This cohort study assesses the prognostic value of body surface area and National Institutes of Health Skin Score on survival outcomes stratified by erythema and sclerosis subtypes of chronic graft-vs-host disease.
Key Points
Question
What is the prognostic value of clinical estimation of cutaneous disease severity in predicting mortality in patients with chronic graft-vs-host disease (cGVHD)?
Findings
In this multicenter cohort study that included 469 patients with cGVHD, for erythema-type cGVHD, body surface area involvement was a better predictor of mortality than the National Institutes of Health cGVHD Skin Score. Sclerotic disease was not associated with mortality and typically did not have antecedent erythema.
Meaning
Findings suggest erythema-type cGVHD is an important clinical prognostic marker, with highest prognostic value when quantified with body surface area assessment.
Abstract
Importance
Prior studies have demonstrated an association between cutaneous chronic graft-vs-host disease (cGVHD) and mortality. Assessment of the prognostic value of different measures of disease severity would assist in risk stratification.
Objective
To compare the prognostic value of body surface area (BSA) and National Institutes of Health (NIH) Skin Score on survival outcomes stratified by erythema and sclerosis subtypes of cGVHD.
Design, Setting, and Participants
Multicenter prospective cohort study from the Chronic Graft-vs-Host Disease Consortium including 9 medical centers in the US, enrolled from 2007 through 2012 and followed until 2018. Participants were adults and children with a diagnosis of cGVHD requiring systemic immunosuppression and with skin involvement during the study period, who had longitudinal follow-up. Data analysis was performed from April 2019 to April 2022.
Exposures
Patients underwent continuous BSA estimation and categorical NIH Skin Score grading of cutaneous cGVHD at enrollment and every 3 to 6 months thereafter.
Main Outcomes and Measures
Nonrelapse mortality (NRM) and overall survival (OS), compared between BSA and NIH Skin Score longitudinal prognostic models, adjusted for age, race, conditioning intensity, patient sex, and donor sex.
Results
Of 469 patients with cGVHD, 267 (57%) (105 female [39%]; mean [SD] age, 51 [12] years) had cutaneous cGVHD at enrollment, and 89 (19%) developed skin involvement subsequently. Erythema-type disease had earlier onset and was more responsive to treatment compared with sclerosis-type disease. Most cases (77 of 112 [69%]) of sclerotic disease occurred without prior erythema. Erythema-type cGVHD at first follow-up visit was associated with NRM (hazard ratio, 1.33 per 10% BSA increase; 95% CI, 1.19-1.48; P < .001) and OS (hazard ratio, 1.28 per 10% BSA increase; 95% CI, 1.14-1.44; P < .001), while sclerosis-type cGVHD had no significant association with mortality. The model with erythema BSA collected at baseline and first follow-up visits retained 75% of the total prognostic information (from all covariates including BSA and NIH Skin Score) for NRM and 73% for OS, with no statistical difference between prognostic models (likelihood ratio test χ2, 5.9; P = .05). Conversely, NIH Skin Score collected at the same intervals lost significant prognostic information (likelihood ratio test χ2, 14.7; P < .001). The model incorporating NIH Skin Score instead of erythema BSA accounted for only 38% of the total information for NRM and 58% for OS.
Conclusions and Relevance
In this prospective cohort study, erythema-type cutaneous cGVHD was associated with increased risk of mortality. Erythema BSA collected at baseline and follow-up predicted survival more accurately than the NIH Skin Score in patients requiring immunosuppression. Accurate assessment of erythema BSA may assist in identifying patients with cutaneous cGVHD at high risk for mortality.
Introduction
Chronic graft-vs-host disease (cGVHD) is the leading cause of morbidity and nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation.1,2,3,4,5,6 Treatment of cGVHD can be complicated by adverse effects, infection, and abrogation of graft-vs-tumor effect. There is substantial need to identify clinical indicators of poor outcomes to target use of prophylactic and preemptive treatment for patients with high-risk cGVHD.7
The skin is an ideal clinical prognostic marker because it is the organ system most frequently involved in cGVHD (60%-80% of patients)8,9,10 and is highly accessible. Cutaneous disease can be categorized into erythema and sclerotic disease as detailed in the 2005 National Institutes of Health (NIH) consensus forms.11,12 The term erythema refers to the many nonsclerotic manifestations of cGVHD and includes morbilliform, lichen planus–like, papulosquamous, and keratosis pilaris–like eruptions, among others. The 2005 NIH Skin Score includes an assessment of body surface area (BSA) of erythema, moveable sclerosis, and nonmoveable sclerosis, which combined with a functional (mobility) and symptomatic (pruritus) assessment, forms a composite score of 0 to 3, with scores above 1 considered moderate to severe. Due to concerns regarding feasibility and reliability of BSA assessments,13 the 2014 NIH consensus eliminated estimation of BSA as a continuous variable in favor of categorical approximation.14,15 The 2014 NIH Skin Score is the primary outcome measure in major clinical trials, including those that supported the recent US Food and Drug Administration approvals of the first treatments targeting cGVHD.16,17,18
Prior studies have demonstrated an association of cutaneous cGVHD activity with survival outcomes. Higher 2005 NIH Skin Score was associated with worse survival in a cohort of patients with cutaneous cGVHD.10 However, the components of the composite 2005 NIH Skin Score and the clinical subtypes of skin disease that drive this survival association remain unclear. Here, we compare the prognostic value of erythema BSA and 2005 NIH Skin Score to identify the most informative assessments for clinical practice and therapeutic trials.
