Risk factors for lung function decline in systemic sclerosis-associated interstitial lung disease in a large single-centre cohort.

OBJECTIVES: The aim of this study was to identify risk factors of percent predicted forced vital capacity (ppFVC) decline in patients with SSc-associated interstitial lung disease (SSc-ILD). METHODS: We identified 484 patients with SSc who had HRCT Chest, of which 312 with ILD. Those with serial pulmonary function tests were included in a longitudinal analysis (n = 184). Linear mixed effect models were fitted to assess the decline in ppFVC over time, and to explore the effect of demographics and baseline characteristics on ppFVC decline. RESULTS: The majority of SSc-ILD patients were female (76.3%) and 51.3% had diffuse cutaneous subset. The mean (s.d.) age was 53.6 (12.7) years, median disease duration since first non-RP symptoms was 2.6 years, and 48.4% of the patients had ILD extent >20% on HRCT. In the univariate analysis, longer disease duration (>2.37 years), ILD extent >20%, and anti-topoisomerase I (ATA) positivity were significantly associated with ppFVC decline. In the multivariate analysis, the only statistically significant variable associated with ppFVC decline was ATA positivity. The overall group's mean decline in ppFVC was -0.28% (P-value 0.029), with -0.13% (n = 163) in those who were alive and -8.28% (P-value 0.0002 for the change in ppFVC trajectory) in patients who died within 2 years. CONCLUSION: Our study confirms that ppFVC is a marker of survival in SSc-ILD, supporting its use for risk stratification to identify patients who may benefit from earlier interventions and treatment. Our study also supports the role of ATA positivity as a predictive marker for ppFVC decline in this population.

Systemic sclerosis associated interstitial lung disease: a conceptual framework for subclinical, clinical and progressive disease.

OBJECTIVES: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). METHODS: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. RESULTS: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. CONCLUSIONS: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Domains and outcome measures for the assessment of limited cutaneous systemic sclerosis: an international collaborative scoping review.

OBJECTIVES: The aim of this study was to comprehensively identify instruments within relevant domains employed to assess lcSSc since the endorsement of its consensus definition in 1988. The overall objective is to inform the creation of a Combined Response Index for Scleroderma Trials Assessing lcSSc (CRISTAL). METHODS: MEDLINE and Embase were searched using terms selected to comprehensively retrieve titles and abstracts mentioning both lcSSc and dcSSc, along with those only mentioning lcSSc, SSc sine scleroderma, limited SSc and/or CREST/CRST. Because our initial assessment of the literature revealed that very few studies included only lcSSc subjects, we also assessed literature that included both cutaneous subsets. A total of 3964 titles and abstracts were screened by two reviewers, and 270 articles were selected for data extraction. RESULTS: We identified 27 domains encompassing 459 instruments. Instruments from 'Skin involvement', 'Pulmonary involvement' and 'Health-related quality of life and general functioning' were the most frequently retrieved. Among the 15 most represented instruments announced as primary end points in efficacy or effectiveness studies, 7 were clinician-reported outcomes (ROs), 7 were patient ROs, and one was a performance outcome (6 min-walk test). The mean proportion of lcSSc patients in studies of lcSSc, including studies that mention both lcSSc and dcSSc, was 56.4%, demonstrating that this subset is underrepresented in the literature, given that the prevalence of lcSSc ranges from 60% to 80% in national registries and international cohorts. CONCLUSION: This scoping literature review provides a comprehensive identification of domains and outcomes used to assess lcSSc. Our results also highlight that lcSSc is underrepresented in the literature.

Treatment for systemic sclerosis-associated interstitial lung disease.

PURPOSE OF REVIEW: This review provides an overview of the current treatments for systemic sclerosis-interstitial lung disease (SSc-ILD) and proposes a conceptual framework for disease management with case scenarios. RECENT FINDINGS: Broad treatment categories include traditional cytotoxic therapies, biologic disease-modifying rheumatic drugs, antifibrotic agents, autologous hematopoietic stem cell transplant, and lung transplantation. The optimal use of each option varies depending on SSc-ILD severity, progression, and comorbidities of individual patients. A high-quality randomized controlled trial demonstrated nintedanib's ability to retard decline of lung function in patients with limited and diffuse cutaneous disease, with established ILD. Tocilizumab, recently approved by the FDA, provides a unique intervention in those with early SSc associated with ILD with elevated acute-phase reactants: two well designed trials showed lung function preservation in phase 2 and phase 3 trials. SUMMARY: Stratifying patients based on key SSc-ILD characteristics (e.g. severity, risk of progression, comorbid disease presentation) may provide a useful guide for practitioners treating SSc-ILD.

