Lauren M. Curtis

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.

Predictive models for ocular chronic graft-versus-host disease diagnosis and disease activity in transplant clinical practice

Ocular chronic graft-versus-host disease is one of the most bothersome common complications following allogeneic hematopoietic stem cell transplantation. The National Institutes of Health Chronic Graft-versus-Host Disease Consensus Project provided expert recommendations for diagnosis and organ severity scoring. However, ocular chronic graft-versus-host disease can be diagnosed only after examination by an ophthalmologist. There are no currently accepted definitions of ocular chronic graft-versus-host disease activity. The goal of this study was to identify predictive models of diagnosis and activity for use in clinical transplant practice. A total of 210 patients with moderate or severe chronic graft-versus-host disease were enrolled in a prospective, cross-sectional, observational study (clinicaltrials.gov identifier: 00092235). Experienced ophthalmologists determined presence of ocular chronic graft-versus-host disease, diagnosis and activity. Measures gathered by the transplant clinician included Schirmer’s tear test and National Institutes of Health 0–3 Eye Score. Patient-reported outcome measures were the ocular subscale of the Lee Chronic Graft-versus-Host Disease Symptom Scale and Chief Eye Symptom Intensity Score. Altogether, 157 (75%) patients were diagnosed with ocular chronic graft-versus-host disease; 133 of 157 patients (85%) had active disease. In a multivariable model, the National Institutes of Health Eye Score (P<0.0001) and Schirmer’s tear test (P<0.0001) were independent predictors of ocular chronic graft-versus-host disease (sensitivity 93.0%, specificity 92.2%). The Lee ocular subscale was the strongest predictor of active ocular chronic graft-versus-host disease (P<0.0001) (sensitivity 68.5%, specificity 82.6%). Ophthalmology specialist measures that were most strongly predictive of diagnosis in a multivariate model were Oxford grand total staining (P<0.0001) and meibomian score (P=0.027). These results support the use of selected transplant clinician- and patient-reported outcome measures for ocular chronic graft-versus-host disease screening when providing care to allogeneic hematopoietic stem cell transplantation survivors with moderate to severe chronic graft-versus-host disease. Prospective studies are needed to determine if the Lee ocular subscale demonstrates adequate responsiveness as a disease activity outcome measure.

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.

IL-2, the next best thing in chronic GVHD therapy?

In this issue of Blood , [Koreth et al][1] have reported that interleukin-2 (IL-2) is effective in chronic graft-versus-host disease (cGVHD) patients who had failed up to two prior lines of therapy.[1][2] ![Figure][3] IL-2 induces both Treg expansion and an increase in the median Treg:Tcon

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.

Impaired Bone Mineral Density in Pediatric Patients with Chronic Graft-versus-Host Disease

Pediatric allogeneic hematopoietic stem cell transplantation (AHSCT) recipients with chronic graft-versus-host disease (cGVHD) are at high risk for endocrinopathies, particularly impaired bone mineral density (BMD). However, rates of BMD impairment in pediatric AHSCT recipients with cGVHD have not been well documented. We report 33 patients with cGVHD who were referred to the National Institutes of Health (NIH) for the Natural History of Clinical and Biological Factors Determining Outcomes in Chronic Graft-versus-Host Disease Study (NCT 0092235) and underwent formal BMD assessment via dual-energy X-ray absorptiometry (DEXA). Not surprisingly, we found much higher rates of BMD impairment than previously reported for pediatric AHSCT recipients who were not stratified by the presence or absence of cGVHD. Most of these patients (73%) had a z-score ≤-2 in at least 1 anatomic site. Although we expected the rate to be higher than that observed for pediatric AHSCT recipients in studies that did not analyze patients with cGVHD separately, this rate is nonetheless extremely high. Furthermore, the overall rate of occult vertebral compression fractures (VCFs) in our cohort was 17%, and the rate was 23% in patients with at least 1 z-score of ≤-2. The rates of BMD impairment and VCF in our pediatric cohort were significantly higher than those seen in the adult AHSCT recipients who were concurrently enrolled on the same study at the NIH and had similar cGVHD severity. We found that older age at cGVHD diagnosis and a greater number of systemic therapies were associated with occult VCF. Moreover, the intensity of current immunosuppression negatively impacted lumbar spine and total hip BMD in this cohort. Our study, although limited by small patient numbers and lack of a control AHSCT recipient group without cGVHD, indicates that children with cGVHD are at a greater risk for BMD impairment than previously appreciated. Given the rising incidence of cGVHD in AHSCT recipients and our findings, we recommend that pre-AHSCT DEXA be incorporated into routine pediatric pretransplantation screening studies. A baseline DEXA study could facilitate longitudinal monitoring of BMD in children, who may be more susceptible than adults to the negative effects of AHSCT on BMD. In addition, given the high risk of BMD impairment in pediatric AHSCT recipients with cGVHD, such patients should undergo BMD evaluation upon developing cGVHD, with continued monitoring thereafter to allow intervention before progression of the BMD impairment to its severe manifestation, VCF.

