Histopathologic findings in ointment pseudo-cheilitis: An alert to dermatopathologists.

Ointment pseudo-cheilitis is a recently recognized distinctive type of self-induced cheilitis. Lesions consist of a variable amount of crusts adhered to the vermilion. These crusts consist of dried saliva and dead cells mixed with applied medications attached to the lip surface. Patients are typically severely anxious or depressed; the condition impacts quality of life. Ointment pseudo-cheilitis is frequently misdiagnosed as exfoliative cheilitis or cheilitis glandularis. Biopsy reports are often non-revealing because there are no established histopathological criteria for this disease, and clinicians usually do not formulate the correct diagnostic hypothesis. Here, we present the histopathological findings of four cases of ointment pseudo-cheilitis. The most consistent finding was the presence of laminated parakeratotic material detached from the epithelium in biopsies that are devoid of other significant diagnostic changes. This material at the lip surface possibly represents physiologic labial desquamation mixed with dried saliva and applied medication. With this report, we intend to alert dermatopathologists to the diagnosis of ointment pseudo-cheilitis if they receive biopsies from patients who present clinically exuberant labial lesions that show only minimal histopathological changes.

Associations of Atopic Dermatitis with Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: Atopic dermatitis (AD) shares similarities with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) regarding pathogenesis involving neuroinflammation and genetics. Nevertheless, evidence on the associations of AD with ADHD and/or ASD is inconclusive. This study aimed to systematically examine the existing evidence on the associations between AD, ADHD, and ASD. METHODS: The Meta-Analysis of Observational Studies in Epidemiology guideline was followed. We searched MEDLINE, Embase, Cochrane Library, and Web of Science databases from their respective inceptions to March 4, 2022. Observational studies providing adjusted estimates and/or prevalences for ADHD and ASD in patients with AD were enrolled. A random-effects model meta-analysis was conducted to calculate pooled odds ratios (ORs) and confidence intervals (CIs). Subgroup analyses according to AD severity, age, geographic location, and study design were performed. RESULTS: Overall, a total of 24 studies with 71,373,639 subjects were enrolled. Our meta-analysis demonstrated significant associations of AD with ADHD (pooled OR: 1.28; 95% CI: 1.18-1.40) and ASD (pooled OR: 1.87; 95% CI: 1.30-2.68). Subgroup analyses revealed that the associations for ADHD were the most prominent in studies evaluating severe AD patients as well as in studies focusing on school-age children and adolescents. Among patients with AD, the pooled prevalence of ADHD was 6.6%, and the respective prevalence of ASD was 1.6%. CONCLUSION: The evidence to date suggests significant associations of AD with ADHD and ASD. Psychiatric consultation and an interdisciplinary approach would benefit patients with AD presented with behavioral symptoms suggestive of ADHD or ASD.

Risk Factors for Nonattendance in Delusional Infestation: A Multicenter Observational Study.

BACKGROUND: Nonattendance is common among patients suffering from delusional infestation (DI) with a risk factor for poorer patient outcomes. OBJECTIVE: The aim of this study was to determine the incidence rate and predictors of nonattendance among patients presenting to a psychodermatology department with DI and the subsequent effect on the success of prescribing new antipsychotics. METHODS: Data of 265 patients were reviewed of the Amsterdam UMC, the Erasmus University Medical Center, the Royal London Hospital, and the Liverpool School of Tropical Medicine between January 2008 and October 2019. RESULTS: We observed that among the patients who attended the first consultation, 57% (n = 144) did not attend their second visit. Recreational drug use was significantly higher in the nonattendance group compared to the attendance group (25% against 18%). Patients who had a history of previously prescribed antipsychotics at the time of the first consultation were less likely to get prescribed antipsychotics from the psychodermatology departments for DI; however, prescribing antipsychotic drugs by the psychodermatology department did not influence nonattendance significantly. CONCLUSIONS: People suffering from DI are at high risk of nonattendance, even in specialist settings. Patients with current illicit drug use and younger patients are particularly at risk of this.

Internalized Stigma in Hidradenitis Suppurativa: A Multicenter Cross-Sectional Study.

