Leora E. Comis

Determinants of functional performance in long-term survivors of allogeneic hematopoietic stem cell transplantation with chronic graft-versus-host disease (cGVHD)

This study examined factors accounting for functional performance limitations in 100 long-term survivors of allogeneic hematopoietic stem cell transplantation with chronic graft-versus-host disease (cGVHD). Functional performance, measured by the SF-36 physical component summary score, was substantially lower (mean=36.8±10.7) than the US population norm of 50 (P<0.001). The most severe decrements were in physical function (mean=38.8±10.9) and physical role function (mean=37.88±11.88); 68% of respondents exceeded the five-point threshold of minimum clinically important difference below the norm on these subscales. Controlling for age and gender, six variables explained 56% of the variance in functional performance: time since cGVHD diagnosis, cGVHD severity, intensity of immunosuppression, comorbidity, functional capacity (distance walked in 2 min, grip strength, and range of motion), and cGVHD symptom bother (F=11.26; P<0.001). Significant independent predictors of impaired performance were intensive systemic immunosuppression, reduced capacity for ambulation, and greater cGVHD symptom bother (P<0.05). Symptom bother had a direct effect on functional performance, as well as an indirect effect partially mediated by functional capacity (Sobel test, P=0.004). Results suggest two possible mechanisms underlying impaired functional performance in survivors with cGVHD and underscore the importance of testing interventions to enhance functional capacity and reduce symptom bother.

Malnutrition in patients with chronic GVHD.

Malnutrition is a known complication of chronic GVHD (cGVHD), but has not been well described in the context of organ-specific manifestations and the recent National Institutes of Health (NIH) criteria. Here, 210 cGVHD patients were analyzed, in a cross-sectional study design, for demographics, transplant-related history, clinical assessments, symptoms, function, quality-of-life, laboratory values and survival in order to determine their associations with nutritional status. Most patients had long-standing, moderate or severe cGVHD and had failed many lines of therapy. Twenty-nine percent (60/210) of subjects were malnourished, using the subjective Patient-Generated Subjective Global Assessment (PG-SGA) questionnaire and evaluation. No demographic or transplant characteristics were associated with malnutrition; cGVHD of the lungs, gastrointestinal (GI) tract and mouth, NIH global score, cGVHD symptoms, worse functioning, low albumin, poorer survival and low BMI were associated with malnutrition. A predictive model was developed from all variables of significance: cGVHD of the lungs, GI tract, mouth and BMI accurately predicted 84.2% of malnourished patients as well as 87.2% of well-nourished patients. The PG-SGA questionnaire may be a useful tool in diagnosing nutritional deficits in cGVHD patients undergoing one-time evaluations. Longitudinal prospective studies should assess the utility of nutritional support interventions in cGVHD.

NIH response criteria measures are associated with important parameters of disease severity in patients with chronic GVHD

Lack of standardized criteria measuring therapeutic response remains an obstacle to the development of better treatments for chronic GVHD (cGVHD). This cross-sectional prospective study examined the concurrent and predictive validity of 18 clinician-reported (‘Form A’) and 8 patient-reported (‘Form B’) response measures proposed by NIH criteria. Concurrent parameters of interest were NIH global score, cGVHD activity, Lee symptom score and SF36 PCS. Patient cohort included 193 adults with moderate-to-severe cGVHD. Measures associated with the highest number of outcomes were lung function score (LFS), 2-min walk, grip strength, 4-point health-care provider (HCP) and patient global scores, 11-point clinician- and patient-reported global symptom severity scores, and Karnofsky performance score (KPS). Measures associated with survival in univariate analyses led to a Cox model containing skin erythema, LFS, KPS, eosinophil count and interval from cGVHD diagnosis to enrollment as jointly associated with survival. In conclusion, 4-point HCP and patient global scores and 11-point clinician- and patient-reported global symptom severity scores are associated with the majority of concurrent outcomes. Skin erythema is a potentially reversible sign of cGVHD that is associated with survival. These results define a subset of measures that should be prioritized for evaluation in future studies.

