggers, probably linked to their unique transcriptome and proteome, associated with their intermediate state between healthy and lesional cells. In addition, the accumulation of pathogenic IL-17-producing resident memory T cells, which can (re)instigate the formation of new lesions, characterises both the NL and never-lesional skin of patients with psoriasis. Although the contribution of NL skin dysbiosis to psoriasis pathophysiology remains to be clarified, the expression of numerous pruritogenic mediators appears to be involved in disease progression due to an iterative itch-scratch cycle. In summary, the NL skin of patients with psoriasis exhibits numerous hallmarks of dormant psoriasis. The fact that these alterations are mostly located in the epidermis suggests that they are readily accessible to topical treatments, which could prevent the recurrence/spread of this chronic disease.

Tolerance of oat-based topical products in cereal-sensitized adults with atopic dermatitis.

BACKGROUND: Few data suggest oat-based cosmetics may cause allergic reactions in atopic subjects, especially when sensitized to cereals. OBJECTIVES: To evaluate the risk of immediate and delayed allergic reactions to repeated and maximized applications (RMA) of oat-containing cosmetics and oat extracts and their tolerance in cereal-sensitized atopic adults. METHODS: Open-label pilot study in 12 cereal-sensitized atopic adults over 45 days. Open tests and RMA were performed with Rhealba oat-containing cosmetics at day 0 (D0) and D10, and from D10 to D31. Patch and prick tests were performed at D7 and D42 with wheat and Rhealba oat extracts and the study cream. RESULTS: The RMA of oat-based cosmetics in cereal-sensitized atopic adults did not induce any immediate or delayed allergic reaction and was well tolerated. No immediate or delayed positive skin test to oat extracts was observed. CONCLUSION: Sensitization to cereals does not increase the risk of allergic reactions to oat-containing cosmetics.

Antibodies to tetanus, diphtheria and pertussis among healthy adults vaccinated according to the French vaccination recommendations.

In this sero-epidemiological study, we investigated humoral immunity to three vaccine-preventable diseases--tetanus, diphtheria and pertussis--among 331 adults (aged 18-60 years) attending vaccination centres for travellers and who had been vaccinated according to national recommendations in France. Serological results showed that the percentage of subjects with antibodies to diphtheria and tetanus decreases with age. Results also confirmed surveillance data on vaccination in France, with 7.6% of the study population (13.4% of those aged 18-29 years) having recently acquired a pertussis infection. These results confirm the importance of following French recommendations for regular boosters for tetanus and diphtheria among adults. They also indicate the need for better implementation of the current recommendations for pertussis-vaccine boosters in adults.

Methotrexate Versus Cyclosporine in Adults with Moderate-to-Severe Atopic Dermatitis: A Phase III Randomized Noninferiority Trial.

BACKGROUND: Methotrexate is currently used to treat atopic dermatitis but has never been assessed versus cyclosporine in adults. OBJECTIVE: This study evaluated the efficacy and safety of methotrexate versus cyclosporine in patients with moderate-to-severe atopic dermatitis. METHODS: Patients were randomized to receive either oral methotrexate (15 mg/wk) or cyclosporine (2.5 mg/kg/d) for 8 weeks. The primary end point was a patient achieving 50% improvement in the SCORing Atopic Dermatitis index (SCORAD 50) at week 8. When the primary end point was not achieved, methotrexate was increased to 25 mg and cyclosporine to 5 mg during the next 16 weeks. The secondary end points were a patient achieving a 50% reduction in the Eczema Area Severity Intensity index (EASI 50) and SCORAD 50 at each visit (ClinicalTrials.gov no. NCT00809172). RESULTS: A total of 97 patients received methotrexate 15 mg (n = 50) or cyclosporine 2.5 mg (n = 47). Regarding the primary end point at week 8, methotrexate was inferior to cyclosporine because the proportion of patients with SCORAD 50 was 8% (4 of 50) in the methotrexate arm versus 42% (18 of 43) in the cyclosporine arm. The difference in percentages for the 2 treatment groups (2-sided 90% CI) was -34% (-48% to -20%). At week 8, methotrexate and cyclosporine dosages were increased in 56% and 49% of the patients, respectively. Regarding EASI 50, the noninferiority end point was reached at week 20 in 92% (22 of 24) of patients in the methotrexate arm and 87% (26 of 30) of patients in the cyclosporine arm. The treatment-related adverse events were more frequent with cyclosporine (P < .0001). CONCLUSIONS: Methotrexate 15 mg/wk was inferior to cyclosporine 2.5 mg/kg/d at week 8. Increasing the doses of methotrexate to 25 mg/wk induced a significant improvement versus cyclosporine at week 20.