BACKGROUND: Hidradenitis suppurativa (HS) causes significant physical, social, and psychological burdens. Internalized stigma, acceptance of negative attitudes and stereotypes of society regarding a person's illness, has not been studied previously in HS. OBJECTIVES: The objective of this study was to investigate the internalized stigma state of HS patients and identify the factors affecting it. METHODS: This multicenter, prospective, cross-sectional study included 731 patients. Internalized Stigma Scale (ISS), Hurley staging, Physician Global Assessment, Dermatology Life Quality Index (DLQI), Skindex-16, Beck Depression Inventory-II (BDI-II), and Visual Analog Scale (VAS)-pain score were used in the study. RESULTS: The mean ISS value (57.50 ± 16.90) was comparable to the mean ISS values of studies in visible dermatological and various psychiatric diseases. A significant correlation was found between the mean values of ISS and all disease activity scores, quality of life measures, BDI-II, and VAS-pain scores. Obesity, family history, low education and income level, vulva/scrotum involvement and being actively treated are significant and independent predictive factors for high internalized stigma in multivariate analysis. CONCLUSIONS: HS patients internalize society's negative judgements, which may create a profound negative effect on access to health care. Therefore, in addition to suppressing disease activity, addressing internalized stigma is fundamental for improving health care quality.

Manifestation of anxiety and depression among pediatric patients with psoriasis: A review.

Psoriasis is a chronic, inflammatory skin disorder with manifestations extending beyond visual presentation to encompass psychological burden. Though the association between psoriasis and mental health disorders in adults is widely accepted, there is inadequate research to generalize these findings to pediatric populations. In this review of the literature, we discuss the prevalence of anxiety and depression among pediatric patients with psoriasis in hopes of raising awareness of these associations and advocating for psychological screening and intervention in dermatology practice.

The Mind Body Connection in Dermatologic Conditions: A Literature Review.

Psychodermatology pertains to the relationship between the skin and brain. This review aims to summarize the evidence of the mind body connection in four psychophysiological conditions: rosacea, atopic dermatitis (AD), acne vulgaris (AV), and psoriasis. A literature search was conducted using several English language databases. All four conditions share similar psychiatric co-morbidities, including but not limited to anxiety, depression, and suicidality. In rosacea, the upregulation of transient receptor potential vanilloid type 1, Toll like receptor 2, and Th17 cells releases downstream products that are simultaneously implicated in mood disorders. Stress exacerbates AV through the hypothalamic-pituitary-adrenal (HPA) system, which alters functioning of sebocytes and Cutibacterium acnes. In AD and psoriasis, the HPA axis influences Th1, Th2, Th22, and Th1, Th17 immune mediated responses, respectively. This leads to the secretion of pro-inflammatory cytokines which are also involved in the pathogenesis of anxiety and depression. Neurotransmitters implicated in mental illness, such as gamma-aminobutyric acid and serotonin, may also play a role in the development of AD and psoriasis. The management of cutaneous disease may mitigate psychological distress, and future research may show the corollary to also be true.

Pharmacological Interventions for Primary Psychodermatologic Disorders: An Evidence Mapping and Appraisal of Randomized Controlled Trials.

BACKGROUND: The lack of clinical guidelines for the treatment of primary psychodermatologic disorders (PPDs) hinders the delivery of optimal care to patients. The review aimed to identify, appraise, and summarize the currently available evidence about the safety and effectiveness of pharmacological management of PPDs through randomized controlled trials (RCTs). METHODS: The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRIMSA) statement and the Global Evidence Mapping Initiative guidance were followed. Medline, Embase, PsycInfo, Cochrane and Scopus were searched, and two reviewers independently completed article review, data extraction, and quality assessment. RESULTS: Among 2618 unique studies, full texts of 83 were reviewed and 21 RCTs were included. Five PDDs were identified: trichotillomania (n = 12), pathologic skin picking (n = 5), nail biting (n = 2), delusional parasitosis (n = 1), and dermatitis from compulsive hand washing (n = 1). Seven different classes of medications were investigated: SSRIs (i.e., fluoxetine, sertraline, and citalopram), tricyclic antidepressants (i.e., clomipramine and desipramine), antipsychotics (i.e., olanzapine and pimozide), anticonvulsant (i.e., lamotrigine), N-acetylcysteine, inositol, and milk thistle. RCT-derived evidence supports the use of antidepressants in trichotillomania (sertraline and clomipramine), pathologic skin picking (fluoxetine), pathologic nail biting and dermatitis from compulsive hand washing (clomipramine or desipramine); antipsychotics in trichotillomania (olanzapine) and delusional parasitosis (pimozide); N-acetyl cysteine in trichotillomania and skin picking. CONCLUSION: Few pharmacotherapies for primary psychodermatologic disorders are assessed through controlled trials in the literature. This review serves as a roadmap for researchers and clinicians to reach informed decisions with current evidence, and to build on it to establish guidelines in the future.

