Recommendations for rosacea diagnosis, classification and management: update from the global ROSacea COnsensus 2019 panel.

BACKGROUND: A transition from a subtyping to a phenotyping approach in rosacea is underway, allowing individual patient management according to presenting features instead of categorization by predefined subtypes. The ROSacea COnsensus (ROSCO) 2017 recommendations further support this transition and align with guidance from other working groups. OBJECTIVES: To update and extend previous global ROSCO recommendations in line with the latest research and continue supporting uptake of the phenotype approach in rosacea through clinical tool development. METHODS: Nineteen dermatologists and two ophthalmologists used a modified Delphi approach to reach consensus on statements pertaining to critical aspects of rosacea diagnosis, classification and management. Voting was electronic and blinded. RESULTS: Delphi statements on which the panel achieved consensus of ≥ 75% voting 'Agree' or 'Strongly agree' are presented. The panel recommends discussing disease burden with patients during consultations, using four questions to assist conversations. The primary treatment objective should be achievement of complete clearance, owing to previously established clinical benefits for patients. Cutaneous and ocular features are defined. Treatments have been reassessed in line with recent evidence and the prior treatment algorithm updated. Combination therapy is recommended to benefit patients with multiple features. Ongoing monitoring and dialogue should take place between physician and patients, covering defined factors to maximize outcomes. A prototype clinical tool (Rosacea Tracker) and patient case studies have been developed from consensus statements. CONCLUSIONS: The current survey updates previous recommendations as a basis for local guideline development and provides clinical tools to facilitate a phenotype approach in practice and improve rosacea patient management. What's already known about this topic? A transition to a phenotype approach in rosacea is underway and is being recommended by multiple working groups. New research has become available since the previous ROSCO consensus, necessitating an update and extension of recommendations. What does this study add? We offer updated global recommendations for clinical practice that account for recent research, to continue supporting the transition to a phenotype approach in rosacea. We present prototype clinical tools to facilitate use of the phenotype approach in practice and improve management of patients with rosacea.

Systemic therapy of ocular and cutaneous rosacea in children.

BACKGROUND: In paediatric rosacea, ocular symptoms are often predominant. Literature about systemic therapy of paediatric ocular rosacea is sparse, though. OBJECTIVE: Analysis of children with ocular rosacea treated systemically, particularly addressing remission and recurrence rates. METHODS: Retrospective study reviewing the medical records of children with ocular rosacea treated with systemic antibiotic therapy. Nine of 19 patients were chosen for detailed analysis. To our knowledge, this is the first study in paediatric ocular rosacea requiring systemic therapy with a larger patient group and a longer follow-up (mean follow-up = 30.2 months). RESULTS: 17 patients (89.5%) suffered from blepharitis, 15 patients (78.9%) from conjunctivitis, twelve patients (63.2%) from chalazia/styes and nine female patients (47.4%) from corneal involvement. We used erythromycin (n = 9) or roxithromycin (n = 1) in patients younger than 8 years and doxycycline (n = 8) or minocycline (n = 1) in patients older than 8 years. Seven of nine patients treated with erythromycin, one of eight patients treated with doxycycline and the patient treated with minocycline achieved a complete remission of ocular and cutaneous symptoms. Two of nine patients treated with erythromycin, seven of eight patients treated with doxycycline and the patient treated with roxithromycin achieved a partial remission. Relapses occurred in the patient treated with minocycline (cutaneous), two of eight patients treated with doxycycline (ocular and cutaneous) and one of nine patients treated with erythromycin (cutaneous). CONCLUSION: To achieve a complete remission of cutaneous and ocular rosacea, a long-term anti-inflammatory treatment of at least 6 months is necessary. The relapse rates seem to be lower than in adults especially in the patients treated with erythromycin.

Long-term oral therapy with valganciclovir in patients with Posner-Schlossman syndrome.