Hospitalisations related to systemic sclerosis and the impact of interstitial lung disease. Analysis of patients hospitalised at the University of Michigan, USA.

OBJECTIVES: To determine the primary reason for hospitalisations in systemic sclerosis (SSc) and impact of underlying interstitial lung disease (ILD) in a tertiary scleroderma centre. METHODS: A retrospective analysis on a subset of a scleroderma cohort from 2011-2019 was performed to assess causes for hospitalisations and mortality. A chart review was performed to extract demographics, primary reason for hospitalisation and inpatient mortality. Admissions were classified as SSc (if hospitalisation reason was related to primary organ dysfunction) and non-SSc related causes. RESULTS: The mean age of the cohort was 53.1 years, 78% were women, and the mean disease duration was 5.2 years. Among 484 patients, 182 (37.6%) were admitted for a total of 634 admissions. In 382 SSc-related admissions, pulmonary hypertension (12.0%) and gastrointestinal dysmotility (11.0%), were major causes of urgent admissions; management of digital vasculopathy (26.1%) was the major reason for elective admissions. In 252 non-SSc related admissions, infection (respiratory:11.5%, skin and soft tissue: 6.3%) was the major reason for urgent admissions, and elective surgery (21.4%) was the major reason for elective admissions. We found 65% of all patients had underlying ILD and a greater proportion of patients with ILD were hospitalised (122 patients). Overall inpatient mortality was 9.3% and the leading cause for mortality was progressive pulmonary hypertension. CONCLUSIONS: Among a large cohort of SSc patients who are followed at a tertiary scleroderma centre, 37.6 % had hospital admissions, while worsening pulmonary hypertension, ILD, cardiac involvement and infectious complications were the major cause of mortality and morbidity.

Management of systemic sclerosis: the first five years.

PURPOSE OF REVIEW: This review provides a risk-stratified and evidence-based management for subsets of systemic sclerosis (SSc) patients in the first five years from disease onset. RECENT FINDINGS: Cardiopulmonary disease remains the primary cause of mortality in SSc patients. Morbidity and mortality in SSc-associated pulmonary arterial hypertension have improved with combination treatment, in either an upfront or sequential treatment pattern. Traditional therapies for interstitial lung disease (SSc-ILD) have targeted those with clinically significant and progressive ILD with immunosuppression. New data suggest a possible paradigm shift, introducing immunosuppressive therapy to patients before they develop clinically significant or progressive ILD. The year 2019 saw the approval of the first FDA-approved therapy for SSc-associated interstitial lung disease, using an antifibrotic agent previously approved for idiopathic pulmonary fibrosis. To date, only autologous hematopoietic stem cell transplant has demonstrated a mortality benefit for SSc-ILD, albeit in a narrow spectrum of SSc-ILD patients. SUMMARY: SSc is a highly heterogeneous autoimmune disease typified by varying clinical trajectories. Its management may be stratified within the first five years by subclassifying patients based on factors that have important prognostic significance: skin distribution and autoantibody status.

Emerging drugs for the treatment of scleroderma: a review of recent phase 2 and 3 trials.

INTRODUCTION: Systemic sclerosis (SSc) has the highest case-specific mortality of all connective tissue diseases. Its underlying disease mechanism affects several organs and remains incompletely understood. Ongoing work clarifying its etiopathogenesis is helping to develop targeted therapy. AREAS COVERED: Several clinical trials have evaluated the safety and efficacy of agents targeting different mechanisms of this disease. This review article reviews those mechanisms and surveys four key recent phase II or III clinical trials that are contributing to the landscape of SSc therapy. The reported trials primarily focus on patients with systemic sclerosis in the early phase of disease. EXPERT OPINION: Traditional therapies for SSc center on immunosuppressive and cytotoxic agents. A new cadre of therapies is borne from improved understandings of SSc pathobiology and target the inflammatory-fibrotic pathways. Scleroderma trials have entered the initial phase of personalized medicine, recognizing molecular subsets that will improve upon cohort enrichment and maximize the measurable benefit of future therapies.