The Effect of Biological Treatment on Stress Parameters Determined in Saliva in Patients with Severe Psoriasis.

Background and objectives: In psoriatic patients, stress is the most common aggravating factor. Despite the use of quality-of-life assessment questionnaires, diagnosing stress in psoriatic patients is not a flawless procedure. This study aimed to assess the usefulness of potential stress biomarkers in saliva for monitoring the treatment of psoriasis. Materials and methods: A total of 104 adult patients with severe psoriasis were included and randomly treated via biological treatment or symptomatic therapy: 84 received biological treatment, with 20 formed a control group receiving symptomatic therapy. The administered biological treatment was adalimumab, whilst in controls calcipotriol/betamethasone dipropionate topical gel and emollients were used. Patients were monitored monthly with a dermatological examination and the dispensing of a biological drug. During each of the four visits, the severity of the disease was assessed (PASI, BSA, and DLQI), and a sample of the patient's saliva was taken. In all the participants, the saliva concentrations of immunoglobulin A (sIgA), α-amylase (sAA), and chromogranin A (CgA) were measured. Results: The majority of patients in both the study and control groups achieved clinical improvement, though favoring the group receiving biological treatment. The concentration of sIgA in the saliva was constantly increasing in the study group during subsequent visits (Fr = 27.26; p < 0.001). Meanwhile, there were no statistically significant changes in the control group during the same follow-up period (Fr = 6.66; p = 0.084). Levels of sAA underwent statistically significant changes in both groups (Fr = 58.02; p < 0.001-study group and Fr = 13.74; p = 0.003-control group). In the study group, a steady, statistically significant increase in sAA was observed from the first to the third visit. In the study group, a downward trend in CgA concentration was observed. In the control group, no significant differences in the level of CgA were obtained. Conclusions: sIgA, sAA, and CgA are potential markers of the severity of psoriasis and the associated stress reaction. Based on the presented observations, only sIgA and CgA seem to be valuable biomarkers for monitoring the effectiveness of the systemic treatment of psoriasis.

The vicious circle effect: stress as effect and cause in patients with psoriasis.

Psoriasis is a common immune-mediated, chronic inflammatory disease, causing adverse effects on patients' quality of life and disease burden. In psychodermatology, psoriasis is included both in the group of dermatological diseases, in which the psychophysiological background plays a key role, and in dermatoses being a potential source of emotional disturbances or being a trigger for the development of secondary mental disorders. A comprehensive view of the patient with psoriasis, not only from the point of view of skin disease, but also as a result of a wide impact of stress, including low self-esteem and inappropriate social perception may have a key influence on improvement of quality of life of these patients.

Alexithymia and Cutaneous Disease Morbidity: A Systematic Review.

BACKGROUND: Alexithymia is a psychological construct that describes one's difficulty in understanding and describing their own emotions as well as differentiating feelings from bodily signals of arousal. In the general population, alexithymia's prevalence is approximately 10%. Alexithymia may act as a triggering factor for many medical and psychiatric disorders. In patients with physical disease, alexithymia's prevalence reaches up to 63%. Additionally, alexithymia is associated with worse outcomes and heightened psychosocial comorbidities. OBJECTIVE: This review continues where an earlier review (Willemsen, 2008) left off to (1) clarify alexithymia's prevalence in dermatology patients and (2) further investigate alexithymia's impact on disease burden, psychosocial comorbidities, and treatment. METHODS: Systematic searches on alexithymia and dermatologic conditions were conducted using PubMed, Embase, PsycInfo, and Web of Science databases from March 8, 2021, to March 12, 2021. Data from eligible publications, which were full-text, clinical studies published after September 1, 2008, and available in English, were extracted by two medical students and summarized. RESULTS: Despite a small number of publications (n = 37), data showed a markedly greater prevalence and severity of alexithymia in patients with alopecia, vitiligo, psoriasis, hidradenitis suppurativa, atopic dermatitis, chronic idiopathic urticaria, and primary focal hyperhidrosis compared to healthy controls. Further, data consistently demonstrate a complex interplay between alexithymia, disease burden, and psychosocial comorbidity. CONCLUSIONS: Identifying and addressing alexithymia in dermatology patients may improve treatment outcomes, associated comorbidities, and health-related quality of life.