BACKGROUND: To assess the short-term and long-term efficacy of oral therapy with valganciclovir in patients with Posner-Schlossman Syndrome (PSS). METHODS: This is a retrospective observational study on 11 patients with PSS treated with valganciclovir. The PSS was diagnosed clinically on the basis of recurrent episodes of anterior uveitis associated with attacks of elevated intraocular pressure (IOP). All patients who did not respond to aciclovir, or whose cytomegalovirus (CMV) DNA polymerase chain reaction (PCR) analysis of the aqueous humour was positive, were treated with valganciclovir (Valcyte®). Initially, the drug was given 900 mg twice daily for 3 weeks, followed by 450 mg twice daily for a mean period of 20 months (range 10-46 months). RESULTS: Eleven patients with mean age of 44 years were included in this study. Four of 11 patients were working in a sanitary profession. Before initiation of valgancicloivir therapy, the highest IOP was 68 mmHg (mean 45 mmHg ±9 mmHg). In the first week of treatment, the IOP decreased significantly (mean 16 mmHg ±10 mmHg) and maintained stability during the entire treatment period. In seven of 11 (63.6 %) patients, valganciclovir led to resolution of inflammatory activity and stable IOP. In six patients, the therapy could be discontinued after a mean of 14 months. However, two patients had a recurrence after discontinuation of valganciclovir treatment. No side effects of therapy were observed. CONCLUSIONS: Long-term oral therapy with valganciclovir seems to lower the recurrence rate in patients with clinically diagnosed PSS.

[Atopic keratoconjunctivitis]. / Atopische Keratokonjunktivitis.

It is useful to define atopic keratoconjunctivitis (AKC) as a non-infectious inflammatory condition of the ocular surface, which is associated with atopy. The pathogenesis of the disorder is not completely understood. The diagnosis is based on the patient's history and the clinical manifestations. Successful management of AKC, which can become a serious condition, requires a multidisciplinary approach that involves prevention, dermatological care and an adequate ophthalmological treatment algorithm.

[Ocular rosacea]. / Ophthalmorosazea.

Half of patients with rosacea develop ocular involvement. The complaints are often nonspecific. The most common ocular manifestation is blepharoconjunctivitis with dry eye, while on rare occasion rosacea keratitis can lead to corneal ulcer, which then requires urgent ophthalmologic consultation. Topical therapy with preservative-free artificial lubricants and lid hygiene is recommended for the primary treatment of ocular rosacea. Secondarily, systemic medications are indicated depending on severity of the ocular and skin findings.

Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

Uveitis in juvenile idiopathic arthritis (JIA) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first-choice therapy, and immunosuppression is commonly used. However, treatment has not been standardized. Representatives from the German Ophthalmological Society, Society for Childhood and Adolescent Rheumatology, and the German Society for Rheumatology reached consensus on a standardized treatment strategy according to disease severity in the individual patient. The recommendations were based on a systematic literature analysis in MEDLINE and consensus expert meetings. Evidence and recommendations were graded, and an algorithm for anti-inflammatory treatment and final statements confirmed in a Delphi method. An interdisciplinary, evidence-based treatment guideline for JIA uveitis is presented.

Increasing sample diversity in psychiatric genetics - Introducing a new cohort of patients with schizophrenia and controls from Vietnam - Results from a pilot study.

