New and Emerging Treatments for Generalized Pustular Psoriasis: Focus on IL-36 Receptor Inhibitors.

Generalized Pustular Psoriasis (GPP) is a rare and severe subtype of psoriasis that significantly impacts patients' quality of life. Until recently, no specific treatment modalities were available, and treatment for GPP followed the guidelines for the treatment of plaque psoriasis, consisting of conventional treatments, such as retinoids, methotrexate, and even biologics, which although effective in some cases, may be associated with significant side effects, necessitating more effective and safe options. The pathophysiology of Generalized Pustular Psoriasis is complex and not fully understood, but there is some overlap with the pathogenesis of Plaque Psoriasis. In GPP, the innate immune system seems to play a more significant role, with the interleukin (IL)-36 pathway being fundamentally involved. Spesolimab and imsidolimab, two recently developed therapeutic agents, target the IL-36 inflammatory pathway by binding to the IL-36 receptor (IL-36R). Both biologics have already been evaluated in phase 1 and 2 clinical trials and have shown promising results in terms of safety and efficacy. IL-36 receptor inhibitors demonstrated great efficacy and good safety profile in the management of patients with GPP, demonstrating their potential to emerge as a leading treatment option. This review aims to explore and summarize the current scientific literature on the most recently developed treatments for GPP.

Dupilumab in Patients with Atopic Dermatitis: A Multicentric, Long-Term, Real-World Portuguese Study.

INTRODUCTION: Several clinical trials have established the efficacy and safety of dupilumab for treating atopic dermatitis (AD). However, literature remains scarce in reporting the long-term effectiveness, safety, and drug survival of dupilumab in real-world settings. This study aimed to describe the latter outcomes of dupilumab in patients with AD. METHODS: This Portuguese, multicentric, observational, retrospective study included consecutive adult patients with AD who initiated dupilumab between January 2019 and September 2023, with a follow-up period up to 30 months. Drug discontinuation and adverse effects data were used to estimate drug survival. Clinical assessments included the Eczema Area and Severity Index (EASI), pruritus numerical rating scale (NRS), and Dermatology Life Quality Index (DLQI). RESULTS: A total of 312 patients were included in the study, with 56.4% being male (median age of 30 years, range 18-83). The 30-month drug survival rate was 82.0%. During the study period, 12.5% of the sample (n = 39 patients) discontinued treatment: 7.3% due to treatment failure, 2.9% due to safety concerns, 1.3% due to complete disease control, 0.6% due to pregnancy, and 0.3% due to lack of compliance. Adverse events not leading to drug discontinuation were noted in 25.6% of the sample (n = 80). Conjunctivitis was the most frequently reported adverse event (17%), followed by facial erythema (9%). At 30 months, the mean EASI decreased significantly from 27.30 ± 11.89 at baseline to 2.92 ± 3.96 (p < 0.001), reflecting an overall improvement of 89.3%. Similarly, pruritus NRS decreased from 7.36 ± 1.90 at baseline to 1.74 ± 2.16 at month 30 (p < 0.001), improving by 76.4%, and mean DLQI changed from 18.0 ± 7.09 at baseline to 2.67 ± 3.95 at month 30 (p < 0.001), decreasing by 85.2%. CONCLUSIONS: This study increases our current understanding of dupilumab in real-world settings, demonstrating its long-term effectiveness and safety in treating AD.

Age affects drug survival rates of interleukin (IL)-17 and IL-23 inhibitors in patients with plaque psoriasis: Results from a retrospective, multicentric, multi-country, cohort study.

