INTRODUCTION: Prior studies have reported that hidradenitis suppurativa (HS) is accompanied by a myriad of physical and mental conditions. However, given the small sample sizes and the limited number of pre-selected comorbidities, these studies do not provide a complete picture of the comorbidity burden of HS in the USA. Moreover, the relationship between HS severity and comorbidity burden has yet to be characterized. Using a large US claims database, we estimated the comorbidity burden associated with HS, stratified by disease severity.
METHODS: A retrospective matched cohort design was used. Patients with HS were classified into two severity cohorts (milder and more severe) using an empirical algorithm based on treatments received. The comorbidity burden was compared between each HS cohort and their matched HS-free cohort, and between patients with milder vs. those with more severe forms of HS.
RESULTS: Several physical and mental comorbidities were found to be more prevalent in both cohorts of patients with milder and more severe forms of HS than in their matched HS-free cohorts. The comorbidity burden also increased greatly as the disease progressed to more severe forms.
CONCLUSIONS: The results of this study highlight the complexity of the comorbidity burden of HS patients and the need for a multidisciplinary approach to optimize the management of HS and its numerous associated comorbidities.
FUNDING: AbbVie, Inc.
BACKGROUND: Hidradenitis suppurativa (HS) and psoriasis are inflammatory skin diseases associated with obesity. Each disease is likely to impact the quality of life of patients, but the relative impact of each disease is unknown.
OBJECTIVES: This study aimed to determine whether skin disease or obesity is more distressing to obese patients who have either psoriasis or HS.
METHODS: A cohort of obese patients with psoriasis and HS was surveyed using a time-trade-off utility. T-tests and regression analysis were used to compare differences in impact on quality of life between skin disease and obesity for patients with HS and psoriasis. Further analyses were adjusted for degree of obesity and severity of disease.
RESULTS: A total of 79 subjects completed the survey. Obese patients with HS were heavier than patients with psoriasis (mean body mass index 38.1 kg/m2 vs. 34.9 kg/m2). Obese patients with either HS or psoriasis were both willing to trade a significantly higher proportion of their life to live without skin disease than to live at a normal weight (p = .01). This effect persisted after controlling for disease severity and weight. Patients with HS were willing to trade significantly more years of life to live at a normal weight than obese patients with psoriasis (14 vs. 7; p < .04).
LIMITATIONS: This was a small study conducted at an academic institution.
CONCLUSION: In this study population, obesity was more severe in patients with HS than in those with psoriasis. Even after controlling for relative severity, HS was more problematic for subjects in this study than weight when these conditions existed concomitantly.
BACKGROUND: Hormonal therapy is a potential treatment for hidradenitis suppurativa (HS). However, few data exist describing the efficacy of spironolactone in treatment of HS.
OBJECTIVE: To assess whether spironolactone treatment improves HS disease severity and patient-reported pain.
METHODS: We performed a single-center chart review of female patients with HS who were treated with spironolactone between 2000 and 2017. Primary outcome measurements included the HS Physician's Global Assessment (HS-PGA), Hurley staging, inflammatory lesion count, fistula count, and a numeric rating scale for pain.
RESULTS: On average, subjects were exposed to 75 mg of spironolactone daily over a 7.1-month follow-up period. Patients achieved significant disease improvement with regard to pain (Δ-1.5 [P = .01]), inflammatory lesions (Δ-1.3 [P = .02]), and HS-PGA score (Δ-0.6 [P < .001]). As expected, no change was found for Hurley stage (Δ0 [P = .32]) or fistulas (Δ0 [P = .73]). There was no difference in improvement between subjects who received less than 75 mg of spironolactone daily (n = 25; average dose, 45 mg/d) and those who received more than 100 mg daily (n = 21; average dose, 112 mg/d).
LIMITATIONS: Retrospective nature, limited sample size, and variations in severity measures documented were limiting factors.
CONCLUSIONS: Management of HS with spironolactone reduces lesion count, HS-PGA score, and pain. Lower doses appear to be effective and may be an appropriate option for patients with tolerability concerns.