Methods
Chronic GVHD Consortium
The Chronic GVHD Consortium is a longitudinal cohort from 9 US medical centers,19 approved by the institutional review board at each participating site. All participants provided written informed consent in accordance with the Declaration of Helsinki. Patients were enrolled from 2007 through 2012 and were 2 years or older with a clinical diagnosis of cGVHD by 2005 NIH consensus criteria11 and receiving systemic treatment for cGVHD (including extracorporeal photopheresis). Incident cases were enrolled less than 3 months from cGVHD diagnosis, while prevalent cases were enrolled 3 months or more from cGVHD diagnosis and less than 3 years from hematopoietic cell transplantation. At baseline and every 3 to 6 months, clinicians and patients reported standardized information on cGVHD organ involvement, censored at relapse or cGVHD resolution for greater than 1 year.
Patient Characteristics and Skin Assessment Measures
We included patients from the Chronic GVHD Consortium with skin involvement and at least 1 follow-up visit (eFigure 1 in Supplement 1). Standardized forms adapted from the 2005 NIH consensus criteria (eFigure 2A and 2B in Supplement 1) were used to define skin involvement.11,12 Transplant clinicians assessed 8 anatomic regions for changes suspected to be related to cGVHD and estimated BSA using the rule of 9s. Body surface area was determined for erythema (any nonsclerotic morphologic characteristic, excluding dyspigmentation and xerosis), moveable sclerosis (lichen sclerosis–like, morphealike), and nonmoveable sclerosis (deep sclerosis, fasciitis) with possible values of 0% to 100% for each manifestation. For erythema, clinicians were provided a list of encompassed morphologic characteristics. However, no formal training was required. The 2005 NIH Skin Score combines BSA assessment with depth of sclerosis and other features.
We defined erythema-type cGVHD as erythema BSA greater than 0%; sclerotic-type cGVHD as BSA greater than 0% of nonmovable and/or movable sclerosis; and combination-type cGVHD as BSA greater than 0% for both at the same study visit. Even if a positive 2005 NIH Skin Score or joint or fascial disease was recorded, we excluded from our analysis patients with 0% BSA for all subtypes of skin disease at all study visits.
Race and ethnicity were mostly self-reported on patient registration into the study. Options were defined by the investigator with an option for “other” and a free-text field for input. Race and ethnicity were collected to assess generalizability of the findings to non-White and Hispanic patients, who are known to be underrepresented in hematopoietic cell transplantation.
Time to cGVHD Onset
We analyzed the time to onset for incident patients with skin involvement at any time (eFigure 1 in Supplement 1): either at enrollment (n = 173 incident patients) or with skin involvement later in the study period (n = 52 incident patients, who were not included in any other analyses). Prevalent cases were excluded from this analysis because date of onset could not be determined. Date of cutaneous disease onset was defined as the first study visit with a recorded BSA greater than 0% for either subtype (erythema or sclerosis). Patients with combination disease were included in both the erythema and sclerosis analyses. A Wilcoxon rank sum test was used to evaluate differences between these 2 subtypes.
Outcomes and Time Point Definitions
Outcomes analysis included all incident (n = 173) and prevalent (n = 94) patients with skin cGVHD at enrollment (total n = 267). We defined 2 time points: T0, the date of baseline examination at study enrollment; and T1, the date of the first study follow-up visit. Time to outcomes were assessed from T1 to avoid survivor bias and inform care of patients who had at least 1 follow-up visit.
Primary outcomes were defined as follows: NRM, the time from T1 to death with relapse as a competing risk; overall survival (OS), the time from T1 to death from any cause; and failure-free survival (FFS), time from T1 to the previously described20 composite of malignancy relapse, death, or addition of a new immunosuppressive medication or treatment intended for systemic treatment of chronic GVHD.
Statistical Analysis
Categorical variables were compared using the Pearson χ2 test. Continuous variables were compared with the Wilcoxon rank sum and Kruskal-Wallis tests.
For all patients with incident and prevalent cutaneous cGVHD at T0, longitudinal BSA over the entire study period was visualized using spaghetti plots. Locally estimated scatterplot smoothed (LOESS) curves were fit to the reported data and censored at n = 20 observations to account for variation at small sample size.21,22 Body surface area body regions with missing data were treated as zero due to paucity of missing data (<1%) (eTable 1 in Supplement 1). Notably, genitalia BSA was recorded as missing in greater than 30% of assessments, demonstrating a practice gap even within a study protocol.
Outcomes for patients with incident and prevalent cutaneous cGVHD at T0 were examined using BSA or 2005 NIH Skin Score assessments at T0 and T1 as predictors in Cox regression models for OS and FFS, and Fine-Gray competing risk regression models for NRM. Models were performed separately for BSA and 2005 NIH Skin Score at T0 and T1 as well as adjusted for within-patient severity by including T0 and T1 scores as covariates. Analyses were stratified by disease type (sclerosis or erythema). Patients with combination disease were included in both analyses. The hazard ratios (HRs) for 2005 NIH Skin Score are expressed as the increase in the risk of having an event per point change on the scale of 0 to 3, while those for BSA are per 10% BSA change on a scale of 0% to 100%. Patients with a failure event (ie, escalation of immunosuppression) before T1 were included in the FFS analysis and counted as having an event at T1. A sensitivity analysis was performed excluding these patients (eTable 2 in Supplement 1). Based on clinical knowledge, all models were adjusted for age at enrollment, race, sex, conditioning intensity, and donor-patient sex combination. Models were not adjusted for stem cell source because a sensitivity analysis demonstrated less than 3% difference in HRs.