BACKGROUND: Scarce data related to the drug survival of biologic agents in psoriasis patients aged ≥65 years is available. OBJECTIVES: To evaluate the drug survival of interleukin (IL)-23 or the IL-17 inhibitors approved for the treatment of moderate-to-severe psoriasis in elderly patients (aged ≥65 years), compared with younger adult patients (aged <65 years), and to identify clinical predictors that can influence the drug survival. METHODS: This retrospective multicentric cohort study included adult patients with moderate-to-severe psoriasis, dissecting two-patient subcohorts based on age: elderly versus younger adults. Kaplan-Meier estimator and proportional hazard Cox regression models were used for drug survival analysis. RESULTS: We included 4178 patients and 4866 treatment courses; 934 were elderly (1072 treatment courses), and 3244 were younger patients (3794 treatment courses). Drug survival, considering all causes of interruption, was higher in patients aged <65 years than in elderly patients overall (log-rank p < 0.006). This difference was significant for treatment courses involving IL-23 inhibitors (p < 0.001) but not for those with IL-17 inhibitors (p = 0.2). According to both uni- and multi-variable models, elder age was associated with an increased risk of treatment discontinuation (univariable analysis: HR: 1.229, 95% CI 1.062-1.422; p < 0.006; multivariable analysis: HR: 1.199, 95% CI 1.010-1.422; p = 0.0377). Anti-IL-23 agents were associated with a reduced likelihood of treatment discontinuation after adjusting for other variables (HR: 0.520, 95% CI 0.368-0.735; p < 0.001). Being previously treated with IL-17 inhibitors increased the probability of discontinuation. CONCLUSION: Elderly patients with psoriasis have an increased risk of biologic treatment discontinuation compared with younger adult patients, particularly, if being treated with IL-23 inhibitors. However, in stratified analyses conducted in elderly patients, IL-23 inhibitors showed higher drug survival rates than IL-17 inhibitors.

Lebrikizumab Improves Quality of Life and Patient-Reported Symptoms of Anxiety and Depression in Patients with Moderate-to-Severe Atopic Dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease for which signs and symptoms have a negative impact on a patient's quality of life (QoL) and mental health. Here, we assess the impact of lebrikizumab on QoL and mental health after 16 weeks of treatment in patients with moderate-to-severe AD. METHODS: Data were analyzed over 16 weeks from two separate phase 3, randomized, placebo-controlled, monotherapy trials (ADvocate1 and ADvocate2). Patient-reported outcomes were assessed using the following measures: Dermatology Life Quality Index (DLQI), EQ-5D-5L visual analogue scale (VAS), EQ-5D-5L index scores (UK and US), Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, and PROMIS Depression. RESULTS: Treatment with lebrikizumab 250 mg every 2 weeks in two studies led to statistically significant improvements (based on nominal p values) versus placebo in DLQI since week 4 (the first timepoint assessed) for the following measures: change from baseline in DLQI total score (ADvocate1 - 7.8 vs - 2.8; ADvocate2 - 7.3 vs - 3.9), proportion of patients with DLQI ≥ 4-point improvement (ADvocate1 69.5% vs 36.2%; ADvocate2 60.5% vs 42.6%), DLQI total score ≤ 5 (ADvocate1 36.7% vs 8.8%; ADvocate2 29.6% vs 10.8%), and DLQI (0, 1) (ADvocate1 12.3% vs 1.7%; ADvocate2 9.2% vs 1.7%). Improvements in DLQI measures, EQ-5D-5L index scores (UK and US), and EQ-5D-5L VAS were sustained through week 16. Additionally, lebrikizumab improved PROMIS Anxiety and PROMIS Depression scores, and improvements were higher in patients with at least a mild score (≥ 55) versus placebo for PROMIS Anxiety (ADvocate1 - 7.43 vs - 1.51; ADvocate2 - 4.95 vs - 0.82) and PROMIS Depression (ADvocate1 - 7.42 vs - 2.46; ADvocate2 - 4.28 vs - 2.00). CONCLUSIONS: Treatment with monotherapy 250 mg lebrikizumab for 16 weeks provided clinically meaningful improvements in outcomes related to QoL and mental health for patients with moderate-to-severe AD. Lebrikizumab-treated patients reported improvements in DLQI as early as week 4, the first measure since baseline. TRIAL REGISTRATION: ClinicalTrials.gov Registration NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2).

Clinical course and disease burden of patients with generalized pustular psoriasis in Portugal: a multicenter retrospective cohort study.