Hidradenitis suppurativa (HS)/acne inversa is a debilitating chronic disease that remains poorly understood and difficult to manage. Clinical practice is variable, and there is a need for international, evidence-based and easily applicable consensus on HS management. We report here the findings of a systematic literature review, which were subsequently used as a basis for the development of international consensus recommendations for the management of patients with HS. A systematic literature review was performed for each of nine clinical questions in HS (defined by an expert steering committee), covering comorbidity assessment, therapy (medical, surgical and combinations) and response to treatment. Included articles underwent data extraction and were graded according to the Oxford Centre for Evidence-based Medicine criteria. Evidence-based recommendations were then drafted, refined and voted upon, using a modified Delphi process. Overall, 5310 articles were screened, 171 articles were analysed, and 65 were used to derive recommendations. These articles included six randomized controlled trials plus cohort studies and case series. The highest level of evidence concerned dosing recommendations for topical clindamycin in mild disease (with systemic tetracyclines for more frequent/widespread lesions) and biologic therapy (especially adalimumab) as second-line agents (following conventional therapy failure). Good-quality evidence was available for the hidradenitis suppurativa clinical response (HiSCR) as a dichotomous outcome measure in inflammatory areas under treatment. Lower-level evidence supported recommendations for topical triclosan and oral zinc in mild-to-moderate HS, systemic clindamycin and rifampicin in moderate HS and intravenous ertapenem in selected patients with more severe disease. Intralesional or systemic steroids may also be considered. Local surgical excision is suggested for mild-to-moderate HS, with wide excision for more extensive disease. Despite a paucity of good-quality data on management decisions in HS, this systematic review has enabled the development of robust and easily applicable clinical recommendations for international physicians based on graded evidence.
Hidradenitis suppurativa (HS) is a complex disease with a dramatic impact on the quality of life of patients that it afflicts. Despite this, there are few treatment options offering long-term relief. The exact pathophysiology of HS is unclear, although the current theory involves follicular obstruction, rupture, and subsequent inflammation leading to fistula and abscess development in intertriginous skin. Several inflammatory modulators have been implicated in the development of HS, including tumor necrosis factor (TNF)-α as well as interleukin (IL)-1β, IL-10, and IL-17. Initial evidence for the use of TNF-α inhibitors in HS stemmed from recognition that inflammatory bowel disease patients treated with these medications saw a concurrent improvement in their HS symptoms. Early case reports and case series illustrated TNF-α inhibitors' value in the treatment of HS. Later, two phase III clinical trials, PIONEER I and PIONEER II, demonstrated that adalimumab is an efficacious treatment for HS. Infliximab represents another effective HS treatment option with its main advantage being dosing flexibility. In contrast, clinical trials have failed to show evidence for application of etanercept in HS. There is limited data on other TNF-α inhibitors such as certolizumab-pegol and golimumab. This review outlines the history, dosing, response, and adverse effects of TNF-α inhibitors in the treatment of HS.
Hidradenitis suppurativa is a severe and debilitating dermatologic disease. Clinical management is challenging and consists of both medical and surgical approaches, which must often be combined for best outcomes. Therapeutic approaches have evolved rapidly in the last decade and include the use of topical therapies, systemic antibiotics, hormonal therapies, and a wide range of immunomodulating medications. An evidence-based guideline is presented to support health care practitioners as they select optimal medical management strategies and is reviewed in this second part of the management guidelines. A therapeutic algorithm informed by the evidence available at the time of the review is provided.
Hidradenitis suppurativa is a chronic inflammatory disorder affecting hair follicles, with profoundly negative impact on patient quality of life. Evidence informing ideal evaluation and management of patients with hidradenitis suppurativa is still sparse in many areas, but it has grown substantially in the last decade. Part I of this evidence-based guideline is presented to support health care practitioners as they select optimal management strategies, including diagnostic testing, comorbidity screening, and both complementary and procedural treatment options. Recommendations and evidence grading based on the evidence available at the time of the review are provided.
OBJECTIVES: Hidradenitis suppurativa (HS) causes substantial morbidity and quality-of-life impairment. We examined demographic/clinical characteristics of patients with HS and treatment patterns, prevalence and healthcare resource utilisation/expenditures related to HS in the real-world.
DESIGN: Retrospective claims data of MarketScan Commercial, Medicare Supplemental and Medicaid databases (2009-2014).