NHANES III equations enhance early detection and mortality prediction of bronchiolitis obliterans syndrome after hematopoietic SCT

Bronchiolitis obliterans syndrome (BOS) is a serious complication of chronic GVHD (cGVHD) following HSCT (hematopoietic SCT). The clinical diagnosis of BOS is based on pulmonary function test (PFT) abnormalities including: FEV1<75% predicted and obstructive FEV1/VC ratio, calculated using reference equations. We sought to determine if the frequency of clinical diagnoses and severity of BOS would be altered by using the recommended NHANES III vs older equations (Morris/Goldman/Bates, MGB) in 166 cGVHD patients, median age 48 (range: 12–67). We found that NHANES III equations significantly increased the prevalence of BOS, with an additional 11% (18/166) meeting diagnostic criteria by revealing low FEV1 (<75%) (P<0.0001), and six additional patients by obstructive ratio (vs MBG). Collectively, this led to an increase of BOS incidence from 17 (29/166) to 29% (41/166). For patients with severe BOS, (FEV1<35%), NHANES III equations correctly predicted death 71.4% vs 50% using MGB. In conclusion, the use of NHANES III equations markedly increases the proportion of cases meeting diagnostic criteria for BOS and improves prediction of survival.

Prevalence and determinants of fatigue in patients with moderate to severe chronic GvHD

Although fatigue is common after allogeneic hematopoietic cell transplantation, little is known about fatigue in patients with chronic GvHD (cGvHD). The aim of this study was to explore factors associated with fatigue in cGvHD. Data were drawn from a sequentially recruited, cross-sectional study of adults with moderate or severe cGvHD (n=263). Respondents were classified as fatigued or not fatigued based on their response to a single item regarding loss of energy from the Lee cGvHD Symptom Scale. In univariate analysis, factors significantly associated with fatigue included performance status, number of prior cGvHD therapies, cGvHD symptom bother, self-assessed physical and mental health, nutritional status, walk velocity and self-reported physical activity. There were no significant associations between fatigue and disease-related cGvHD variables. Multivariable logistic regression demonstrated that being less active and having pulmonary and/or muscle/joint symptoms were independently associated with fatigue. In conclusion, clinically significant fatigue was prevalent in more than one-third of subjects with cGvHD, and was disabling. Absence of association with measures of cGvHD severity underscores the need to elucidate the pathogenesis of fatigue and its relationship with inflammatory activity. Pulmonary and muscle/joint symptoms and physical inactivity represent potential targets for intervention in clinical studies.

A Brief Historical Perspective of Cancer Rehabilitation and Contributions From the National Institutes of Health

People who have cancer diagnoses often need care throughout their lives through all stages of their illness. These stages include diagnosis, primary treatment, survivorship, and end of life. The management of people with cancer, now a common and chronic illness with long‐term survival improving, is complex, challenging, and rapidly changing. Rehabilitation for people with cancer diagnoses is a new specialty and is charged with providing care throughout the trajectory of illness and wellness to maximize potential for function and mitigate disability. Rehabilitation interventions include the application of physical and occupational therapeutics, speech and language interventions, and physical medicine in order to help patients reach their individual goals and to promote life satisfaction. The Department of Rehabilitation in the Clinical Center of the National Institutes of Health has pioneered this field through research and clinical care models over the past 40 years. Staff of this department has supported clinical research investigators at the National Institutes of Health in their exploration of new treatments using chemotherapies, surgery, radiation, and psychosocial interventions. They have also engaged in research specific to rehabilitation to devise and improve functional outcome measures, design exercise interventions, devise orthotics, and prosthetic devices for adaptation to functional loss. Collectively, the staff has published widely in oncology textbooks and professional journals in order to share findings and improve the quality of cancer rehabilitation treatment across the continuum of care.

Prevalence of isolated joint involvement in chronic graft-versus-host disease: comment on the article by Inamoto et al.