Pediatric skin picking disorder: A review of management.

Skin picking disorder (SPD) commonly presents in childhood; often, families will first turn to dermatologists for evaluation. It is imperative that dermatologists accurately diagnose and treat the disorder as children are vulnerable to face significant negative psychosocial impacts. This article reviews the limited literature on the management of SPD in pediatric patients to better prepare dermatologists for educating families and recommending treatment options. We discuss studies evaluating behavioral and pharmacologic therapies, as well as emerging skin barrier treatments.

Psychiatric Consequences of Skin Conditions: Multiple Case Study Analysis with Literature Review.

This review of current literature demonstrates the psychological implications of skin conditions. Skin conditions of varying severity can impact the quality of patients' lives and have psychiatric consequences. This impact provides a need for healthcare providers to consider the psychological implications of one's skin conditions and their effect on quality of life. The psychological challenges that arise from varying skin conditions show the potential need for both dermatological and psychiatric interventions. The following literature review details the psychiatric consequences of skin conditions under various conditions. It first looks at literature highlighting the psychiatric consequences experienced through various age ranges, from adults to adolescents and children. The paper then explores multiple skin conditions and their psychological effect before highlighting some of the interactions that stress has on the skin that could further exacerbate one's condition. Finally, it examines how patients characterize their experience with their skin condition and goes into some clinical case studies of patients with psychological implications as a result of their skin disorder. The paper also highlights the magnitude of dermatologic patients experiencing psychological conditions in conjunction with their skin conditions.

Severe nondiabetic plantar mal perforant in an adolescent girl with anorexia nervosa.

PURPOSE: We describe the case of a severe skin ulcer of the heel in an adolescent girl hospitalised for anorexia nervosa (AN) associated with a severe excessive exercise. METHODS: This case report includes retrospective anamnestic and clinical data from the patient's medical record. A literature review was conducted on the dermatological changes described in AN. CONCLUSION: Severe starving syndrome in AN due to intake restriction and pathological associated behaviours can cause serious somatic complications, including psycho-dermatological lesions. We describe a rare case of a nondiabetic plantar "mal perforant" resulting from multiple risk factors including prolonged undernutrition, excessive exercise, and significant psychiatric comorbidity with self-injury. We suggest that, in this context, one should include a particular attention to the risk of non-visible skin complications reflecting both the AN symptoms severity and the severity of the patient's psychological distress requiring individualised and specialised multidisciplinary approach. LEVEL OF EVIDENCE: Level V, case report.

Cosmetic procedure use as a type of substance-related disorder.

BACKGROUND: A role for addiction psychiatry in aesthetic treatment-seeking behavior has been evidenced for ultraviolet light tanning. OBJECTIVE: We aim to demonstrate an initial proof of concept for the presence of addictive behaviors in cosmetic procedure use. METHODS: Adults visiting a cosmetic dermatology practice with history of at least 1 cosmetic procedure and consideration of at least 1 cosmetic procedure in the past 12 months were included. Two previously validated instruments in the detection of alcohol use disorder, the Cut Down, Annoyed, Guilty, Eye-Opener (CAGE) questionnaire, and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria were modified to evaluate participants for a substance-related disorder (SRD) in cosmetic procedures. RESULTS: Of 153 adults, 34 (22.2%) met modified CAGE criteria, and 40 (26.1%) met modified DSM-V criteria. Results from both instruments were significantly associated (P < .0002). Significant differences in consideration and use of cosmetic treatments were found in SRD positive versus negative groups (P < .0001 and P = .009, respectively). LIMITATIONS: Preliminary criteria for SRD in cosmetic procedure use in this study has not yet been validated. CONCLUSIONS: A type of SRD involving cosmetic procedures may exist, and qualifying individuals may have increased cosmetic treatment use. Future efforts to rigorously validate an instrument for SRD detection in cosmetic procedures use are warranted for future research and clinical application.