CHRONOVAC VOYAGEUR: A study of the immune response to yellow fever vaccine among infants previously immunized against measles.

For administration of multiple live attenuated vaccines, the Advisory Committee on Immunization Practices recommends either simultaneous immunization or period of at least 28days between vaccines, due to a possible reduction in the immune response to either vaccine. The main objective of this study was to compare the immune response to measles (alone or combined with mumps and rubella) and yellow fever vaccines among infants aged 6-24months living in a yellow fever non-endemic country who had receivedmeasles and yellow fever vaccines before travelling to a yellow fever endemic area. SUBJECTS AND METHODS: A retrospective, multicenter case-control study was carried out in 7 travel clinics in the Paris area from February 1st 2011 to march 31, 2015. Cases were defined as infants immunized with the yellow fever vaccine and with the measles vaccine, either alone or in combination with mumps and rubella vaccine, with a period of 1-27days between each immunization. For each case, two controls were matched based on sex and age: a first control group (control 1) was defined as infants having received the measles vaccine and the yellow fever vaccine simultaneously; a second control group (control 2) was defined as infants who had a period of more than 27days between receiving the measles vaccine and yellow fever vaccine. The primary endpoint of the study was the percentage of infants with protective immunity against yellow fever, measured by the titer of neutralizing antibodies in a venous blood sample. RESULTS: One hundred and thirty-one infants were included in the study (62 cases, 50 infants in control 1 and 19 infants in control 2). Of these, 127 (96%) were shown to have a protective titer of yellow fever antibodies. All 4 infants without a protective titer of yellow fever antibodies were part of control group 1. DISCUSSION: The measles vaccine, alone or combined with mumps and rubella vaccines, appears to have no influence on humoral immune response to the yellow fever vaccine when administered between 1 and 27days. The absence of protective antibodies against yellow fever was observed only among infants who received both vaccines simultaneously. CONCLUSION: These results may support a revision of current vaccination recommendations concerning the administration of these two live attenuated vaccines either on the same day or at least 28days apart. Our findings show no statistically significant difference if the interval between both vaccines is more than 24 h, but the immune response seems to be reduced when the two vaccines are given at the same time.

Measles virus infection of human keratinocytes: Possible link between measles and atopic dermatitis.

BACKGROUND: Measles virus (MV) infection is marked with a skin rash in the acute phase of the disease, which pathogenesis remains poorly understood. Moreover, the association between measles and progression of skin diseases, such as atopic dermatitis (AD), is still elusive. OBJECTIVE: We have thus analysed the susceptibility of human keratinocytes to MV infection and explore the potential relationship between MV vaccination and the pathogenesis the AD. METHODS: We performed immunovirological characterisation of MV infection in human keratinocytes and then tested the effect of live attenuated measles vaccine on the progression of AD in adult patients, in a prospective, double-blind study. RESULTS: We showed that both human primary keratinocytes and the keratinocyte cell line HaCaT express MV receptors and could be infected by MV. The infection significantly modulated the expression of several keratinocyte-produced cytokines, known to be implicated in the pathogenesis of inflammatory allergic diseases, including AD. We then analysed the relationship between exposure to MV by vaccination and the progression of AD in 20 adults during six weeks. We found a significant decrease in CCL26 and thymic stromal lymphopoietin (TSLP) mRNA in biopsies from acute lesions of vaccinated patients, suggesting MV-induced modulation of skin cytokine expression. Clinical analysis revealed a transient improvement of SCORAD index in vaccinated compared to placebo-treated patients, two weeks after vaccination. CONCLUSIONS: Altogether, these results clearly demonstrate that keratinocytes are susceptible to MV infection, which could consequently modulate their cytokine production, resulting with a beneficial effect in the progression of AD. This study provides thus a proof of concept for the vaccination therapy in AD and may open new avenues for the development of novel strategies in the treatment of this allergic disease.