OBJECTIVES: Genome-Wide Association Studies (GWAS) of Schizophrenia (SCZ) have provided new biological insights; however, most cohorts are of European ancestry. As a result, derived polygenic risk scores (PRS) show decreased predictive power when applied to populations of different ancestries. We aimed to assess the feasibility of a large-scale data collection in Hanoi, Vietnam, contribute to international efforts to diversify ancestry in SCZ genetic research and examine the transferability of SCZ-PRS to individuals of Vietnamese Kinh ancestry. METHODS: In a pilot study, 368 individuals (including 190 SCZ cases) were recruited at the Hanoi Medical University's associated psychiatric hospitals and outpatient facilities. Data collection included sociodemographic data, baseline clinical data, clinical interviews assessing symptom severity and genome-wide SNP genotyping. SCZ-PRS were generated using different training data sets: (i) European, (ii) East-Asian and (iii) trans-ancestry GWAS summary statistics from the latest SCZ GWAS meta-analysis. RESULTS: SCZ-PRS significantly predicted case status in Vietnamese individuals using mixed-ancestry (R2 liability = 4.9%, p = 6.83 × 10-8), East-Asian (R2 liability = 4.5%, p = 2.73 × 10-7) and European (R2 liability = 3.8%, p = 1.79 × 10-6) discovery samples. DISCUSSION: Our results corroborate previous findings of reduced PRS predictive power across populations, highlighting the importance of ancestral diversity in GWA studies.

[Problems associated with treating ocular disease in underlying inflammatory rheumatic disease]. / Probleme bei der Versorgung von Augenerkrankungen im Rahmen entzündlich rheumatischer Grunderkrankungen.

Ocular findings can be very typical for general disorders associated with rheumatological diseases. Of these ocular diseases, scleritis and uveitis are of particular significance. The present article discusses and attempts to solve the problems which can be seen when ocular inflammation is associated with rheumatological disorders. The identification of "uveitis" should not be sufficient to initiate diagnosis and therapy, but rather its localisation and, where possible, also its etiology should be known. These can usually be found with good clinical investigation and careful patient history. Only rarely are ocular and rheumatological inflammation active at the same time, as will be discussed later using HLA-B27-associated uveitis and juvenile idiopathic arthritis-associated uveitis as examples. It is important in the case of ocular inflammation that the indication for treatment be made by an ophthalmologist. Finally, the role of the rheumatologist in the treatment of this patient group will be described in detail.

Imaging considerations for in vivo 13C metabolic mapping using hyperpolarized 13C-pyruvate.

One of the challenges of optimizing signal-to-noise ratio (SNR) and image quality in (13)C metabolic imaging using hyperpolarized (13)C-pyruvate is associated with the different MR signal time-courses for pyruvate and its metabolic products, lactate and alanine. The impact of the acquisition time window, variation of flip angles, and order of phase encoding on SNR and image quality were evaluated in mathematical simulations and rat experiments, based on multishot fast chemical shift imaging (CSI) and three-dimensional echo-planar spectroscopic imaging (3DEPSI) sequences. The image timing was set to coincide with the peak production of lactate. The strategy of combining variable flip angles and centric phase encoding (cPE) improved image quality while retaining good SNR. In addition, two aspects of EPSI sampling strategies were explored: waveform design (flyback vs. symmetric EPSI) and spectral bandwidth (BW = 500 Hz vs. 267 Hz). Both symmetric EPSI and reduced BW trended toward increased SNR. The imaging strategies reported here can serve as guidance to other multishot spectroscopic imaging protocols for (13)C metabolic imaging applications.

Update of the evidence based, interdisciplinary guideline for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

BACKGROUND: Uveitis in juvenile idiopathic arthritis (JIAU) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first line therapy, and disease modifying anti-rheumatic drugs (DMARDs) are commonly used. However, treatment has not been standardized. METHODS: Interdisciplinary guideline were developed with representatives from the German Ophthalmological Society, Society for Paediatric Rheumatology, Professional Association of Ophthalmologists, German Society for Rheumatology, parents' group, moderated by the Association of the Scientific Medical Societies in Germany. A systematic literature analysis in MEDLINE was performed, evidence and recommendations were graded, an algorithm for anti-inflammatory treatment and final statements were discussed in a consensus meeting (Nominal Group Technique), a preliminary draft was fine-tuned and discussed thereafter by all participants (Delphi procedure). RESULTS: Consensus was reached on recommendations, including a standardized treatment strategy according to uveitis severity in the individual patient. Thus, methotrexate shall be introduced for uveitis not responding to low-dose (≤ 2 applications/day) topical corticosteroids, and a TNFalpha antibody (preferably adalimumab) used, if uveitis inactivity is not achieved. In very severe active uveitis with uveitis-related deterioration of vision, systemic corticosteroids should be considered for bridging until DMARDs take effect. If TNFalpha antibodies fail to take effect or lose effect, another biological should be selected (tocilizumab, abatacept or rituximab). De-escalation of DMARDs should be preceded by a period of  ≥ 2 years of uveitis inactivity. CONCLUSIONS: An interdisciplinary, evidence-based treatment guideline for JIAU is presented.