The prognostic value of BSA and 2005 NIH Skin Score assessments at T0 and T1 was calculated as previously described.23 Each assessment was considered separately in the Cox and competing risk models and a likelihood ratio χ2 (LR) statistic was generated. The LR statistic provides an index of the amount of prognostic information contained in the variable but is also influenced by other factors, such as sample size. We compared nested models using the likelihood ratio test (LRT) to isolate the added contribution of a variable to the prognostic model. Lastly, we calculated an index of the relative prognostic value of BSA and 2005 NIH Skin Score by dividing the LR statistic by that of the full model resulting when all prognostic information was included. A 2-sided P value of .05 was considered significant. We used R 4.1.1 (R Foundation for Statistical Computing). We adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Results
Demographics and Baseline Characteristics
Nine participating sites enrolled 661 patients into the Chronic GVHD Consortium from 2007 through 2012, of which 469 had follow-up data (eFigure 1 in Supplement 1). Excluded patients were more likely to be a race other than White, younger, and to relapse or die (eTable 3 in Supplement 1). Of the 469 patients with cGVHD, 267 (57%) had cutaneous cGVHD at T0, and 89 (19%) more developed skin involvement later during the study period (total n = 356) (eFigure 1 in Supplement 1). Table 1 summarizes baseline patient characteristics. Compared with patients without skin involvement, patients with skin cGVHD were more likely to be male (61% vs 51%; P = .04), White (94% vs 87%; P = .02), and have a peripheral blood stem cell source (92% vs 85%; P = .02). Patients with skin involvement also had shorter time from cGVHD diagnosis to T0 (median [IQR], 1.1 [0-7.8] months vs 1.9 [0.5-8.3] months; P = .05) and were classified as having predominantly moderate or severe disease by 2005 NIH Skin Score (64% had a score >1). Twelve patients had skin cGVHD by percentage BSA with NIH Skin Score of 0, likely representing very mild disease by clinician assessment.
Table 1. Patient Characteristics by Skin cGVHD and by Erythema and/or Sclerosis at Enrollment.
| Characteristic | No. (%) | P value, no skin vs skin cGVHDa | No. (%) | P value, types of skin cGVHDb | |||
|---|---|---|---|---|---|---|---|
| No skin cGVHD | Skin cGVHD | Erythema only | Erythema and sclerosis | Sclerosis only | |||
| Patients | 202 (43) | 267 (57) | NA | 164 (61) | 42 (16) | 61 (23) | NA |
| Case | |||||||
| Incident | 116 (57) | 173 (65) | .10 | 124 (76) | 23 (55) | 26 (43) | <.001 |
| Prevalent | 86 (43) | 94 (35) | 40 (24) | 19 (45) | 35 (57) | ||
| Demographics | |||||||
| Sex | |||||||
| Female | 99 (49) | 105 (39) | .04 | 60 (37) | 16 (38) | 29 (48) | .32 |
| Male | 103 (51) | 162 (61) | 104 (63) | 26 (62) | 32 (52) | ||
| Race | |||||||
| American Indian | 1 (<1) | 1 (<1) | .26 | 0 | 1 (2) | 0 | .09 |
| Asian | 11 (5) | 7 (3) | 5 (3) | 1 (2) | 1 (2) | ||
| Black | 6 (3) | 3 (1) | 2 (1) | 0 | 1 (2) | ||
| Pacific Islander | 2 (1) | 0 | 0 | 0 | 0 | ||
| White | 179 (89) | 252 (94) | 157 (96) | 92.9 (39) | 56 (92) | ||
| Multiracial | 2 (1) | 2 (1) | 0 | 2.4 (1) | 1 (2) | ||
| Unknown | 1 (<1) | 2 (1) | 0 | 0 | 2 (3) | ||
| Age, mean (SD), y | 50 (13) | 51 (12) | .70 | 51 (13) | 50 (12) | 49 (12) | .49 |
| Diagnosis | |||||||
| AML | 66 (33) | 88 (33) | .38 | 56 (34) | 12 (29) | 20 (33) | .88 |
| ALL | 19 (9) | 29 (11) | 21 (13) | 3 (7) | 5 (8) | ||
| CML | 10 (5) | 7 (3) | 5 (3) | 1 (2) | 1 (2) | ||
| CLL | 14 (7) | 24 (9) | 14 (8) | 3 (7) | 7 (12) | ||
| MDS | 29 (14) | 47 (18) | 26 (16) | 10 (24) | 11 (18) | ||