SETTING: USA.
PARTICIPANTS: Patients aged ≥12 years with ≥3 non-diagnostic outpatient or inpatient claims with an HS diagnosis code and ≥12 months continuous enrolment with medical and pharmacy benefits before (preindex) and after (postindex) the earliest diagnosis of HS (index) were included.
RESULTS: There were 11 325 Commercial/Medicare patients (mean age 37.4 years) and 5164 Medicaid patients (mean age 28.3 years). HS was more common in Medicaid than Commercial/Medicare patients (0.301% and 0.098%, respectively, in 2014). Cellulitis and psychiatric disorders were the most common comorbidities and oral antibiotics and narcotics were the most frequently prescribed drugs preindex, with ≥10% increase postindex in both populations. HS-related inpatient costs decreased while outpatient costs increased from preindex to postindex. Medicaid patients had several risk factors that may be associated with poor outcomes (eg, high rates of prescription pain medication use, comorbidities, drug discontinuation/interruption/holiday, emergency department (ED) visits and hospitalisation).
CONCLUSIONS: Commercial/Medicare and Medicaid HS beneficiaries experience high comorbidity burden but use different treatment modalities to manage HS. Results suggest a substantial unmet need exists among this patient population, with Medicaid patients experiencing a particularly high burden of disease and expensive healthcare resource utilisation.
Patients with hidradenitis suppurativa (HS) are often undertreated and there are limited efficacious therapies available for treating this population. Biologics are an emerging therapeutic modality used in the management of many inflammatory conditions including HS. Implementation of biologics is typically reserved for moderate-to-severe cases or in those cases that are refractory to treatment. Though many biologics have been trialed for use in HS, only one biologic, adalimumab, is currently US FDA (Food and Drug Administration) approved for the treatment of moderate-to-severe HS. Limitations in the use of biologics for HS include the many scoring systems utilized in research studies and the relatively few well-designed, adequately powered clinical trials.
Patients with hidradenitis suppurativa (HS) often experience disease flares, which can culminate in a visit to the emergency department (ED) and inpatient admission. Appropriate management of HS patients in the acute setting is integral to controlling disease activity, limiting further sequelae, and preventing readmission. The pathophysiology of HS is poorly understood but likely involves a host of hormonal, microbial, and immunological factors. Laboratory abnormalities, including leukocytosis, thrombophilia, an elevated erythrocyte sedimentation rate, as well as an elevated C-reactive protein level, are common in HS patients and generally represent a chronic inflammatory state rather than overt infection. The Hurley staging system is an appropriate way to triage patient severity and guide treatment, as reviewed in this article. In all cases, expedited outpatient follow-up with dermatology and primary care is imperative to limiting disease morbidity.
BACKGROUND: Weekly adalimumab (Humira® ) is approved for the treatment of hidradenitis suppurativa (HS) based on the 12-week placebo-controlled periods of the two phase III PIONEER trials.
OBJECTIVES: Using PIONEER integrated trial results, we aimed to evaluate the optimal medium-term adalimumab maintenance dosing strategy for moderate-to-severe HS.
METHODS: Each trial had two double-blind periods; 12-week Period A and 24-week Period B. Patients randomized to adalimumab 40 mg every week (ADAew) (Period A), were rerandomized in Period B to ADAew (ADAew/ew), ADA every other week (ADAew/eow), or placebo (ADAew/pbo). Placebo-randomized patients were reassigned in Period B to ADAew (PIONEER I) or placebo (PIONEER II). The primary outcome was HS Clinical Response (HiSCR). Patients who lost response during Period B were discontinued from the study and offered an option to enter the open-label extension (OLE) to receive ADAew. Results are reported across the two study periods, and data were combined from the two study periods and the OLE.
RESULTS: For week-12 HiSCR achievers, the HiSCR week-36 rate was 48·1% (ADAew/ew) vs. 46·2% (ADAew/eow) and 32·1% (ADAew/pbo). Combining (post hoc) these patients with week-12 partial responders further differentiated outcomes in Period B (ADAew/ew 55·7% vs. ADAew/eow 40·0% and ADAew/pbo 30·1%). Period-B adverse-event rates were ADAew/ew 59·6% vs. ADAew/eow 57·4% and ADAew/pbo 65·0%. One patient (ADAew/ew) reported a serious infection.