Psychiatric morbidity, stress and quality of life among geriatric dermatology patients: Therapeutic considerations from an Indian perspective.

We aimed to determine the prevalence of psychiatric morbidities, stress and quality of life, the pattern of skin diseases and associated psychosocial factors in geriatric population. Patients aged 60 years and older were recruited. Demographics and dermatological history and findings were collected using a preset Proforma. Geriatric depression scale (GDS), hospital anxiety and depression scale (HADS), perceived stress scale (PSS), and dermatology life quality index (DLQI) were instituted in all the patients. A total of 310 patients were included in the study, 173 males and 137 females. Infectious diseases (39.6%), papulosquamous diseases (17.1%), and eczema (15.5%) were common disorders. 45.5% were depressed and 43.2% had anxiety (hospital anxiety and depression scale). 55.8% had depression (geriatric depression rating scale), 20.3% had high stress and 11% had extremely large effect on DLQI. Divorced/widowed patients experienced more depression (p = 0.037) and had more impairment in quality of life (p = 0.05). Patients living in three generation family experienced more impairment in quality of life (p = 0.000). Our study demonstrated high prevalence of psychiatric morbidities in geriatric dermatology patients. It implies the need of special care with more attention to psychiatric co morbidities. The role of psychiatry-dermatology liaison clinic may benefit these patients.

Psychodermatology knowledge and awareness in Chinese dermatologists: Results of a survey study.

To assess the knowledge, awareness, practice patterns, and attitudes of Chinese dermatologists toward psychocutaneous disorders and explore their interest in continuing medical education (CME) of psychodermatology. An online survey study was conducted from October to November 2019. The survey questionnaire link was sent to the members of the national and local association of dermatology through a social media App. After confirming the informed consent to enrol in the study, the participants filled out the online questionnaire anonymously. About 1047 dermatologists completed the survey. The most common diagnoses referred to the psychiatrist from Chinese dermatologists were venereal phobia (51.77%), delusion of parasitosis (44.03%), and trichotillomania (32.28%). Compared with dermatologists, Traditional Chinese Medicine (TCM) dermatologists had less training experience on psychodermatologic CME (4.21% vs 8.34% who had attending more than twice CME, P < .05). Although TCM dermatologist experience more frequency with psychodermatology (24.21% TCM vs 15.71% dermatologists), they had lower comfort level in treating psychodermatologic patients (51.58% TCM vs 58.89% dermatologist) (P > .05). While 818 (78.13%) dermatologists never received any training course, 84.53% of the dermatologists expressed interest in attending CME events on psychodermatology. The most popular CME themes of psychodermatology were emotional disorders related to skin diseases, delusion of parasitosis, and trichotillomania. Chinese dermatologists have insufficient knowledge and awareness toward psychodermatology. TCM dermatologists have higher awareness on psychocutaneous diseases compared with dermatologists. Psychodermatology continuing medical education programs should be carried out as soon as possible.

The Sense of Stigmatization in Patients with Plaque Psoriasis.

BACKGROUND: Psoriasis is a systemic inflammatory disease capable of creating stigmatization in the form of social exclusion and decrement of psychological conditions. AIM: The aim of the study was to determine the level of stigmatization in patients with plaque psoriasis. METHODS: The study included 166 patients with plaque psoriasis (55.6% women and 44.3% men) with Psoriasis Area and Severity Index scores ≤10. The age of the study patients ranged between 18 and 72 years (arithmetic mean = 37.4; median = 38; standard deviation [SD] = 11.0). The mean age at the diagnosis of psoriasis was 21.5 years (median = 20; SD = 9.1) and disease duration varied from 2 to 59 years (arithmetic mean = 15.8; median = 15; SD = 11.3). The study patients completed the Polish version of the 6-item Stigmatization Scale and the 33-item Feelings of Stigmatization Questionnaire and a survey developed by the authors of this study, containing questions about the participants' sociodemographic characteristics (sex, age, place of residence, marital status, education, employment status) and information about their disease (location of psoriatic lesions, time elapsed since the diagnosis of psoriasis). RESULTS: The mean score for the 6-item Stigmatization Scale for the whole study group was 7.6 out of 18 points (median = 7; SD = 3.8; minimum = 0; maximum = 17). The average score for the 33-item Stigma Feelings Questionnaire in our series was 84.5 out of 165 points (median = 88; SD = 20.9; minimum = 30; maximum = 136). A statistically significant sex-related difference was observed in the 6-item Stigmatization Scale scores, with higher stigmatization levels found in men than in women (p = 0.0082). Moreover, significantly higher levels of stigmatization were observed in countryside dwellers (p = 0.0311) and unmarried persons (p = 0.0321). Patients with a longer history of the disease (≥15 years) scored significantly higher on the 6-item Stigmatization Scale (p = 0.0217) than those in whom psoriasis lasted less long, and presented with higher, at the threshold of statistical significance, scores for the 33-item Feelings of Stigmatization Questionnaire. CONCLUSIONS: Stigmatization awareness should be promoted among physicians and psoriatic patients to improve psoriasis management.