| NHL | 36 (18) | 38 (14) | 25 (15) | 4 (10) | 9 (15) | ||
| HD | 9 (4) | 5 (2) | 2 (1) | 2 (5) | 1 (2) | ||
| MM | 8 (4) | 9 (6) | 9 (6) | 4 (10) | 6 (10) | ||
| AA | 3 (2) | 2 (1) | 1 (1) | 1 (2) | 0 | ||
| Other | 8 (4) | 19 (7) | 5 (3) | 2 (5) | 1 (2) | ||
| Stem cell source | |||||||
| Peripheral blood | 172 (85) | 247 (92) | .02 | 149 (91) | 39 (93) | 59 (97) | .33 |
| Bone marrow | 17 (8) | 14 (5) | 9 (6) | 3 (7) | 2 (3) | ||
| Cord blood | 13 (6) | 6 (2) | 6 (4) | 0 | 0 | ||
| Conditioning intensity | |||||||
| Nonmyeloablative | 94 (46) | 133 (50) | .48 | 87 (53) | 20 (48) | 25 (42) | .29 |
| Myeloablative | 108 (54) | 132 (50) | 76 (47) | 22 (52) | 35 (58) | ||
| Female donor into male recipient | 52 (26) | 77 (29) | .46 | 47 (29) | 12 (29) | 18 (30) | >.99 |
| GVHD prophylaxisc | |||||||
| Classic CNI | 165 (82) | 204 (76) | .23 | 132 (81) | 33 (79) | 39 (64) | .05 |
| Other CNI | 30 (15) | 47 (18) | 20 (12) | 8 (19) | 19 (31) | ||
| Cyclophosphamide | 2 (1) | 1 (<1) | 1 (1) | 0 | 0 | ||
| Other | 5 (3) | 15 (6) | 11 (7) | 1 (2) | 3 (5) | ||
| Prior acute GVHD | |||||||
| Yes | 132 (65) | 169 (63) | .65 | 108 (66) | 22 (52) | 39 (64) | .27 |
| No | 70 (35) | 98 (37) | 56 (34) | 20 (48) | 22 (36) | ||
| Prior acute GVHD, skind | |||||||
| Yes | 85 (43) | 117 (48) | .38 | 81 (52) | 15 (40) | 21 (39) | .16 |
| No | 111 (57) | 129 (52) | 74 (48) | 22 (60) | 33 (61) | ||
| cGVHD type | |||||||
| Classic cGVHD | 142 (70) | 174 (65) | .24 | 90 (55) | 33 (79) | 51 (84) | <.001 |
| cGVHD with acute features | 60 (30) | 93 (35) | 74 (45) | 9 (21) | 10 (16) | ||
| Overall cGVHD severitye | |||||||
| None | 1 (<1) | 0 | <.001 | 0 | 0 | 0 | .02 |
| Mild | 121 (60) | 98 (37) | 73 (44) | 10 (24) | 15 (25) | ||
| Moderate | 71 (35) | 136 (51) | 75 (46) | 25 (60) | 36 (59) | ||
| Severe | 9 (4) | 33 (12) | 16 (10) | 7 (17) | 10 (16) | ||
| 2005 NIH Skin Scoref | |||||||
| 0 | 164 (81) | 15 (6) | <.001 | 12 (7) | 0 (0) | 3 (5) | <.001 |
| 1 | 23 (11) | 83 (31) | 71 (43) | 7 (17) | 5 (8) | ||
| 2 | 11 (5) | 98 (37) | 47 (29) | 15 (36) | 36 (59) | ||
| 3 | 4 (2) | 71 (27) | 34 (21) | 20 (48) | 17 (28) | ||
| Other organ involvement | |||||||
| Skin-limited | 0 | 32 (12) | <.001 | 23 (14) | 4 (10) | 5 (8) | .42 |
| Oral | 131 (65) | 153 (57) | .10 | 110 (67) | 22 (52) | 21 (34) | <.001 |
| Gastrointestinal | 66 (33) | 73 (27) | .21 | 44 (27) | 14 (33) | 15 (25) | .60 |
| Eye | 105 (52) | 125 (47) | .27 | 74 (45) | 22 (52) | 29 (48) | .70 |
| Joint and fascia | 44 (22) | 90 (34) | .005 | 21 (13) | 20 (48) | 49 (80) | <.001 |
| Lung | 59 (29) | 49 (18) | .006 | 27 (16) | 6 (14) | 16 (26) | .19 |
| Genital | 19 (10) | 26 (10) | >.99 | 13 (9) | 5 (12) | 8 (14) | .50 |
| Time from transplantation to enrollment, median (IQR), mo | 12 (8-19) | 12 (8-20) | .80 | 9 (6-13) | 14 (9-23) | 23 (16-29) | <.001 |
| Time from cGVHD diagnosis to enrollment, mo | 1.9 (0.5-8.3) | 1.1 (0.0-7.8) | .05 | 0.7 (0.0-2.9) | 2.6 (0.0-12.1) | 6.0 (0.5-18.2) | <.001 |
| Follow-up time, median (IQR), mo | |||||||
| From T0g | 101 (52-125) | 93 (39-125) | .17 | 101 (42-127) | 51 (31-120) | 77 (41-119) | .43 |
| From T1g | 96 (45-118) | 87 (33-118) | .18 | 94 (38-122) | 48 (27-114) | 72 (33-112) | .29 |
Abbreviations: AA, aplastic anemia; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; BSA, body surface area; cGVHD, chronic graft-vs-host disease; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CNI, calcineurin inhibitor; GVHD, graft-vs-host disease; HD, Hodgkin disease; MDS, myelodysplastic syndrome; MM, multiple myeloma; NA, not applicable; NHL, non-Hodgkin lymphoma; NIH, National Institutes of Health; T0, baseline visit; T1, first follow-up visit.