CONCLUSIONS: Weekly adalimumab treatment, effective throughout 36 weeks, was the optimal maintenance medium-term dosing regimen for this population. At least partial response after 12 weeks with continued weekly dosing had better outcomes than dose reduction or interruption. Patients who do not show at least a partial response to weekly adalimumab by week 12 are unlikely to benefit from continued therapy. No new safety risks were identified. What's already known about this topic? Hidradenitis suppurativa (HS) is a chronic inflammatory disease, commonly misinterpreted as an infection and treated with long-term antibiotic regimens or surgical incisions. Based on the chronicity of HS and the lack of evidence for efficacious and safe long-term HS treatments, it is important to evaluate medium- to long-term therapies for HS. Weekly adalimumab (Humira® ) is approved for the treatment of moderate-to-severe HS based on the two phase III PIONEER trials. What does this study add? This study pooled data from the two PIONEER trials, providing a more robust assessment of outcomes. After at least partial treatment success with weekly adalimumab short-term therapy (12 weeks), continuing weekly dosing during the subsequent 24 weeks had better outcomes than dose reduction or treatment interruption. Patients who do not show at least a partial response to weekly adalimumab by week 12 are unlikely to benefit from continued therapy.
Hidradenitis suppurativa (HS; also designated as acne inversa) is a chronic inflammatory disorder, which affects the intertriginous skin and is associated with numerous systemic comorbidities. The estimated prevalence of HS is 1% in most studied countries. Typically starting in early adulthood, cutaneous inflamed nodules, abscesses and pus-discharging tunnels develop in axillary, inguinal, gluteal and perianal body sites. The comorbidities of HS include metabolic and cardiovascular disorders, which contribute to reduced life expectancy. A genetic predisposition, smoking, obesity and hormonal factors are established aetiological factors for HS. Cutaneous changes seem to start around hair follicles and involve activation of cells of the innate and adaptive immune systems, with pivotal roles for pro-inflammatory cytokines such as tumour necrosis factor, IL-1β and IL-17. The unrestricted and chronic immune response eventually leads to severe pain, pus discharge, irreversible tissue destruction and scar development. HS has profound negative effects on patients' quality of life, which often culminate in social withdrawal, unemployment, depression and suicidal thoughts. The therapeutic options for HS comprise antibiotic treatment, neutralization of tumour necrosis factor and surgical intervention together with lifestyle modification. Nevertheless, there is an enormous need for awareness of HS, understanding of its pathogenesis and novel treatments.
Introduction: Hidradenitis suppurativa (HS) is a chronic skin disorder characterized by inflammatory nodules, abscesses, and fistulae. Patients tend to present in young adulthood and are predominantly female. The pathogenesis of HS involves apopilosebaceous gland follicle occlusion and affected areas often occur where this type of gland predominates. Treatment selection depends on HS severity, which is included in different scoring systems. In recent years, biological therapies have been evaluated and used with increasing frequency in moderate-to-severe HS disease.Areas covered: This review focuses on biological therapies for HS as assessed in case reports, case series, and clinical trials. The efficacy, hidradenitis suppurativa scoring systems, and long-term results of these therapies are discussed depending on the studies' endpoints.Expert opinion: Adalimumab is currently the only FDA-approved HS biological therapy. Some patients do not experience treatment efficacy with adalimumab at 40 mg/week, which may result in increasing the dose or seeking other treatments. Infliximab is the next line of HS treatment with demonstrated efficacy. Other biological therapies being studied have demonstrated efficacy in small patient groups, but lack study power. Further studies may provide answers to seeking treatment options for patients who fail to improve on current standard HS treatment.
BACKGROUND: Methotrexate is an immunomodulatory therapy that may offer benefit to patients with hidradenitis suppurativa (HS). Despite its theoretical advantages, there is a paucity of available data regarding long-term methotrexate use in patients with HS.
OBJECTIVE: This study aimed to assess whether methotrexate treatment leads to improvement in HS disease severity.