Clinical Presentation of Mucosal Acute and Chronic Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) may affect any mucosal site and is a significant source of patient morbidity. Acute and chronic GVHD at various mucosal sites share similarities in symptoms, clinical signs, and histopathologic features. Early and accurate diagnosis of GVHD, in conjunction with timely intervention, is key to minimizing discomfort and unnecessary medication exposure, and to preventing irreversible organ damage and functional deficits. In stem cell transplant patients, GVHD must be distinguished from other causes of mucosal inflammation and discomfort, including medication effect, infection, and malignancy. Careful surveillance of mucosal sites is key to prevention, detection, and management of GVHD and other complications of stem cell transplantation. Significant advances in our understanding of the presentation and pathogenesis of GVHD continue to drive further clarification of classification, staging, and management of GVHD at mucosal sites (Figs. 4.1, 4.2, 4.3, 4.4, 4.5, and 4.6; Tables 4.1, 4.2, 4.3, 4.4, 4.5, and 4.6).

Achalasia in a Patient Undergoing Hematologic Stem Cell Transplant After Exposure to Tacrolimus

Calcineurin inhibitors (CNIs) are effective agents used for prevention of graft-vs-host disease after allogeneic hematopoietic stem cell transplant or for organ rejection in solid-organ transplant. However, CNIs have a wide range of adverse effects that may necessitate changing to another CNI or immunosuppressive agent. We report a case of acute myeloid leukemia in which achalasia developed after exposure to tacrolimus, as revealed by esophagram results. The patients symptoms and signs were ameliorated after a change to cyclosporine. This case is the first in the literature to reveal achalasia associated with tacrolimus. Achalasia should be part of a differential diagnosis of upper gastrointestinal symptoms in patients undergoing transplant, and changing to another CNI may be a useful therapeutic intervention.

Predictors for Permanent Discontinuation of Systemic Immunosuppression in Severely Affected Chronic Graft-Versus-Host Disease Patients

Predicting the duration of systemic therapy in patients with chronic graft-versus-host disease (cGVHD) is of critical clinical importance when counseling patients and for treatment planning. cGVHD characteristics associated with this outcome have not been studied in severely affected patients. The National Institutes of Health (NIH) cGVHD scoring provides a standardized set of organ severity measures that could represent clinically useful and reproducible predictive characteristics. We analyzed 227 previously treated patients most with moderate (n = 54) or severe (n = 170) cGVHD defined by NIH criteria who were prospectively enrolled in a natural history protocol (NCT00092235). Patients received a median of 4 prior systemic therapy regimens and were seen at the NIH for a single time-point visit and were then monitored for survival and ability to discontinue cGVHD systemic therapy. With a median follow-up of 71.1 months, the cumulative incidence of systemic therapy discontinuation was 9.5% (95% confidence interval, 6.0% to 13.9%) at 2 years and 27.7% (95% confidence interval, 20.9% to 34.8%) by 5 years after the initial visit. Factors associated with a higher incidence of immunosuppression discontinuation included lower NIH global severity (P = .019) and lung (P = .030) scores and less extensive deep sclerosis (<37% body surface area, P = .024). Lower patient- and clinician-reported 0 to 10 severity NIH scores and noncyclosporine prophylaxis regimens were also associated with higher incidence of immunosuppression discontinuation (P <.05). In conclusion, we found low success rates for immune suppression discontinuation in previously treated patients who were severely affected with cGVHD. NIH scoring and clinical measures provide new standardized disease-specific tools to predict discontinuation of systemic therapy.

Clinical Significance of IgE in a Large Cohort of Patients with Moderate or Severe Chronic Graft-versus-Host Disease

in arterial and venous thromboelastography parameters: potential roles of shear stress and oxygen content. J Cardiothorac Vasc Anesth. 2002;16(5):551–554. [5] White H, Zollinger C, Jones M, Bird R. Can thromboelastography performed on kaolin-activated citrated samples from critically ill patients provide stable and consistent parameters?. Int J Lab Hematol. 2010; 32(2):167–173. [6] Johansson PI, Bochsen L, Andersen S, Viuff D. Investigation of the effect of kaolin and tissue-factor-activated citrated whole blood, on clotforming variables, as evaluated by thromboelastography. Transfusion. 2008;48(11):2377–2383.