Development and Evaluation of the Psychosocial Adaptation Questionnaire among Patients with Chronic Skin Disease.

BACKGROUND/OBJECTIVE: Chronic skin disease (CSD) often has physiological, psychological, and social impacts, which requires the patient to adjust to achieve psychosocial adaptation (PSA). As a standardized assessment instrument was lacking, we developed a PSA questionnaire for patients with CSD (PSAQ-CSD). METHODS: According to the steps of questionnaire development, a systematic process of scoping review, qualitative research, content validity expert review, testing in a sample of 321 adults, item analysis, and classical test theory methods were applied. RESULTS: Following item analysis and exploratory factor analyses, 18 items were eventually entered into the model of confirmatory factor analyses, with a cumulative contribution of 65.435%. Three subscales were developed: emotional, self-cognitive, and social dimensions. Item analysis, exploratory factor analyses, and content validity expert review narrowed the subscales to 8, 6, and 4 items, respectively. CONCLUSIONS: The 18-item PSAQ-CSD has been confirmed to have good internal consistency reliability and convergent and discriminant validity. It may be a useful tool to evaluate the PSA among patients with CSD and provide a basis for further research.

Implementation of the PsoWell™ Model for the Management of People with Complex Psoriasis.

The Psoriasis and Well-being (PsoWell)™ training programme, incorporating motivational interviewing, improves clinicians' knowledge and skills to manage complex psoriasis, including behaviour change. The aims of this study were to deliver the PsoWell™ training programme to dermatology specialists, and to evaluate the acceptability and feasibility of implementing the PsoWell™ model across dermatology services. Framework analysis of 19 qualitative semi-structured interviews was performed, following delivery of nine, 1-day PsoWell™ training days involving 119 participants. Two themes were identified: "Perceptions and Priorities" and "Awareness", sub-divided into: "Awareness Not Competence" and "Increasing Awareness". The PsoWell™ model was found to be acceptable and feasible to implement across dermatology settings. Participants were more skilled and motivated to address psycho-logical issues, including behaviour change, but wanted further training to ensure competency. The trainees claimed that scepticism among some colleagues regarding whole-patient management might prevent uptake. Data show-ing the impact on health outcomes are needed and might overcome scepticism. Remote consultation could adopt the PsoWell™ approach.

Nocebo Effects on Cowhage-evoked Itch: A Randomized Controlled Trial of Classical Conditioning and Observational Learning.

To investigate learning processes underlying nocebo effects on itch, this study measured the efficacy of classical conditioning and observational learning for inducing nocebo effects on cowhage-evoked itch and scratching behaviour. A total of 58 healthy female participants were assigned to classical conditioning, observational learning, or sham conditioning groups. In the classical conditioning group, experimenters associated the application of an inert gel with increased itch intensity themselves. In the observational learning group, a video of the conditioning paradigm was shown. Nocebo effects were measured as the difference in itch or scratching between control and nocebo test phase trials, compared between learning and control groups. Compared with sham conditioning, classical conditioning induced a significant nocebo effect on itch, while observational learning did not. No nocebo effect on scratching was detected. These results highlight the role that learning through direct experiences plays in pruritic symptoms. Future research should investigate how a patient's history of unsuccessful treatments shapes treatment outcomes.