Pearson χ2 test compared categorical variables. Wilcoxon test compared continuous variables.
Pearson χ2 test compared categorical variables. Kruskal-Wallis test compared continuous variables.
Classic CNI regimens include tacrolimus or cyclosporine and methotrexate or mycophenolate mofetil. Other CNI regimens include tacrolimus or cyclosporine and other medications not included in classic regimens.
Total of n = 27 missing data on prior acute GVHD, skin.
Clinician-reported severity.
N = 38 with 2005 NIH Skin Score greater than 0 and BSA of 0 for erythema or sclerosis. N = 15 with 2005 NIH Skin Score of 0 and BSA greater than 0 for erythema or sclerosis.
Time to death or last known follow-up date.
Of the 267 patients with skin cGVHD at T0, the majority had erythema-only subtype (162 of 267 [61%]) (Table 1). Erythema-only disease had more patients with cGVHD with acute features and oral cGVHD and fewer patients with joint and fascial disease compared with combination and sclerotic-only disease.
Temporal Characteristics of Erythema and Sclerosis
We compared time to onset and response to treatment between erythema and sclerosis subtypes because this may inform optimal timing of assessments. In the 225 incident patients with cutaneous cGVHD during the study period (n = 173 at enrollment and n = 52 later; eFigure 1 in Supplement 1), erythema presented sooner and in a more concentrated time frame (median [IQR], 268 [194-430] days) after transplant compared with sclerosis (577 [369-825] days; P < .001) (Figure 1A and B). Most skin cGVHD appeared within 100 days of cGVHD diagnosis, with erythema-type occurring earlier (median [IQR], 0 [0-0] days) than sclerosis (95 [0-400] days; P < .001).
Figure 1. Onset and Response to Treatment of Erythema and Sclerosis.
Among 225 incident patients who enrolled with skin involvement or developed skin involvement during the study, erythema occurred earlier compared with sclerosis. A, Onset from transplant. B, From study enrollment. Skin chronic graft-vs-host disease (cGVHD) in incident and prevalent patients with skin involvement at the time of enrollment (n = 267) was more responsive for erythema compared with sclerosis. Spaghetti plot of body surface area (BSA) over time for erythema-type (n = 206) (C) and sclerosis-type (n = 103) cGVHD (D) (n = 42 patients with combination disease are included in both plots). A locally estimated scatterplot smoothed (LOESS) curve (orange) demonstrates the overall trend fitting the reported data, censored at n = 20 observations. Lines ending with a filled circle represent patients who died; lines without a filled circle represent patients lost to follow-up. Wilcoxon test compared continuous variables.
The first manifestation of skin involvement was erythema in 148 (66%) patients, combination disease in 30 (13%), and sclerosis in 47 (21%) (eFigure 3 in Supplement 1). Of the patients with erythema as initial skin manifestation, 24 of 148 (24%) went on to develop sclerosis at a median (IQR) of 371 (155-551) days later. Of the patients with sclerosis as initial skin manifestation, only 7 of 47 (15%) later developed erythema at a median (IQR) of 188 (168-246) days. Most cases (77 of 112 [69%]) of sclerotic disease did not have prior erythema reported, although prior erythema may have gone unobserved.
In the 267 patients with cutaneous cGVHD at enrollment, erythema was more responsive to treatment than sclerosis (Figure 1C and D). The median (IQR) baseline BSA of erythema (n = 206) was 11% (4%-41%), and the median (IQR) change to first follow-up was −9% (−32% to −2%) (eTable 4 in Supplement 1). The median (IQR) baseline BSA of sclerosis (n = 103) was 9% (2%-22%), and the median (IQR) change to the next follow-up visit was −1% (−8% to 3%). Incident sclerosis was more responsive than prevalent sclerosis (median [IQR], −4% [−11% to 0%] vs 0% [−4% to 5%]) (eFigure 4 and eTable 4 in Supplement 1).
Association Between BSA and 2005 NIH Skin Score and Mortality
In the 267 patients with cutaneous cGVHD at the enrollment baseline assessment (T0), a total of 103 (39%) died, 79 (30%) died without relapse of malignancy, and 219 (82%) experienced a failure event. The median (IQR) total follow-up time from the follow-up visit (T1) to death or last study visit was 87 (33-118) months. Table 2 displays the adjusted association of BSA and 2005 NIH Skin Score with OS, NRM, and FFS in patients with erythema at T0 (n = 206) (univariable analysis in eTable 5 in Supplement 1). After adjusting for age, race, sex, conditioning intensity, and donor sex mismatch (Table 2), BSA involvement of erythema at T1 was associated with NRM (HR, 1.33; 95% CI, 1.19-1.48; P < .001), OS (HR, 1.28 per 10% increase in BSA; 95% CI, 1.14-1.44; P < .001), and FFS (HR, 1.11; 95% CI, 1.02-1.22; P = .02). These associations were unchanged when adjusted for within-patient severity in the mutually adjusted model. In a sensitivity analysis of T1 erythema of only the anterior trunk, an anatomic region amenable to efficient clinical and photographic assessments, associations were similar (data not shown). By contrast, 2005 NIH Skin Score at T1 was not associated with NRM but was associated with OS and FFS with similar association per full unit change (scale, 0-3) as BSA erythema had per a 10% increase (scale, 0%-100%). As an illustration, cumulative incidence curves demonstrate higher NRM in patients with greater than 10% BSA compared with 10% or less BSA at T1 (P = .002), while there was no significant difference by 2005 NIH Skin Score greater than 1 compared with 1 or less (P = .35) (supporting data in Figure 2). In patients with sclerosis at T0 (n = 103), BSA and 2005 NIH Skin Score at T0 and T1 were not associated with OS or NRM but were associated with FFS (eTable 6 in Supplement 1).