OBJECTIVES: Generalized pustular psoriasis (GPP) is a rare, life-threatening skin inflammatory disorder. This study aimed to describe the disease course, treatment strategies, and healthcare utilization among patients with GPP in Portugal. METHODS: This multicentric, observational, retrospective study included consecutive adult patients with GPP undergoing a dermatology evaluation in different reporting institutions by experienced dermatologists between 2002 and 2023. RESULTS: A total of 59 patients were assessed. Most of the cohort had a previous history of plaque psoriasis (71%) and 83% presented at least one comorbidity. At the initial encounter, 64% of the cohort needed hospitalization. Systemic involvement was common, including fever (37%), and elevated white blood cell count and erythrocyte sedimentation rate/C-reactive protein (49%). Nearly, 73% of patients initiated systemic drugs, and 70% had to discontinue the first treatment. During the study, 98% of patients experienced at least one flare. At the last visit, 3.4% of patients had died, and 71.2% exhibited signs of active disease despite undergoing treatment. CONCLUSIONS: Our study demonstrates that GPP is a chronic, debilitating condition associated with systemic involvement, frequent flares, and hospitalizations, despite receiving multiple systemic treatments. Improved disease awareness and new treatments are needed to improve patient care and decrease the burden of the disease.

Matching-Adjusted Indirect Comparison of the Efficacy at Week 32 of Tralokinumab and Dupilumab in the Treatment of Moderate-to-Severe Atopic Dermatitis.

INTRODUCTION: Tralokinumab and dupilumab are biological agents licensed for the treatment of moderate-to-severe atopic dermatitis (AD) in adult patients who are candidates for systemic treatment. However, no head-to-head studies of their efficacy have been conducted. This study indirectly compared the efficacy of tralokinumab and dupilumab, both in combination with topical corticosteroids (TCS), at week 32. METHODS: An unanchored matching-adjusted indirect comparison was conducted using individual patient data (IPD) from the ECZTRA 3 tralokinumab trial and aggregate data from the LIBERTY AD CHRONOS dupilumab trial. IPD were selected by applying inclusion criteria from LIBERTY AD CHRONOS and weighting to match summary baseline characteristics-age, sex, race, body mass index, disease duration, Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), Dermatology Life Quality Index (DLQI) and SCORing Atopic Dermatitis index-of patients treated with dupilumab. Week 32 outcomes of interest were 50%, 75% or 90% improvements in EASI (EASI-50, EASI-75 and EASI-90), IGA scores of 0 or 1 (IGA 0/1), ≥ 4-point improvement in worst daily pruritus numerical rating scale (NRS) score, and mean improvements in DLQI and the Patient Oriented Eczema Measure (POEM). RESULTS: After matching, tralokinumab and dupilumab, both in combination with TCS, showed similar efficacy across clinical response endpoints at week 32 (IGA 0/1, tralokinumab 49.9% vs dupilumab 39.3%; EASI-50, 78.9% vs 77.5%; EASI-75, 71.5% vs 71.9%; EASI-90, 53.3% vs 56.2%). The mean change from baseline in DLQI was statistically significantly larger in the matched tralokinumab plus TCS population than in the dupilumab plus TCS arm (- 12.1 vs - 10.4, p = 0.005). Changes in POEM and worst daily pruritus NRS were similar in the two groups. CONCLUSION: The results of this analysis demonstrate that, in combination with TCS, tralokinumab and dupilumab have similar efficacy in the treatment of moderate-to-severe AD at 32 weeks of therapy.

Burden of atopic dermatitis in Europe: A population-centred approach leveraging web search data in 21 European countries.

BACKGROUND: The complexity, high prevalence, and substantial personal and socioeconomic burden collectively render atopic dermatitis (AD) a major public health concern. Using crowdsourced Internet data has the potential to provide unique insights into this concern, as demonstrated by several previous studies. However, a comprehensive comparison across European countries remains lacking. OBJECTIVES: The study aimed to investigate AD-related web searches across Europe to assess spatiotemporal variations and associations between disease-related and external factors. METHODS: AD-related web search data were extracted for 21 European countries between February 2019 and January 2023. Descriptive analysis and autocorrelation functions were performed to examine spatiotemporal patterns. Correlations (r) were used to evaluate the associations between web searches and disease-related, socioeconomic and meteorological data. RESULTS: Over 241 million AD-related web searches were identified, with search volume varying substantially among European countries (p < 0.001) and correlating with AD prevalence and disease burden (both r = 0.51, p = 0.019). Search volume increased between 2019 and 2023 in all countries and seasonally peaked in January and March. Negative correlations with median population age (r = -0.46, p = 0.039), number of general practitioners (r = -0.29, p = 0.226) and specialists (r = -0.27, p = 0.270) were observed. Moderate to strong correlations were found between search volume and cold, humid and windy weather with fewer sunshine hours, while higher online interest typically occurred 1-3 months after such weather conditions. CONCLUSION: The study highlights the great potential of online crowdsourced data analysis, for example, to investigate the impact of climate change or to identify unmet needs at a population level. Furthermore, the growing online interest in AD and the corresponding seasonal peaks emphasize the necessity of adapting treatment plans, intensifying public health campaigns, and disseminating reliable online information by governments and healthcare providers, especially during these periods.