Management of systemic sclerosis-associated interstitial lung disease.

PURPOSE OF REVIEW: To review the recently published data and provide a practical overview for management of systemic sclerosis-interstitial lung disease (SSc-ILD). RECENT FINDINGS: Published evidence shows considerable practitioner variability in screening patients for ILD. Recent published data support use of cyclophosphamide or mycophenolate mofetil as first-line treatment of SSc-ILD. For patients not responding to first-line therapies, consideration is given to rituximab as rescue therapy. Recent trials of hematopoietic autologous stem cell transplantation have demonstrated benefit in patients with progressive SSc-ILD. Antifibrotic agents are approved in idiopathic pulmonary fibrosis; studies with antifibrotics are underway for SSc-ILD. SUMMARY: The specter of rapidly progressive lung disease requires clinicians to risk stratify patients according to known predictors for progression and rigorously monitor for symptoms and advancing disease. The abovementioned therapies promise improved efficacy and favorable side-effect profiles compared to cyclophosphamide.

Therapeutic Approaches to Systemic Sclerosis: Recent Approvals and Future Candidate Therapies.

Systemic sclerosis is the rheumatic disease with the highest individual mortality. The severity of the disease is determined by the extent of fibrotic changes to cutaneous and internal organ tissues, the most life-threatening visceral manifestations being interstitial lung disease, SSc-associated-pulmonary arterial hypertension and myocardial involvement. The heterogeneity of the disease has initially hindered the design of successful clinical trials, but considerations on classification criteria have improved patient selection in trials, allowing the identification of more homogeneous groups of patients based on progressive visceral manifestations or the extent of skin involvement with a focus of patients with early disease. Two major subsets of systemic sclerosis are classically described: limited cutaneous systemic sclerosis characterized by distal skin fibrosis and the diffuse subset with distal and proximal skin thickening. Beyond this dichotomic subgrouping of systemic sclerosis, new phenotypic considerations based on antibody subtypes have provided a better understanding of the heterogeneity of the disease, anti-Scl70 antibodies being associated with progressive interstitial lung disease regardless of cutaneous involvement. Two targeted therapies, tocilizumab (a monoclonal antibody targeting interleukin-6 receptors (IL-6R)) and nintedanib (a tyrosine kinase inhibitor), have recently been approved by the American Food & Drug Administration to limit the decline of lung function in patients with SSc-associated interstitial lung disease, demonstrating that such better understanding of the disease pathogenesis with the identification of key targets can lead to therapeutic advances in the management of some visceral manifestations of the disease. This review will provide a brief overview of the pathogenesis of SSc and will present a selection of therapies recently approved or evaluated in this context. Therapies evaluated and approved in SSc-ILD will be emphasized and a review of recent phase II trials in diffuse cutaneous systemic sclerosis will be proposed. We will also discuss selected therapeutic pathways currently under investigation in systemic sclerosis that still lack clinical data in this context but that may show promising results in the future based on preclinical data.

Systemic Sclerosis-Associated Interstitial Lung Disease: How to Incorporate Two Food and Drug Administration-Approved Therapies in Clinical Practice.

Systemic sclerosis (SSc; scleroderma) has the highest individual mortality of all rheumatic diseases, and interstitial lung disease (ILD) is among the leading causes of SSc-related death. Two drugs are now approved by the US Food and Drug Administration (FDA) and indicated for slowing the rate of decline in pulmonary function in patients with SSc-associated ILD (SSc-ILD): nintedanib (a tyrosine kinase inhibitor) and tocilizumab (the first biologic agent targeting the interleukin-6 pathway in SSc). In addition, 2 generic drugs with cytotoxic and immunoregulatory activity, mycophenolate mofetil and cyclophosphamide, have shown comparable efficacy in a phase II trial but are not FDA-approved for SSc-ILD. In light of the heterogeneity of the disease, the optimal therapeutic strategy for the management of SSc-ILD is still to be determined. The objectives of this review are 2-fold: 1) review the body of research focused on the diagnosis and treatment of SSc-ILD; and 2) propose a practical approach for diagnosis, stratification, management, and therapeutic decision-making in this clinical context. This review presents a practical classification of SSc patients in terms of disease severity (subclinical versus clinical ILD) and associated risk of progression (low versus high risk). The pharmacologic and nonpharmacologic options for first- and second-line therapy, as well as potential combination approaches, are discussed in light of the recent approval of tocilizumab for SSc-ILD.