Table 2. Association of BSA and 2005 NIH Skin Score With Survival Outcomes in Patients With Erythema at Enrollmenta.
| Skin assessment | NRM (n = 206, 60 events)b | OS (n = 206, 82 events)b | FFS (n = 206, 163 events)b | |||
|---|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | |
| 2005 NIH skin score—individual models (per point increase)c | ||||||
| T0 | 1.40 (1.10-1.79) | .007 | 1.31 (1.03-1.67) | .03 | 1.09 (0.92-1.30) | .31 |
| T1 | 1.14 (0.88-1.49) | .32 | 1.33 (1.08-1.63) | <.001 | 1.22 (1.05-1.42) | .01 |
| 2005 NIH skin score—mutually adjusted model (per point increase) c , d | ||||||
| T0 | 1.38 (1.07-1.79) | .02 | 1.20 (0.93-1.56) | .16 | 1.02 (0.85-1.22) | .81 |
| T1 | 1.04 (0.79-1.37) | .77 | 1.25 (1.00-1.56) | .05 | 1.21 (1.03-1.42) | .02 |
| Erythema BSA—individual models (per 10% increase)c | ||||||
| T0 | 1.08 (0.99-1.18) | .09 | 1.03 (0.95-1.12) | .46 | 0.98 (0.92-1.05) | .58 |
| T1 | 1.33 (1.19-1.48) | <.001 | 1.28 (1.14-1.44) | <.001 | 1.11 (1.02-1.22) | .02 |
| Erythema BSA—mutually adjusted model (per 10% increase) c , d | ||||||
| T0 | 1.06 (0.97-1.16) | .18 | 1.01 (0.93-1.09) | .90 | 0.98 (0.92-1.04) | .47 |
| T1 | 1.31 (1.18-1.47) | <.001 | 1.28 (1.13-1.44) | <.001 | 1.11 (1.02-1.22) | .02 |
Abbreviations: BSA, body surface area; FFS, failure-free survival; HR, hazard ratio; NIH, National Institutes of Health; NRM, nonrelapse mortality; OS, overall survival; T0, baseline visit; T1, first follow-up visit.
All models adjusted for age, race, sex, conditioning intensity, and female donor into male recipient.
Total of n = 1 excluded from multivariable regression analyses due to missing conditioning intensity; n = 1 excluded from FFS regression analysis due to missing date for failure event.
Hazard ratios for 2005 NIH Skin Score expressed as the increase in the risk of having an event per 1-point increase on the scale of 0 to 3; HRs for erythema BSA are expressed as the increase in having an event per 10% BSA increase on a scale of 0% to 100%.
Mutually adjusted models are adjusted for 2005 NIH Skin Score or BSA score at both baseline visit (T0) and first follow-up visit (T1).
Figure 2. NRM According to BSA and 2005 NIH Skin Score for Patients With Erythema at First Follow-up Visit.
Cumulative incidence of nonrelapse mortality (NRM) in patients with erythema is higher for (A) body surface area (BSA) greater than 10% vs 10% or less at first follow-up visit and (B) 2005 National Institutes of Health (NIH) Skin Score of 2 or 3 vs NIH Skin Score of 0 or 1 at first follow-up visit. A χ2 test compared variables.
Comparison of BSA and 2005 NIH Skin Score in Predicting Mortality
Table 3 and eTable 7 in Supplement 1 demonstrate the relative prognostic strengths of BSA and 2005 NIH Skin Score assessments for predicting survival outcomes in patients with erythema. By the LRT, the model with T0 and T1 (model 3) BSA did not differ significantly from the full prognostic model (model 7 incorporating all predictors), retaining 75% of the predictive power for NRM, 73% for OS, and 66% for FFS. Thus, consideration of sclerosis and functional assessments in the 2005 NIH Skin Score did not add significant prognostic information when erythema was present.