Influence of Clinical and Psychosocial Factors on the Adherence to Topical Treatment in Psoriasis.

(1) Background: Psoriasis is a common chronic inflammatory skin disease with different manifestations, affecting the quality of life at social, emotional, and professional dimensions and requiring long-term treatment. This study aimed to investigate the effect of psychosocial and clinical factors on adherence to topical treatment in psoriasis. (2) Methods: Self-reported measures and weighing the medicines were used to assess adherence. Psychopathological symptoms were measured using the Brief Symptoms Inventory (BSI). Social and clinical factors were assessed by a sociodemographic and clinical questionnaire. Adherence to treatment with topical medication was assessed using a sample of 102 psoriasis patients. (3) Results: The explanatory models of adherence to topical treatment in psoriasis translated into positive associations between adherence and the education level (higher education) (p = 0.03; φ = 0.23), the single-family household (p = 0.01; φ = 0.44), active employment status (p = 0.05; φ = -0.19), familiar history of psoriasis (p = 0.04; φ = -0.21), and the presence of obsessive-compulsive symptoms (p = 0.01; d = 0.29). (4) Conclusions: In patients who present the characteristics identified that influence non-adherence, instructions should be reinforced to increase adherence. The experimental mortality (39.6%) reduced the sample size, representing a limitation of the study.

Risankizumab, a therapeutic alternative for psoriasis in people living with HIV.

The management of psoriasis in individuals with human immunodeficiency virus (HIV) presents a unique challenge, marked by a more severe progression and limited efficacy of first- and second-line treatments. Although conventional systemic therapies might be considered, these agents are immunosuppressants, making their use challenging in people living with HIV (PLHIV). Biologic agents are frequently used in individuals with moderate-to-severe psoriasis, but their efficacy and safety data in PLHIV are very limited, as this patient group tends to be excluded from clinical trials. Risankizumab is a selective interleukin-23 (IL-23) inhibitor that has demonstrated a favourable safety profile and high efficacy in long-term studies and clinical practice. This current case report presents two clinical cases of PLHIV with plaque psoriasis who were effectively treated with the biologic agent risankizumab, with no reported safety issues. Although there are limited data on the use of biologics in PLHIV, this case series suggests that IL-23 inhibitors, namely risankizumab, might be a valuable therapeutic option for this population. Additional research and larger studies are needed to gain a more comprehensive understanding of the long-term safety and efficacy of IL-23 inhibitors in individuals affected by HIV.

Tildrakizumab for the treatment of moderate-to-severe psoriasis: a 52-week, real-world Portuguese multicentric study.

Background: Real-world evidence plays a pivotal role in validating the efficacy of biologic drugs beyond the controlled environment of randomized trials. This study aimed to evaluate the effectiveness of tildrakizumab in treating moderate-to-severe psoriasis within a real-world setting over a 52-week period in Portugal. Methods: This multicentric, prospective, observational study included adult patients with moderate-to-severe psoriasis. All participants received tildrakizumab 100 mg at weeks 0 and 4, followed by a maintenance dose every 12 weeks, and were monitored for 52 weeks. Primary endpoints were determined based on Psoriasis Area and Severity Index (PASI) assessments at baseline, 16 (±2) weeks, 28 (±2) weeks and 52 (±2) weeks. Results: A total of 54 patients were enrolled in the study (56% men, mean age of 50.3 ± 14.4 years). Half of the sample (n=27) had no prior experience with biologic treatments. About 74% of patients (n=40) presented at least one comorbidity during the study, with psoriatic arthritis being the most prevalent (29.6%). By week 52, there was a significant decrease in the mean PASI from 17.8±10.3 at baseline to 1.3±1.9 (p<0.001), indicating an overall improvement of 93%. By week 52, more than 85% of patients attained PASI ≤5, more than 80% reached PASI ≤3, and nearly 60% achieved PASI ≤1. Infections were observed in 9.3% of patients, and one patient required hospitalization (1.9%). The cumulative proportion of patients continuing treatment at 52 weeks was 88.9%. Conclusions: This study demonstrates that tildrakizumab is an effective and safe agent for the treatment of moderate-to-severe psoriasis in a diverse, real-world setting.