Tocilizumab Prevents Progression of Early Systemic Sclerosis-Associated Interstitial Lung Disease.

OBJECTIVE: Tocilizumab (TCZ) has demonstrated lung function preservation in 2 randomized controlled trials in early systemic sclerosis (SSc). This effect has yet to be characterized in terms of radiographically evident quantitative lung involvement. We undertook this study to assess the impact of TCZ on lung function preservation in a post hoc analysis, stratifying treatment arms according to the degree of lung involvement. METHODS: The focuSSced trial was a phase III randomized placebo-controlled trial of TCZ in patients with SSc and progressive skin disease. Participants underwent baseline and serial spirometry along with high-resolution chest computed tomography at baseline and at week 48. Quantitative interstitial lung disease (QILD) and fibrosis scores were assessed by computer software. We classified QILD into the following categories of lung involvement: mild (>5-10%), moderate (>10-20%), and severe (>20%). RESULTS: Of 210 participants recruited for the trial, 136 patients (65%) had ILD. The majority of these patients (77%) had moderate-to-severe involvement (defined as >10% lung involvement). The TCZ arm demonstrated preservation of forced vital capacity percent predicted (FVC%) over 48 weeks (least squares mean change in FVC% = -0.1) compared to placebo (-6.3%). For mild, moderate, and severe QILD, the mean ± SD change in FVC% in the TCZ arm at 48 weeks were -4.1 ± 2.5% (n = 11), 0.7 ± 1.9% (n =19), and 2.1 ± 1.6% (n = 26), respectively, and in the placebo group were -10.0 ± 2.6% (n = 11), -5.7 ± 1.6% (n = 26), and -6.7 ± 2.0% (n = 16), respectively. Similar treatment-related preservation findings were seen independent of fibrosis severity. CONCLUSION: TCZ in early SSc-associated ILD with progressive skin disease stabilized FVC% over 48 weeks, independent of the extent of radiographically evident QILD.

Domains and outcome measures for the assessment of limited cutaneous systemic sclerosis: a scoping review protocol.

INTRODUCTION: Limited cutaneous systemic sclerosis (lcSSc) is the most frequent subset of systemic sclerosis. Despite this, lcSSc is not the major focus of clinical studies. The lack of interventional studies in lcSSc is due, in part, to a paucity of relevant outcome measures to effectively evaluate this subset. A combined response index dedicated to lcSSc would facilitate development of well-designed trials and approval of new drugs. The objective of this scoping review is to perform a broad and comprehensive identification of the outcome measures (core set items) within relevant domains, which have been used so far to assess lcSSc. METHODS AND ANALYSIS: The planned scoping review will be based on the approach proposed by Arksey et al and further developed by Levac et al. Development and reporting will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Extension for Scoping Reviews checklist and guidelines. The development of the search strategy was guided by the concepts of domains and outcomes based on the Outcome Measures in Rheumatology approach and by the different names and definitions of SSc, with a specific emphasis on their occurrence in clinical trial studies. Two databases will be searched: MEDLINE and Embase. Studies in English, published from the year 1988 onwards, will be included, since 1988 corresponds to the publication of LeRoy's first consensus definition of lcSSc. Data will be extracted and analysed using a standardised charting tool. ETHICS AND DISSEMINATION: No ethical approval is required for this study. The results will be submitted to an international peer-reviewed journal and scientific conferences, informing the discussion on which items should be included in a combined response index dedicated to lcSSc (the CRISTAL project: Combined Response Index for Scleroderma Trial Assessing lcSSc).

Clinical characteristics, visceral involvement, and mortality in at-risk or early diffuse systemic sclerosis: a longitudinal analysis of an observational prospective multicenter US cohort.