Table 3. Prognostic Value of Erythema BSA and 2005 NIH Skin Score in Patients With Erythema at Enrollment.
| Model | NRM (n = 206, 60 events)a | OS (n = 206, 82 events)a | FFS (n = 206, 163 events)a | |||
|---|---|---|---|---|---|---|
| LRχ2 | %b | LRχ2 | %b | LRχ2 | %b | |
| 0. Age, race, sex, transplant type, case type | 3.2 | 13.7 | 3.9 | 17.9 | 2.5 | 21.6 |
| 1. Model 0 + BSAT0 | 5.9 | 25.1 | 4.5 | 20.3 | 2.8 | 24.7 |
| 2. Model 0 + BSAT1 | 16.1 | 68.5 | 16.1 | 73.3 | 6.9 | 61.1 |
| 3. Model 0 + BSAT0 + BSAT1 | 17.6 | 75.1 | 16.1 | 73.4 | 7.5 | 65.8 |
| 4. Model 0 + NIHT0 | 8.7 | 37.1 | 8.9 | 40.4 | 3.5 | 31.0 |
| 5. Model 0 + NIHT1 | 4.3 | 18.1 | 10.7 | 48.7 | 8.9 | 78.0 |
| 6. Model 0 + NIHT0 + NIHT1 | 8.8 | 37.5 | 12.6 | 57.6 | 8.9 | 78.5 |
| 7. Model 0 + NIHT0 + NIHT1 + BSAT0 + BSAT1 | 23.5 | 100 | 21.9 | 100 | 11.4 | 100 |
| Comparison (difference) | LRχ2 | P valuec | LRχ2 | P valuec | LRχ2 | P valuec |
| Model 3 vs model 7 (BSAT0+T1 compared with full) | 5.9 | .05 | 5.8 | .05 | 3.9 | .14 |
| Model 6 vs model 7 (NIHT0+T1 compared with full) | 14.7 | <.001 | 9.3 | .009 | 2.4 | .30 |
Abbreviations: BSA, body surface area; NRM, nonrelapse mortality; OS, overall survival; FFS, failure-free survival; LRχ2, log likelihood χ2 test statistic; NIH, National Institutes of Health; T0, baseline visit; T1, first follow-up visit.
Total of n = 1 excluded from multivariate regression analyses due to missing conditioning intensity; n = 1 excluded from FFS regression analysis due to missing date for failure event.
Relative prognostic value of individual model compared with model 7 (full model) calculated by dividing LRχ2 statistics.
P value from the likelihood ratio test for nested models.
Compared with the prognostic power of erythema BSA, measuring the 2005 NIH Skin Score at T0 and T1 (Table 3 model 6) had significantly lower predictive power, retaining only 38% of the full prognostic model for NRM (LRT, 14.7; P < .001) and 58% for OS (LRT, 9.3; P = .009). The prognostic power of BSA and 2005 NIH Skin Score were similar for FFS, although the overall predictive strength was low. Significant BSA associations still held under a strict Bonferroni-corrected P value threshold of 0.0083 (3 outcomes, 2 time points).
In patients with sclerosis, the prognostic strength of BSA and 2005 NIH Skin Score assessments was low. There was no difference between the 2 measures in predicting OS and NRM (eTable 8 in Supplement 1).
Discussion
In this prospective cohort study, we demonstrate that erythema and sclerosis subtypes of cutaneous cGVHD have distinct clinical evolution, challenging the belief that these manifestations are the progression of epidermal inflammation to deeper damage. Erythema is a clinical prognostic marker for mortality, and BSA should be measured and reported for patients with cGVHD. While prior work challenges the interrater reliability between expert and clinician BSA estimation (intraclass correlation coefficient, 0.57),13 its prognostic significance highlights the critical role of expert dermatologists in assessing cGVHD and the need for novel methods for accurate BSA estimation.
Jacobsohn et al10 previously reported that a baseline 2005 NIH Skin Score of 3 was associated with higher overall mortality (HR, 2.9; 95% CI, 1.5-5.7) and NRM (HR, 4.5; 95% CI, 2.2-9.4) compared with no skin involvement. Our study builds on this work, demonstrating that the association is significant only for patients with erythema-type disease and cannot be extrapolated to patients with sclerosis.
We show that erythema BSA measured as a continuous variable is the key driver of the prognostic value and outperforms the composite 2005 NIH Skin Score, which contains BSA as a categorical variable, in predicting survival. One reason for this finding is statistical: information is lost by categorizing a continuous variable. Additionally, composite scoring reduces discriminatory ability between the 2 types of skin findings. This especially attenuates the skin’s utility as a biomarker in the setting of combination disease because scores are driven by stable sclerotic features, and erythema changes are missed. Though crafted with the intention to standardize disease assessments, the NIH Skin Score does not adequately capture the significant differences observed between erythema and sclerosis and likely between more nuanced morphologic presentations.
Curtis et al24 demonstrated that presence of erythema with greater than 3% BSA was associated with increased overall mortality compared with those with less than 3% BSA (HR, 2.0; 95% CI, 0.99-4.0). We add that there is value in collecting erythema serially over time as a continuous variable on a scale of 0% to 100%. We recommend against categorization by arbitrary thresholds. Our illustrative Kaplan-Meier cumulative incidence curves (Figure 2) would appear similar if we selected the 3% threshold used by Curtis et al instead of 10%, but would still lose information. The follow-up visit erythema BSA as a continuous variable had high predictive power with no significant prognostic information added with the addition of baseline and follow-up 2005 NIH Skin Score. Erythema-type disease is generally treatment responsive, and persistent erythema may signal a more severe phenotype—for example, cGVHD with acute features or refractory pulmonary or gastrointestinal involvement. The mechanism that drives the association between erythema BSA and survival was not explicitly evaluated; however, prior studies from the Chronic GVHD Consortium have shown that immunosuppression-related infection and cGVHD organ failure are the major factors associated with NRM.25 Further studies are required to confirm whether early treatment with therapies that optimize response and limit immunosuppression are ideal for patients with erythema-type cGVHD.