METHODS: We conducted an institutional review board-approved, single-center, retrospective chart review of patients with HS who were treated with methotrexate between 2000 and 2018. Primary outcome measurements included the HS Physician's Global Assessment (HS PGA), Hurley staging, abscess count, fistula count, and inflammatory nodule count.
RESULTS: A total of 29 patients were identified; 14 were excluded for reasons including never starting methotrexate and missing follow-up data. For remaining patients (n = 15), the average cumulative dose of methotrexate was 520.1 mg (range, 30-1665 mg) and the average length of treatment was 11.7 months (range, 1-38 months). Patients taking methotrexate as a primary therapy had a higher cumulative dose and length of treatment (520.13 mg; 14.6 months) compared with those taking biologics concomitantly (468.44 mg; 9.1 months). Patients using methotrexate as primary therapy demonstrated nonsignificant reductions in HS PGA, inflammatory nodule count, and abscess count. Patients on concomitant biologic therapy failed to demonstrate any change in HS PGA, inflammatory nodule count, and abscess count.
LIMITATIONS: Limitations of the study include its retrospective nature, small sample size, length of time on methotrexate between groups, and homogeneity of the patient population.
CONCLUSION: Methotrexate may represent an effective treatment option in older patients with lower body mass indices but fails to offer benefit in patients taking concurrent biologic therapy.
BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory, skin condition associated with many comorbidities and often has a substantial impact on patients' lives.
OBJECTIVES: To evaluate symptom burden and health-related quality of life (HRQoL) at baseline in patients with HS in an observational, real-world, clinical setting using several tools including a validated HS-specific instrument.
METHODS: This study evaluated HRQoL data from the international UNITE HS disease registry. Administration of patient-reported outcome (PRO) instruments and collection of data were executed per local regulations. All data were assessed using descriptive statistical methods.
RESULTS: PRO data from 529 adults and 65 adolescents were evaluated. Most adults (64.5%) and adolescents (73.8%) were classified as Hurley Stage II with substantial disease burden at baseline. HS had a large effect (mean DLQI = 12.6) and moderate effect (mean CDLQI = 6.9) on the lives of adults and adolescents, respectively. Approximately 58% of adults and 41% of adolescents had anxiety scores beyond the normal range; 30% of adults and 16% of adolescents exhibited symptoms of depression. Based on HSSA and HSIA scores, approximately 30% of adults reported a substantial burden of multiple HS clinical symptoms and more than 45% reported a significant emotional impact of HS that adversely affected their intimate relationships. Only 60% of adults were employed and of those, 64% reported at least some degree of impairment while working because of HS.
CONCLUSIONS: Based on PROs collected from patients enrolled in the UNITE registry, a real-world, clinical setting, HS has a significant negative impact on the everyday lives of patients affected by this disease.
BACKGROUND: Hidradenitis suppurativa (HS), also known as acne inversa, is a recurring, painful, chronic, and sometimes disfiguring inflammatory skin disease.
OBJECTIVES: Our objective was to report the baseline clinical characteristics, natural history, and associated outcomes of patients with HS from the ongoing, prospective, non-interventional UNITE registry that is collecting data regarding the natural history and associated outcomes of HS.
METHODS: Patients with inflammatory HS lesions were enrolled, including adolescents (aged 12 to < 18 years) and adults (aged ≥ 18 years). None had participated in previous or current originator-adalimumab studies/registries. Patients received treatment consistent with site-specific, routine clinical practice. HS disease status was assessed by HS lesions and disease flare; treatment and outcomes data were collected at enrolment and every 6 months for ≤ 4 years.
RESULTS: Enrolment (N = 594; 89.1% adults; 10.9% adolescents) occurred from 29 October 2013 to 29 December 2015 at 73 sites in 12 countries. At baseline, the majority were female (69.7%) and White (81.2%), had moderate-to-severe disease (Hurley stage II or III; 93.3%), and had undergone prior procedures/surgery for HS (68.7%). In total, 61.6% of adults and 49.2% of adolescents were obese; 40.2% of patients reported current tobacco use. Scarring due to lesions occurred in 91.2% of patients. The prevalence of comorbidities of interest was as follows: depression (13.3%), other psychiatric disorders (9.6%), inflammatory bowel disease (2.7%), diabetes (9.1%), and polycystic ovary syndrome (5.2%).