early infancy; it frequently evolves into an afebrile chronic arthritis; and in many cases systemic JIA resolves completely over time, never to return. These differences should give us pause about classifying systemic JIA together with the monogenic autoinflammatory diseases. One peril entailed in making premature conclusions about the biology of systemic JIA is that important pathogenic mechanisms may be overlooked. Autoinflammatory diseases are commonly, albeit perhaps imprecisely, regarded as diseases of innate immunity. From this point of view, T cells and B cells might be assumed to be irrelevant. However, IL-1 is a critical modulator of lymphocytic immunity, including Th17 cell differentiation and Treg cell function. The goal of the review was to raise the possibility that IL-1 and other cytokines might engender T cell–driven pathology in systemic JIA, taking a cue from mice deficient in IL-1 receptor antagonist in which T cell–mediated arthritis develops (1). Indeed, the largest genome-wide association study in systemic JIA, which is still published only in abstract form, identifies a clear if relatively weak association of systemic JIA with the HLA class II locus, a hallmark of antigen-driven T cell autoimmunity (2). A further complication in assigning systemic JIA to the autoinflammatory family is that excessive immunity and immunodeficiency are sometimes hard to tell apart. This point is illustrated by the innate immune–sensing protein nucleotidebinding oligomerization domain–containing protein 2 (NOD2). Gain-of-function mutations affecting NOD-2 result in the autoinflammatory disease Blau syndrome. Loss-of-function mutations can result in inflammatory bowel disease, potentially through failure to properly defend the intestinal barrier (3,4). From this point of view, it is interesting that patients with systemic JIA and macrophage activation syndrome often bear mutations that result in defective cell–cell killing. Such mutations are postulated to impair control of activated macrophages, thereby leading to enhanced inflammation. Cell–cell killing is also a key mechanism for control of viruses, and it is legitimate to question whether mishandling of viral infections (i.e., immunodeficiency) might represent an important early step in the pathogenesis of systemic JIA. If this is the case, one could debate whether systemic JIA is really a primary autoinflammatory disease. Finally, it is by now well recognized that the “autoinflammatory” label is not typically all or none. Even in diseases with relatively clear antigen-driven autoimmunity, such as rheumatoid arthritis (RA) and lupus, innate immune mechanisms including neutrophils and complement represent important mediators of tissue injury. It is therefore to be expected that variation in innate immune function might affect the incidence and severity of diseases of many types. Indeed, in parts of the world where FMF is common, heterozygous carriers of MEFV mutations appear to exhibit a greater predilection for JIA, a higher incidence of Henoch-Schönlein purpura and other vasculitides, and more severe RA (5–7). In fact, most inflammatory diseases should probably be conceptualized as residing in an autoinflammatory–autoimmune continuum (8). Systemic JIA is no exception, and I share with Drs. Rigante and Cantarini the opinion that systemic JIA probably lies closer to the autoinflammatory end of the spectrum than most other subtypes of JIA, although enthesitis-related arthritis (perhaps driven by HLA–B27 misfolding) might make a competing claim (9). Only further research will tell for sure. Dr. Nigrovic’s work is supported by grants from the Rheumatology Research Foundation, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Allergy and Infectious Diseases, and the Cogan Family Fund. He has received consulting fees from Alkermes, Momenta Pharmaceuticals, Novartis, and Genentech, and research support from the Baxter BioScience Foundation.

Psychosocial Characteristics of Women with a Delayed Diagnosis of Turner Syndrome

Objectives To characterize the psychosocial profiles of adult women diagnosed with Turner syndrome before (early diagnosis) and at or after (late diagnosis) 13 years of age. Study design Women with Turner syndrome ages 22 and older at evaluation (n = 110) participated in a cross‐sectional study at the National Institutes of Health. Researchers performed nonparametric and logistic regression analyses to assess early and late diagnosis cohorts on measures of depression, substance use, and perceptions of competence and identity. Results Of study participants, 47% received a Turner syndrome diagnosis at or after age 13 years. Median age at diagnosis was 12.0 years (range, 0‐43). Covariate‐adjusted models revealed that women with late diagnoses had an increased likelihood of developing mild to severe depressive symptoms (OR, 7.36) and a decreased likelihood of being perceived as competent (OR, 0.26). Women with a late diagnosis also exhibited more frequent substance use compared with women with early diagnoses. Conclusions These data suggest that Turner syndrome diagnoses received at or after age 13 years may contribute to adverse outcomes related to depression, substance use, and perceptions of competence. Delayed Turner syndrome diagnoses may place women and girls at risk for negative psychosocial development extending into adulthood. These findings indicate it is important for pediatricians to evaluate psychosocial domains in girls with Turner syndrome regularly, particularly among those diagnosed at age 13 years or older. Trial registration ClinicalTrials.gov: NCT00006334.