Treatment Of Post-Operative Chylothorax: The Role Of Intranodal Lymphangiography And Thoracic Duct Disruption.

Thoracic duct embolization has been increasingly adopted as a first-line therapy of chylothorax and this procedure includes lipiodol lymphangiography, thoracic duct access and embolization. Lymphangiography itself has a therapeutic role, with volume-dependent success rates of 37%-97% and even a reported 100% success rate in outputs of < 500 mL/day. We present a clinical case of a 48-years-old man diagnosed with esophageal squamous cell carcinoma, who underwent esophagectomy and presented with post-operative high-output (> 1L/day) chylothorax; thoracic duct embolization was proposed. Even though thoracic duct access and embolization were not achieved due to technical and anatomical factors, lipiodol lymphangiography and possibly thoracic duct maceration (after several punctures/attempts) contributed to the clinical success of the procedure, and this chylothorax with output values superior to those reported in the literature resolved within three days. As such, the therapeutic role of intranodal lymphangiography and thoracic duct disruption should be taken into account.

Causal agents of Stemphylium-induced foliar diseases of tomatoes and other Solanaceae hosts in Brazil.

AIM: An extensive survey was done to clarify the prevalent Stemphylium species on Solanaceae plants across Brazil, and their host ranges. METHODS AND RESULTS: Eighty nine (89) Stemphylium isolates were obtained from naturally infected tomatoes as well as S. paniculatum, potato, eggplant, scarlet eggplant (Solanum aethiopicum var. gilo), Physalis angulata, and Capsicum species. Phylogenetic analyses encompassing the ITS-5.8S rDNA and glyceraldehyde-3-phosphate dehydrogenase genomic regions placed the isolates into two distinct groupings with either Stemphylium lycopersici or S. solani. Isolates of S. lycopersici (n = 81) were obtained infecting tomato, potato, eggplant, S. paniculatum, and P. angulata. Isolates of S. solani (n = 8) were detected in natural association with scarlet eggplant and tomato. Two isolates of S. lycopersici displayed a wide experimental host range in greenhouse bioassays, infecting accessions of 12 out of 18 species. Ocimum basilicum (Lamiaceae) was the only experimental host outside the Solanaceae family.

Treatment of Psoriasis Patients with Latent Tuberculosis Using IL-17 and IL-23 Inhibitors: A Retrospective, Multinational, Multicentre Study.

BACKGROUND: Tuberculosis has a major global impact. Immunocompetent hosts usually control this disease, resulting in an asymptomatic latent tuberculosis infection (LTBI). Because TNF inhibitors increase the risk of tuberculosis reactivation, current guidelines recommend tuberculosis screening before starting any biologic drug, and chemoprophylaxis if LTBI is diagnosed. Available evidence from clinical trials and real-world studies suggests that IL-17 and IL-23 inhibitors do not increase the risk of tuberculosis reactivation. OBJECTIVE: To evaluate psoriasis patients with treated or untreated newly diagnosed LTBI who received IL-17 and IL-23 inhibitors and the tolerability/safety of tuberculosis chemoprophylaxis. METHODS: This is a retrospective, observational, multinational study from a series of 14 dermatology centres based in Portugal, Spain, Italy, Greece and Brazil, which included adult patients with moderate-to-severe chronic plaque psoriasis and newly diagnosed LTBI who were treated with IL-23 or IL-17 inhibitors between January 2015 and March 2022. LTBI was diagnosed in the case of tuberculin skin test and/or interferon gamma release assay positivity, according to local guideline, prior to initiating IL-23 or IL-17 inhibitor. Patients with prior diagnosis of LTBI (treated or untreated) or treated active infection were excluded. RESULTS: A total of 405 patients were included; complete/incomplete/no chemoprophylaxis was administered in 62.2, 10.1 and 27.7% of patients, respectively. The main reason for not receiving or interrupting chemoprophylaxis was perceived heightened risk of liver toxicity and hepatotoxicity, respectively. The mean duration of biological treatment was 32.87 ± 20.95 months, and only one case of active tuberculosis infection (ATBI) was observed, after 14 months of treatment with ixekizumab. The proportion of ATBI associated with ixekizumab was 1.64% [95% confidence interval (CI): 0-5.43%] and 0% for all other agents and 0.46% (95% CI 0-1.06%) and 0% for IL-17 and IL-23 inhibitors, respectively (not statistically significant). CONCLUSIONS: The risk of tuberculosis reactivation in patients with psoriasis and LTBI does not seem to increase with IL-17 or IL-23 inhibitors. IL-17 or IL-23 inhibitors should be preferred over TNF antagonists when concerns regarding tuberculosis reactivation exists. In patients with LTBI considered at high risk for developing complications related to chemoprophylaxis, this preventive strategy may be waived before initiating treatment with IL-17 inhibitors and especially IL-23 inhibitors.