Absence of efficacy of nonviable Lactobacillus acidophilus for the prevention of traveler's diarrhea: a randomized, double-blind, controlled study.

BACKGROUND: Diarrhea is the most common illness associated with international tourism. We evaluated the efficacy of a probiotic preparation of nonviable Lactobacillus acidophilus (hereafter referred to as LA) for the prevention of traveler's diarrhea. METHODS: We conducted a randomized, double-blind, controlled trial. Travelers were randomized to receive either LA or placebo twice daily from 1 day before their departure to 3 days after their return. On each day of the trip and the week following the return, travelers had to record the number and consistency of stools and their adherence to the treatment. Diarrhea was defined as > or =3 unformed stools in a 24-h period. RESULTS: From January 2001 to September 2004, a total of 174 subjects were randomized to each treatment group. Half of the travelers went to West Africa, and organized tours or backpacking were the most common modes of traveling. The incidence of diarrhea did not differ between the 2 groups; it was 61.4 cases per 100 person-months in the LA group (95% confidence interval [CI], 44.1-85.5) and 43.4 cases per 100 person-months in the placebo group (95% CI, 30.0-62.9) (P=.14). Adjustment for travel duration and other variables did not reveal any difference between the 2 groups (adjusted hazard ratios comparing the LA and placebo groups were 1.43 [95% CI, 0.87-2.36] in an intent-to-treat analysis and 1.38 [95% CI, 0.79-2.39] in an efficacy analysis). CONCLUSIONS: There was no beneficial effect of treatment with LA for the prevention of travelers' diarrhea. More studies are required to assess the efficacy of other specific probiotics (e.g., a Lactobacillus rhamnosus GG preparation) for preventing traveler's diarrhea.

Improvement of atopic dermatitis skin symptoms by Vitreoscilla filiformis bacterial extract.

Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease. The first line treatment of AD relies on the daily use of emollients to restore the skin barrier impairment associated with the disease. Vitreoscilla filiformis (V.f.) is a non photosynthetic bacterium and extracts of V.f. are endowed with properties which balance cutaneous immune-homeostasis. The aim of our study was to investigate the efficacy and safety of a 5% V.f. extract-containing ointment on mild to moderate AD in a randomised, double-blind, vehicle-controlled trial. Thirteen patients applied the treatment and the vehicle on symmetrical AD lesions (left versus right side of the body) twice daily for 4 weeks. The assessment of AD severity was done at each visit (Day 0, Day 14 and Day 28) using the modified eczema area and severity index (mEASI). Treatment with the ointment containing 5% V.f. extract significantly improved the AD skin symptoms. Beneficial effects were observed after two weeks of treatment and increased thereafter. These results suggest that V.f. extract could be favourably added to AD skin care emollients formulated for AD.

Methotrexate for the treatment of adult atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease mediated by allergen-specific T cells which are recruited and activated in lesional skin. Methotrexate (MTX) is an old systemic agent used at low dosage for the treatment of psoriasis, another T cell-mediated skin disorder. Since MTX has been shown to improve the clinical symptoms of eczema in a model of antigen-specific dermatitis in mice, we postulated that it could be an effective treatment of AD. In the present open retrospective study, we report our results on the treatment of moderate to severe AD by MTX. Twenty patients (17 to 68-years-old) with low responses to routine therapies were treated (three months to 2 1/2 years) with a weekly dose of MTX ranging from 7.5 to 25 mg. The evaluation was made on physician's global assessment after 3 months of MTX use, and showed that 75% (15/20) of patients improved after 3 months of MTX use, among which 13/20 with an improvement>70%. The beginning of improvement was observed between the fourth and the eighth week after MTX was initiated. Tolerance was good. However, nausea and increase of liver enzymes were observed in 5 patients and required discontinuation of MTX in 2 patients. In conclusion, MTX seems to be an effective and safe treatment of AD. Placebo-controlled clinical trials are needed to confirm our observations and to define more precisely the effectiveness and safety of MTX in adult AD.