CONCLUSIONS: In this population from the UNITE HS registry, obesity and smoking were common, and disease burden was high, manifesting as multiple lesions, scarring, surgical history, and considerable comorbidities.
BACKGROUND: Increased interest in hidradenitis suppurativa (HS) research is encouraging. A critical analysis of the state of HS literature may demonstrate the strength of existing knowledge and highlight current gaps.
OBJECTIVES: To analyse changes in HS literature from 2008 to 2018 with focus on quantity and quality of annual publications.
METHODS: Review of all indexed publications reporting on HS on PubMed. Publications were categorized based on study design, study topic and treatment type where applicable. Publications were dichotomized into high level of evidence and low level of evidence groups. Linear regression analyses were performed to investigate the change in publication number over time. Annual average growth rate and distribution of high versus low level of evidence publications were calculated.
RESULTS: Publication number increased over time overall (R2 = 0.64, P = 0.003) and for all publication types except randomized clinical trials. Case reports and case series represented the majority of HS publications (n = 479, 40.3%). Treatment was the main focus of publications (n = 445, 37.6%) with increasing interest in medical management evident in recent years. Distribution of low level of evidence studies (n = 974) compared with high level of evidence studies over time (n = 209) was significant (x2 : 11.45, P = 0.0007). High level of evidence studies had a higher average annual growth rate (49.9%) compared with low level of evidence studies (23.7%). Few randomized clinical trials were performed (n = 16), focusing equally on medical or procedural treatments.
CONCLUSIONS: Hidradenitis suppurativa research is undergoing a tremendous shift, suggesting rapid maturation of the field. Current HS literature, however, remains primarily based on limited clinical observation data, with a particular lack of randomized clinical trials. Despite this, the increase in high level of evidence studies is encouraging and may herald a shift towards improved disease understanding and treatment paradigms.
The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogenesis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st International Hidradenitis Suppurativa Research Symposium held March 30-April 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote "Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy." (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, there is no doubt that the desired renaissance of solid basic HS research is progressing with rapid steps and that HS has developed deep roots among inflammatory diseases in Dermatology and beyond, recognized as "the only inflammatory skin disease than can be healed". This anniversary article of 43 research-performing authors from all around the globe in the official journal of the European Hidradenitis Suppurativa Foundation e.V. (EHSF e.V.) and the Hidradenitis Suppurativa Foundation, Inc (HSF USA) summarizes the evidence of the intense HS clinical and experimental research during the last 15 years in all aspects of the disease and provides information of the developments to come in the near future.
LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Describe the pathogenesis of hidradenitis suppurativa. 2. Discuss perioperative multimodal therapy of hidradenitis suppurativa, including medical optimization. 3. Determine an appropriate surgical plan with excision and reconstruction based on hidradenitis suppurativa severity, size, and anatomical location.
SUMMARY: Successful treatment of hidradenitis suppurativa requires a multidisciplinary team approach and multimodal therapy.
INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disorder characterized by nodules, abscesses, fistulae, and significant scarring in intertriginous areas rich in apocrine glands. Immunomodulator drugs, including biologics, are a mainstay of treatment for this disease.
AREAS COVERED: This review details the safety profiles of various biologic therapies currently available commercially that have been tried for HS as assessed in clinical trials and observational studies. As the only Food and Drug Administration (FDA)-approved medication for the treatment of moderate-to-severe HS, adalimumab is discussed in the most detail. Additional biologic medications, including tumor necrosis factor α (TNFα) inhibitors, interleukin 1 (IL-1) inhibitors, IL-12 and IL-23 inhibitors, IL-17 inhibitors, and IL-23 inhibitors, are discussed as well. Safety concerns in special populations, including pregnant women and children, are outlined.
EXPERT OPINION: Existing data support excellent short-term and long-term safety profiles for adalimumab, although caution must be taken with use in high-risk patient populations, including those with chronic infections or increased risk of malignancy. Based on their safety data for other indications, additional biologic agents appear safe in HS as well. However, further research is needed to fully understand the safety profiles of these medications in the HS population.