Emerging Oral Therapies for the Treatment of Psoriasis: A Review of Pipeline Agents.

The introduction of biologic agents for the treatment of psoriasis has revolutionized the current treatment landscape, targeting cytokines in the interleukin (IL)-23/IL-17 pathway and demonstrating strong efficacy and safety profiles in clinical trials. These agents however are costly, are associated with a risk of immunogenicity, and require administration by intravenous or subcutaneous injection, limiting their use among patients. Oral therapies, specifically small molecule and microbiome therapeutics, have the potential to be more convenient and cost-effective agents for patients and have been a focus of development in recent years, with few targeted oral medications available for the disease. In this manuscript, we review pipeline oral therapies for psoriasis identified through a search of ClinicalTrials.gov (30 June 2022-1 October 2023). Available preclinical and clinical trial data on each therapeutic agent are discussed. Small molecules under development include tumor necrosis factor inhibitors, IL-23 inhibitors, IL-17 inhibitors, phosphodiesterase-4 inhibitors, Janus kinase inhibitors, A3 adenosine receptor agonists, and sphingosine-1-phosphate receptor 1 agonists, several of which are entering phase III trials. Oral microbials have also demonstrated success in early phase studies. As new oral therapies emerge for the treatment of psoriasis, real-world data and comparative trials are needed to better inform their use among patients.

Guselkumab-Treated Patients with Plaque Psoriasis Who Achieved Complete Skin Clearance for ≥ 156 Consecutive Weeks: A Post-Hoc Analysis From the VOYAGE 1 Clinical Trial.

BACKGROUND: Treatment of moderate-to-severe plaque psoriasis with biologics, such as guselkumab, has demonstrated greater efficacy over traditional non-biologic treatments. However, given patient diversity, greater understanding of the relationship between patient characteristics, positive clinical outcomes, and long-term response to biologics is crucial for optimizing treatment choices. MATERIALS AND METHODS: This post-hoc analysis of the 5-year VOYAGE 1 clinical trial compares baseline characteristics of patients maintaining a Psoriasis Area and Severity Index (PASI) score of 0 at all visits for ≥ 156 consecutive weeks (PASI = 0 group) with those that never achieve PASI = 0 (comparator group), using descriptive statistics and a multiple logistic regression model. Guselkumab plasma trough concentrations in both response groups were assessed from Weeks 4-156. RESULTS: Of patients who started guselkumab treatment at Week 0 or at Week 16 after switching from placebo, 22.7% (112/494) maintained PASI = 0 for ≥ 156 consecutive weeks. Numerical differences in baseline characteristics, including age, obesity, diabetes, PASI score, disease duration, smoking status, and psoriatic arthritis comorbidity, were identified between the PASI = 0 group and comparator group. Plasma guselkumab levels were consistently higher in the PASI = 0 group. Multiple logistic regression analysis revealed absence of diabetes, lower Dermatology Life Quality Index score at baseline, and higher Week 4 guselkumab plasma concentration as significantly (p < 0.05) associated with the PASI = 0 group. CONCLUSION: A substantial (22.7%) number of guselkumab-treated patients in the VOYAGE 1 clinical trial maintained complete skin clearance for a consecutive period of ≥ 156 weeks. Factors associated with this outcome may suggest clinical benefits of holistic treatment approaches. TRIAL REGISTRATION: NCT02207231.