Interferon-alpha--a new therapeutic option in refractory juvenile Behçet's disease with CNS involvement.

OBJECTIVE: To report the successful treatment with recombinant human IFN- alpha 2a (rhIFN-alpha2a) in two male adolescents suffering from severe treatment-resistant Behçet's disease (BD) with central nervous system (CNS) involvement. METHODS: The patients were 14- and 15-yrs old. Both met the International Study Group for Behçet's disease, O'Duffy and the Japanese criteria for the classification or diagnosis of BD. Signs of CNS involvement were impaired sensorimotor function of the left arm, hemiparesis of right arm and leg, dizziness and walking instability in Patient 1, weakness of both legs, impaired bladder-, bowel- and sexual function in Patient 2 and vasculitic lesions on cranial MRI in both patients. RhIFN-alpha2a was administered initially at 3 million IU/day for 4 weeks followed by 3 x 3 million IU/week. RESULTS: Complete remission was achieved in Patient 1 (reduction in BD activity score from 17 to 2). Patient 2 experienced remarkable improvement (reduction of BD activity score from 23 to 15). In both patients the MRI lesions improved. Patient 2 had mild flu-like symptoms as adverse effect. CONCLUSION: RhIFN-alpha2a was effective and well tolerated in these juvenile patients with severe neurological BD. Regarding the serious consequences following ocular and CNS affection and adverse effects of steroid dependency, administration of rhIFN-alpha2a at an earlier time point needs to be considered.

[Scleromalacia associated with varicella-zoster virus]. / Varizella-zoster-Virus-assoziierte Skleromalazie.

BACKGROUND: Scleromalacia usually appears following vasculitis in systemic rheumatoid diseases, especially as a late symptom of rheumatoid arthritis. CASE REPORT: A 67-year-old woman was referred to our hospital for further evaluation with the diagnosis of a "fast-growing tumor" of the left eye. Sixteen months ago she had suffered from herpes zoster ophthalmicus-associated keratouveitis and trabeculitis in the same eye. Scleromalacia associated with varicella-zoster virus (VZV) was diagnosed after the biomicroscopic and gonioscopic examination of the eye was completed and a systemic disease had been ruled out. One week after beginning systemic application of acyclovir (5 x 800 mg daily) and prednisolone (30 mg daily), the anterior chamber inflammation regressed and a fibrosis seemed to appear in the atrophic scleral area. CONCLUSION: Although scleral atrophy mostly appears as a late sign of systemic rheumatoid diseases, it might also develop secondary to infectious diseases. Scleromalacia associated with varicella-zoster virus has been previously described only in a few cases. Scleromalacia is a vision-threatening complication of zoster ophthalmicus which responds well to combination therapy with systemic antiviral and anti-inflammatory agents.

Mycophenolate mofetil in the treatment of uveitis in children.

