This study, named “PSOTHERMES” (trial registration: NCT02098213), was a multicenter, controlled, parallel group, open-label randomized trial, with an immediate intervention—delayed intervention methodology. Patients with plaque psoriasis were randomized to the intervention group (spa treatment within 45 days of inclusion), or to the control group (spa treatment starting at least 4.5 months after the inclusion visit and after assessment of the primary endpoint).
The study was conducted in France between January 2015 and November 2018. A French ethics committee (CPP “Sud-Ouest et Outre Mer III” 2013) approved the study and informed written consent was obtained from all patients.
The 15 investigators involved in inclusion and assessment procedures were dermatologists in hospital or private practice, independent of the spa therapy centers, who had been recruited mainly through the French Psoriasis Research Group (GRPso).
Study population, inclusion criteria, and assessment procedures
Inclusion criteria were as follows: patients over 18 years old, plaque psoriasis of more than 1-year duration, diagnosed by a dermatologist, Dermatology Life Quality Index (DLQI) score > 10, and stable treatment in the last 6 months. The patient had to be available for 3-week course of spa therapy within 45 days of inclusion and 4.5 months after inclusion according to randomization, and to attend 4 follow-up visits over 12 months.
The main non-inclusion criteria were phototherapy in the last 3 months; guttate, pustular or erythrodermic psoriasis, or isolated nail psoriasis; any contraindication to hydrotherapy (immune deficiency, progressive heart disease, progressive neoplasia, a contagious infectious disease, unhealed skin lesions); foreseeable intolerance of spa therapy (intolerance to heat, baths, swimming pools, etc.); pregnancy or breast feeding; psychiatric illness that would preclude study compliance; and recent spa therapy in the current spa resort season. All ongoing treatments were permitted by the protocol.
We recruited potential participants among the investigators’ patients, and also through the press, social networks, and the French Psoriasis Association. A first phase of screening was carried out by telephone by the coordination center to provide information about the study and to verify the individual’s eligibility. Randomization was centralized and electronic, through the e-CRF website.
For each participant, the study lasted 12 months, with clinical evaluations at the inclusion visit, at 4.5, 6, 9, and 12 months. At each visit, the data from a clinical examination and ongoing treatments were recorded and the participant filled in several questionnaires—DLQI (Basra et al. 2008), EuroQol, VQ-Dermato (Grob et al. 1999), and Perceived Stress Scale (PSS) (Cohen et al. 1983)—and indicated their level of pain and pruritus on a visual analogue scale (VAS).
The participants received psoriasis spa therapy in the establishment of their choice among the five French spa therapy centers participating in the study: La Roche Posay, Uriage, Saint-Gervais, Avène, and Molitg-Les-Bains. The composition of the natural thermal mineral waters differed in their composition from one center to another.
The immediate spa therapy group (hereafter called the “intervention group”) was requested to attend a 3-week course of spa therapy at focused on dermatology within 45 days after inclusion, while the control group received usual patient care until the visit at 4.5 months, then attended a 3-week course of dermatology-oriented spa therapy.
Procedures during the spa therapy were the subject of a prior consensus between the 5 participating thermal spa centers. The 18-day dermatology-oriented course of spa therapy was centered around the following 4 treatments (carried out daily): a filiform shower (water pressure of 4 to 15 bars), followed by balneotherapy in a pool (simple or bubbling bath for 20 min), full body and facial sprays (5 to 10 min), and localized treatment (bath, spray, showers, etc.) depending on the center. In addition to these treatments, participants attended two workshops per week: “relaxation or sophrology” and “hygiene and hydration.”
Outcome measures assessments
The primary outcome measure was QoL specific to dermatology assessed through the DLQI score at 4.5-month post-randomization. In brief, DLQI evaluates the overall impact of skin disease on patients. It has 10 questions; the total score can range from 0 (no repercussions) to 30 (significant deterioration in quality of life) and 10 is the threshold at which there is a very large effect on QoL.12 Success was defined as a DLQI score at 4.5 months of ≤ 10.
The secondary outcome measures were as follows: change in the QoL specific to dermatology assessed by the evolution of the DLQI score; the proportion of patients with a DLQI ≤ 5 and the proportion of patients with a French-validated VQ-Dermato score (Grob et al. 1999) ≤ 35; any improvement in overall QoL assessed using the EQ5D-3L questionnaire; effect clinical improvement in psoriasis, assessed using the PASI score; evaluation of pain and pruritus via VAS completed by the patient. To evaluate patients’ medical care, we collected psoriasis treatments, hospitalizations, specialist consultations, and the evolution of overall metabolism indicators by measuring waist circumference, body mass index (BMI), and blood pressure; and an evaluation of the side effects of spa therapy according to the usual pharmacovigilance criteria. Investigators evaluated all these secondary endpoints at the inclusion, 4.5-, 6-, 9-, and 12-month visits.
Sample size calculation
The initial hypothesis was a proportion of patients with DLQI ≤ 10 of 25% at 4.5 months in the intervention (immediate spa therapy) group versus 10% in the control-delayed group. We thus planned to include 130 patients per group, or 260 in total, with an alpha risk of 0.05 and power of 80%.
Given the uncertainties relating to these hypotheses, the protocol provided for a reassessment of the number of subjects required after the first 100 inclusions, without an intermediate analysis. The success rate observed when reassessing the number of subjects required was 54% (both groups combined). With an alpha of 5% and a power of 80%, the number of subjects required would thus have been 49 patients per group, or 98 in total. When this number of patients was reached, it was nevertheless decided to continue inclusions until the end of the spa season to take into account of patients being lost to follow-up.
Statistical analysis was in intention to treat. We present qualitative variables using number and frequency; and mean and standard deviation; or median and IQR (25th and 75th percentiles) for continuous variables, according to the distribution of the data, as well as the minimum and maximum values. We compared the success rate in the two groups using a Chi2 test. The relative risk (RR) of success with its 95% confidence interval (95% CI), the number needed to treat (NNT), and the effect size are also presented.
To analyze the change over time (M0–M4.5) of the quantitative secondary endpoints, we used a mixed model with analysis of the time*treatment interaction.
For qualitative secondary endpoints, we use the Chi2 test to compare the two groups at 4.5 months (if the conditions of application were met, otherwise Fisher’s exact test).
The statistical tests are carried out with a type one risk of error (alpha) of 5%.
Statistical analysis was performed after database lock using Stata 15.0 software (StataCorp, College Station, Texas).
More details can be found in the online supplementary material.