Sclerosis-type disease was not associated with OS or NRM, as in prior studies.26,27 In the present cohort, sclerosis appeared more responsive to treatment than previously reported, with 53% of patients improving in 2005 NIH Skin Score (eTable 4 in Supplement 1).26 Sclerosis was also detected earlier in the posttransplant course compared with a prior study by Inamoto et al26 (median, 11 months). These findings suggest that sclerosis can be reversible, and we hypothesize that early detection and treatment is critical in patients with sclerosis. Sclerosis was associated with FFS, a composite outcome primarily tied to escalation of immunosuppression (62% of events), and highlights the refractory nature of sclerotic disease. Prior studies have demonstrated limitations of standard scales like the 2005 NIH Skin Score for measuring meaningful changes in sclerosis,10,28 a shared difficulty with other sclerosing disorders like systemic sclerosis.29 The lack of associations that we found with NRM and OS in patients with sclerosis highlights the need for better metrics of sclerosis-type disease.30
Limitations
This study has limitations. The population was predominantly White, and BSA assessments of erythema may be less reliable in patients with darker skin. The Chronic GVHD Consortium does not provide granular information on erythema morphologic characteristics, which limits the ability to prognosticate by subtype of erythema. As there is no single outcome capturing cGVHD survival, we follow the standard method of examining overall consistency and trend across NRM, OS, and FFS.20 We did not control for treatment regimen or extracutaneous organ involvement. While we did find that certain organ systems were affected concurrently, we found no difference in baseline involvement of highly morbid organs, such as the lungs or gastrointestinal tract. Immunosuppressive regimens were heterogeneous in type and dosage, making baseline comparisons difficult, though prior studies adjusting for treatment demonstrate no impact on the association between clinical severity and survival.24 Outcomes may be affected by recent changes in cGVHD treatment, and thus the applicability of our results in a more recent cohort remains to be determined. Since all patients in this study received systemic immunosuppression, results may not apply to patients with mild cutaneous cGVHD or other cGVHD phenotypes (eg, stable sclerosis) that are not treated with systemic agents. By the design of our prognostic analyses, results only apply to patients with a baseline and follow-up skin evaluation.
Conclusions
In this prospective cohort study, findings suggest that erythema-type cGVHD is common, occurs early during cGVHD, and can prognosticate mortality when persistent. Percentage BSA of erythema collected longitudinally outperforms the 2005 NIH Skin Score in predicting OS and NRM and is comparable in predicting FFS. Future studies should focus on early detection and improving accuracy and efficiency of erythema BSA assessments, such as with photodocumentation,31,32 so that BSA can be introduced as an outcome measure in clinical practice and trials.
eTable 1. Number of visits with missing, zero, or non-zero body surface area of cGVHD, by anatomic location for 1151 assessments (at baseline and follow-up visits)
eTable 2. Sensitivity analysis for failure-free survival in patients with erythema at study enrollment, excluding patients with a failure event prior to first follow-up visit
eTable 3. Patient characteristics by inclusion status
eTable 4. Median (IQR) change in BSA and NIH Skin Score over time for patients with skin cGVHD at enrollment
eTable 5. Univariable analysis of covariates with survival outcomes among patients with erythema at enrollment
eTable 6. Association of sclerosis BSA and NIH Skin Score with survival outcomes among patients with sclerosis at enrollment
eTable 7. Relative prognostic value of erythema BSA and NIH Skin Score models using the likelihood ratio test among patients with erythema at enrollment
eTable 8. Prognostic value of sclerosis BSA and NIH Skin Score among patients with sclerosis at enrollment
eFigure 1. Flowchart of patient selection
eFigure 2A. The 2005 NIH Response Skin Scale
eFigure 2B. The 2005 NIH Skin Score
eFigure 3. Clinical evolution of skin cGVHD subtypes
eFigure 4. Change in BSA over time for patients with sclerotic cGVHD at enrollment, among incident or prevalent disease
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Number of visits with missing, zero, or non-zero body surface area of cGVHD, by anatomic location for 1151 assessments (at baseline and follow-up visits)
eTable 2. Sensitivity analysis for failure-free survival in patients with erythema at study enrollment, excluding patients with a failure event prior to first follow-up visit
eTable 3. Patient characteristics by inclusion status
eTable 4. Median (IQR) change in BSA and NIH Skin Score over time for patients with skin cGVHD at enrollment
eTable 5. Univariable analysis of covariates with survival outcomes among patients with erythema at enrollment
eTable 6. Association of sclerosis BSA and NIH Skin Score with survival outcomes among patients with sclerosis at enrollment
eTable 7. Relative prognostic value of erythema BSA and NIH Skin Score models using the likelihood ratio test among patients with erythema at enrollment
eTable 8. Prognostic value of sclerosis BSA and NIH Skin Score among patients with sclerosis at enrollment
eFigure 1. Flowchart of patient selection
eFigure 2A. The 2005 NIH Response Skin Scale
eFigure 2B. The 2005 NIH Skin Score
eFigure 3. Clinical evolution of skin cGVHD subtypes
eFigure 4. Change in BSA over time for patients with sclerotic cGVHD at enrollment, among incident or prevalent disease
Data Sharing Statement