BACKGROUND: Mycophenolate mofetil (MMF) is a new immunosuppressive agent that effectively controls the intraocular inflammation in adults. PURPOSE: To assess the efficacy of MMF in uveitis in children and to analyse the possible side effects. PARTICIPANTS AND METHODS: A retrospective analysis was carried out on 17 children (32 eyes) with intraocular inflammation treated with MMF and followed up at the University Eye Hospital Tuebingen, Tuebingen, Germany, between 2000 and 2005. All children had chronic non-infectious uveitis and received MMF for at least 6 months. All patients were given steroids or other immunosuppressive agents before initiating treatment with MMF. RESULTS: 17 children (10 boys and 7 girls) with a mean age of 8 (range 2-13) years at the onset of uveitis were examined. The average duration of follow-up after initiation of MMF was 3 (range 2-5) years. A steroid-sparing effect was achieved in 88% of the patients. The oral prednisolone was successfully discontinued in 41% children and reduced to a daily dose of < or =5 mg in 47% of the children. 24% of the patients remained relapse-free during the treatment, but a reduction in the relapse rate was observed in all other patients except one. Visual acuity was increased or maintained in 13 children (76%). Mild side effects (headache, rash, gastrointestinal discomfort) occurred in 7 patients (41%) and were the cause of discontinuation of MMF in 1 patient. CONCLUSION: The results of our study are encouraging and suggest that MMF is an effective agent also in the treatment for uveitis in children, with marked steroid-sparing potential and an acceptable side effect profile.

[Two children with intermediate uveitis and granuloma annulare from the same neighbourhood]. / Zwei Kinder mit intermediärer Uveitis und Granuloma anulare in derselben Nachbarschaft.

Two children from the same neighbourhood presented with concomitant granuloma annulare (GA) and intermediate uveitis (IU) at an interval of 2 weeks. A coincidence seemed unlikely, as IU is very rare in children and even more so in connection with GA. Thorough diagnosis was performed to exclude other associated diseases. No systemic disease, no special features of vaccination or medication, no history of infection, and no toxic cause could be found. An association between GA and IU based on other, as yet undiagnosed factors, is still possible. Therefore, when evaluating patients with newly diagnosed IU, clinical work-up should also include medical history and examination to rule out GA.

MAGIC or not MAGIC--does the MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome really exist? A case report and review of the literature.

INTRODUCTION: In 1985, Firestein et al. described 5 patients with relapsing polychondritis and Behçet's disease (BD) and proposed the term "MAGIC" syndrome as an acronym for "Mouth and Genital ulcers with Inflamed Cartilage". We report on an additional case of this syndrome and critically review the literature. RESULTS: From 1985 to 2004 eleven cases of MAGIC syndrome were described. All patients had chondritis and oral aphthous ulcers, as well as ocular inflammation (mainly anterior uveitis or scleritis/episcleritis). Most patients also presented with genital ulcers and arthritis. In one case, aortic aneurysm, in another aortic insufficiency was described, one had meningoencephalitis, one had antiphospholipid syndrome and one was HIV positive. Before 1985, we could find 4 additional probable cases. Our own patient presented with oral and genital ulcers, auricular chondritis and episcleritis. HLA-typing was performed and revealed HLA-B*51, B*15, DRB1*04x and DRB1*11x. Only in one Japanese patient from the literature, HLA-typing was available and revealed HLA-B*56, B*62, DRB1*0406 and DRB1*0901. CONCLUSIONS: Relapsing polychondritis is associated with HLA-DRB1*04 suballeles, but not necessarily only with those being associated with RA (DRB1*0401 and 0404). In 2 MAGIC patients these suballeles were found. All patients described in the literature had typical polychondritis, but not all did fulfil the classification criteria for BD. Many features of both diseases overlap and are not specific. As polychondritis is associated with other inflammatory rheumatic conditions such as SLE, spondyloarthropathy, rheumatoid arthritis and systemic vasculitides in 30% of all cases, we suggest that MAGIC syndrome is not a disease entity, but merely the association of BD with polychondritis.

[Uveitis and the aging]. / Die Uveitis des alternden Menschen.

Uveitis can be found in all age groups, but the age of disease onset may provide important information on the etiology of the disease. New data on the epidemiology of uveitis disclose a higher incidence and prevalence in older patients then has previously been found. Masquerade syndromes which mimic uveitis may be found especially in younger and older patients. These have to be excluded from regular intraocular inflammation. Here, intraocular lymphoma plays a major role which is most often associated with severe clinical, diagnostic and therapeutic challenges. One of the major complications of uveitis is cataract formation. Keeping in mind the importance of pre- and postoperative treatment, even implantation of an intraocular lens in older patients with uveitis is currently a safe procedure.