BACKGROUND: Early diffuse cutaneous systemic sclerosis (dcSSc) has the highest case fatality among rheumatic diseases. We report baseline characteristics, current immunosuppressive therapies, progression of skin and internal organ involvement, and mortality in a multicenter prospective cohort from the United States (US) of America. METHODS: We performed a longitudinal analysis of participants from 12 US centers, from April 2012 to July 2020. All participants had early dcSSc or were at-risk for dcSSc, with ≤2 years since the first non-Raynaud's phenomenon (RP) symptom. RESULTS: Three hundred one patients were included with a baseline median disease duration of 1.2 years since RP and a mean modified skin score of 21.1 units. At baseline, 263 (87.3%) had definite dcSSc and 38 (12.7%) were classified as at-risk; 112 (49.6%) patients were positive for anti-RNA polymerase III antibodies. The median follow-up duration was 24.5 months (IQR = 10.3-40.7 months). One hundred ninety (63.1%) participants were treated with an immunosuppressive therapy, of which mycophenolate mofetil was most used at baseline and follow-up. Of 38 who were classified as at-risk at baseline, 27 (71%) went on to develop dcSSc; these patients were characterized by higher baseline mean HAQ-DI (0.8 versus 0.4, p = 0.05) and higher baseline mRSS (8.8 versus 4.4, p < 0.01) in comparison with those who remained as limited cutaneous SSc. In the overall cohort, 48 participants (21.1%) had clinically significant worsening of skin fibrosis, mainly occurring in the first year of follow-up; 41 (23.3%) had an absolute forced vital capacity decline of ≥10%. Twenty participants (6.6%) died, of which 18 died in the first 3 years of follow-up. Cardiac involvement (33.3%), gastrointestinal dysmotility (22.2%), and progressive interstitial lung disease (ILD) (16.7%) were the main causes of death. CONCLUSION: This US cohort highlights the management of early SSc in the current era, demonstrating progression of skin and lung involvement despite immunosuppressive therapy and high mortality due to cardiac involvement.

Considerations for a combined index for limited cutaneous systemic sclerosis to support drug development and improve outcomes.

Systemic sclerosis (SSc; systemic scleroderma) is characterized by a heterogeneous range of clinical manifestations. SSc is classified into limited cutaneous SSc (lcSSc) and diffuse cutaneous subgroups (dcSSc) based on the extent of skin involvement. Randomized controlled trials in scleroderma have mainly focused on dcSSc partly because the measurement of skin involvement, critical for evaluating a therapeutic intervention is more dynamic in this subset. Nonetheless, lcSSc, the most common cutaneous subset (about 2/3), is also associated with significant morbidity and detrimental impact on health-related quality of life. The lack of interventional studies in lcSSc is partly due to a lack of relevant outcome measures to evaluate this subgroup. Combining several clinically meaningful outcomes selected specifically for lcSSc may improve representativeness in clinical trials and responsiveness of outcomes measured in randomized controlled trials. A composite index dedicated to lcSSc combining such relevant outcomes could advance clinical trial development for lcSSc by providing the opportunity to test and select among candidate drugs that could act as disease-modifying treatments for this neglected subgroup of SSc. This proposed index would include items selected by expert physicians and patients with lcSSc across domains grounded in the lived experience of lcSSc. This article reviews the reasons behind the relative neglect of lcSSc, discusses the current state of outcome measures for lcSSc, identifies challenges, and proposes a roadmap for a combined lcSSc-specific treatment response index.

Outcome measurement instrument selection for lung physiology in systemic sclerosis associated interstitial lung disease: A systematic review using the OMERACT filter 2.1 process.

OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) is a research organization focused on improving health care outcomes for patients with autoimmune and musculoskeletal diseases. The Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD) Working Group on Lung Physiology is a group within OMERACT charged with identifying outcome measures that should be implemented in studies of patients with CTD-ILD. The OMERACT Filter 2.1 is an evidence-based algorithm used to identify outcome measures that are truthful, feasible, and able to discriminate between groups of interest. Our objective was to summate evidence (published literature, key opinion leader input, patient perspectives) that would influence the CTD-ILD Working Group's vote to accept or reject the use of two measures of lung physiology, the forced vital capacity (FVC) and the diffusion capacity of carbon monoxide (DLco) for use in randomized controlled trials (RTCs) and longitudinal observational studies (LOSs) involving patients with systemic sclerosis associated ILD (SSc-ILD). METHODS: Patient Research Partners (those afflicted with SSc-ILD) and the CTD-ILD Working Group on Lung Physiology were polled to assess their opinion on the FVC and DLco in terms of feasibility; the CTD-ILD Working Group was also queried on these instruments' face and content validity. We then conducted a systematic literature review to identify articles in the SSc-ILD population that assessed the following measurement properties of FVC and DLco: (1) construct validity, (2) test-retest reliability, (3) longitudinal construct validity, (4) clinical trial discrimination/sensitivity to detect change in clinical trials, and (5) thresholds of meaning. Results were summarized in a Summary of Measurement Properties (SOMP) table for each instrument. OMERACT CTD-ILD Working Group members discussed and voted on the strength of evidence supporting these two instruments and voted to endorse, provisionally endorse, or not endorse either instrument. RESULTS: Forty Patient Research Partners reported these two measures are feasible (are not an unnecessary burden or represent an infeasible longitudinal assessment of their disease). A majority of the 18 CTD-ILD Working Group members voted that both the FVC and DLco are feasible and have face and content validity. The systematic literature review returned 1,447 non-duplicated articles, of which 177 met eligibility for full text review. Forty-eight studies (13 RCTs, 35 LOSs) were included in the qualitative analysis. The FVC SOMP table revealed high quality, consistent data with evidence of good performance for all five measurement properties, suggesting requisite published evidence to proceed with endorsement. The DLco SOMP table showed a lack of data to support test-retest reliability and inadequate evidence to support clinical trial discrimination. There was unanimous agreement (15 [100%]) among voting CTD-ILD Working Group members to endorse the FVC as an instrument for lung physiology in RCTs and LOSs in SSc-ILD. Based on currently available evidence, DLco did not meet the OMERACT criteria and is not recommended for use in RCTs to represent lung physiology of SSc-ILD. The OMERACT Technical Advisory Group agreed with these decisions. CONCLUSION: The OMERACT Filter 2.1 was successfully applied to the domain of lung physiology in patients with SSc-ILD. The FVC was endorsed for use in RCTs and LOSs based on the Working Group's vote; DLco was not endorsed.

Treatment of systemic sclerosis-associated interstitial lung disease: Lessons from clinical trials.

Systemic sclerosis-associated interstitial lung disease remains a leading cause of mortality. Despite decades of clinical trials, the treatment effects of disease modifying anti-rheumatic drugs continue to be modest and there remains a great need for therapies that attenuate and hopefully ameliorate parenchymal lung disease. In this review, we highlight the key clinical trials that have shaped the management strategies employed by the authors, providing their strength of recommendation based on level of evidence. We also review lessons learned in more recent years, suggesting a benefit in targeting patients with subclinical interstitial lung disease with high risk for progression early in the disease course, as well as the benefit seen in a large clinical trial leading to the first Food and Drug Administration-approved treatment for systemic sclerosis-associated interstitial lung disease. These lessons come in a context of heterogeneity of patient populations and response to therapy, as well as the inherent constraints of time-limited studies to detect meaningful outcomes for patients.

Early-onset schizophrenia is associated with impaired adolescent development of attentional capacity using the identical pairs continuous performance test.

The authors examined performance on the Continuous Performance Test-Identical Pairs "numbers" task in adolescents with schizophrenia (n=59) and healthy controls (n=55). Adjusting for an estimate of premorbid intelligence and socioeconomic status, patients performed worse than normal controls on all three d' conditions (2-digit, 3-digit, 4-digit). However, there was a significant group-by-age-by-condition interaction (F[4,100]=4.69, p<.01) indicating an interaction between development and disease state. At the simplest level of the task (2-digit) the difference between patients with schizophrenia and controls was evident at all ages; while for the more difficult levels of the task (3-digit, 4-digit), differences between groups gradually increased across the tested age span (10 to 20 years of age). Premorbid social isolation was associated with worse attentional performance in patients, suggesting a relationship and continuity with negative symptoms. These data suggest that attentional differences in adolescents with schizophrenia are better captured by different tasks at different ages. The discrepant findings of attentional impairments reported in the literature for adolescents with schizophrenia could reflect the underlying etiological complexity of the disorder that may have a variable impact on involved brain regions and neurocognitive functioning.

Deficits in memory strategy use are related to verbal memory impairments in adolescents with schizophrenia-spectrum disorders.

OBJECTIVE: To assess the nature of learning and verbal memory deficits in adolescents with schizophrenia-spectrum disorders (SzS) (i.e., schizophrenia, schizoaffective disorder, and schizophreniform disorder). METHOD: Sixty patients with SzS (mean age=16.1 years, S.D. = 2.2) and 60 age- and gender-matched diagnosis-free healthy volunteers were assessed using the California Verbal Learning Test (CVLT). Planned analyses were conducted to assess the following aspects of memory: span of apprehension, verbal learning, short-term and long-term memory, rate of forgetting, interference, and organizational strategies. Adolescents with schizophrenia (Sz) were compared to those with schizoaffective disorder (SzA). Second, patients' test profiles were compared to those of controls. Relationships between initial learning and overall verbal learning with organizational strategy were explored. RESULTS: Neurocognitive profiles did not significantly differ between Sz and SzA participants. Patients performed significantly worse than healthy comparison subjects on measures of span of apprehension, verbal learning, short- and long-term memory, and organizational strategies after adjusting for differences in premorbid intelligence. No group differences were found in rate of forgetting or susceptibility to proactive or retroactive interference. CONCLUSIONS: Adolescents with SzS are characterized by significant verbal memory dysfunction similar to what has been observed in adults with first-episode schizophrenia. Deficits in consistency of learning over several trials, as well as a strong relationship between semantic organizational strategies and reduced learning capacity, implicate dysfunction of the dorsolateral prefrontal cortex as a contributor to verbal memory deficits in adolescents with SzS.

Clozapine: its impact on aggressive behavior among children and adolescents with schizophrenia.

OBJECTIVE: To evaluate the effectiveness of clozapine on aggressive behavior for treatment-refractory adolescents (age range 8.5-18) with schizophrenia (295.x) at Bronx Children's Psychiatric Center. METHOD: Clozapine treatment was administered in an open-label fashion using a flexible titration schedule. The frequency of administration of emergency oral and injectable medications and the frequency of seclusion events 3 months immediately before and from 12 to 24 weeks of clozapine treatment (when optimal clozapine levels were achieved) were compared. RESULTS: Twenty clozapine-treated children (mean +/- SD dose at week 24, 476 +/- 119 mg) were included. A statistically significant decrease in the frequency of the administration of emergency oral medications, the administration of emergency injectable medications, and seclusion events was found in adolescents during weeks 12 to 24 of clozapine treatment compared with their baseline condition before clozapine initiation. CONCLUSIONS: These preliminary data indicate the benefits of clozapine treatment in adolescents with treatment-refractory schizophrenia for aggressive behaviors. Although open data limit conclusions from this study, it is important that there was a clinically significant improvement in aggressive behaviors that enabled patients to be discharged to a less restrictive setting. Additional controlled clinical trials of clozapine are needed in treatment-refractory children and adolescents.

Hematological adverse events in clozapine-treated children and adolescents.

OBJECTIVE: To retrospectively examine rates of hematological adverse events (HAEs) in psychiatrically ill, hospitalized children treated with clozapine. METHOD: Clozapine treatment was administered in an open-label fashion using a flexible titration schedule, and data from weekly complete blood counts was obtained. The rate of neutropenia and agranulocytosis (HAEs) development was determined for 172 eligible patients (mean age at clozapine initiation, 15.03 +/- 2.13 years) with a median observation period of 8 months. RESULTS: Neutropenia (absolute neutrophil count <1,500/mm) developed in 23 (13%) patients and agranulocytosis (absolute neutrophil count <500/mm) in one (0.6%) patient. The cumulative probability of developing an initial HAE at 1 year of clozapine treatment was 16.1% (95% confidence interval 9.7%-22.5%). Eleven (48%) of 24 patients who developed an HAE were successfully rechallenged on clozapine. Eight (5%) of 172 patients from this sample eventually discontinued clozapine because of an HAE (one agranulocytosis, seven neutropenia). CONCLUSIONS: The occurrence of HAEs is a significant risk associated with the administration of clozapine. However, in this sample, few children actually discontinued therapy because of an HAE and the incidence of agranulocytosis does not appear higher than what has been reported in the adult literature.