Ignorance is not bliss: Statistical power is not probability of trial success.

The purpose of this commentary is to place probability of trial success, or assurance, in the context of decision making in drug development, and to illustrate its properties in an intuitive manner for the readers of Clinical Pharmacology and Therapeutics. The hope is that this will stimulate a dialog on how assurance should be incorporated into a quantitative decision approach for clinical development and trial design that uses all available information.

Clinical Trial Simulations From a Model-Based Meta-Analysis of Studies in Patients With Advanced Hepatocellular Carcinoma Receiving Antiangiogenic Therapy.

A mixed effect model describing median overall survival (mOS) in patients with advanced hepatocellular carcinoma (aHCC) treated with antiangiogenic therapy (AAT) was developed from literature data. Data were extracted from 59 studies, representing 4,813 patients. The final model included estimates of mOS after AAT (8.5 months) or placebo (7.1 months) administration. The mOS increased 21% when the AAT was sorafenib (SOR) or 42% when locoregional therapy was coadministered. The mOS decreased when patients received prior systemic therapy (↓7%) or concomitant chemotherapy (↓4%) or the percentage of patients with hepatitis B increased (↓∼0.4%/%). Clinical trial simulations of a phase II comparative trial predicted an mOS ratio (placebo:AAT) of 0.687 or 0.831, with a 65% or 22% probability of demonstrating superiority, for SOR or other AATs, respectively. Additionally, the 95% confidence interval (CI) of the simulated median mOS ratio for non-SOR AATs was similar to the 95% CI of the hazard ratio (HR) observed in the trial.

Cytokines, cytokine antagonists and soluble adhesion molecules in patients with ocular Behçet's disease treated with human recombinant interferon-alpha2a. Results of an open study and review of the literature.

OBJECTIVE: To elucidate the influence that interferon-alpha exerts on the cytokine network in active ocular Behçet's disease (BD). METHODS: Fifty patients with active ocular BD were treated with human recombinant interferon-alpha2a (rhIFN-alpha2a). Serum was analysed for the presence of IL-10, TNF-alpha, IL-8, IL-6, sIL-2R, IFN-gamma, IFN-alpha, IL-12, IL-4, sTNFRI (p55), sTNFRII (p75), IL-1RA, G-CSF, sE-selectin, sVCAM-1, sICAM-1 and neopterin before initiation of and at several time points during IFN treatment and compared to 21 healthy controls. RESULTS: The levels of IFN-alpha IL1-RA and sTNFRII were significantly increased in the patients at baseline in comparison to healthy controls. During treatment with rhIFN-alpha2a, when remission was achieved as defined by the scoring system used, a significant increase in levels of IFN-alpha, IL-2R, TNF-alpha, sTNF-RII, sICAM-1, sVCAM-1, neopterin in the serum was observed, with a tendency towards increased IL-1RA as well. In contrast, leuko- and thrombocyte counts and sE-selectin serum levels significantly decreased. Positive correlations were found between IFN dosage or serum levels and sVCAM-I, neopterin, sTNF-RII and sIL-2R, between sVCAM-1, sIL-2R, TNF-alpha, sTNF-RII and neopterin, sICAM-I and sVCAM-1, sIL2-R and sTNF-RII, and, finally, between sIL2-R and sICAM-I. CONCLUSIONS: IFN-alpha exerts diverse influences mainly on cytokine antagonists and soluble adhesion molecules. Because sTNF-RII and IL-1RA were increased by IFN-alpha treatment, these might be interesting alternative treatment options in refractory BD. Some of the side-effects of IFN-alpha may be caused by activation of monocytes, which is reflected by an increase in neopterin serum levels.