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Published in final edited form as: Transplant Cell Ther. 2021 Jun 6;27(9):738–746. doi: 10.1016/j.jtct.2021.05.030

Methods to assess disease activity and severity in cutaneous chronic graft-versus-host disease: a critical literature review

Hadir Shakshouk 1,2, Eric R Tkaczyk 3, Edward W Cowen 4, Rokea A el- Azhary 1, Shahrukh K Hashmi 5, Saad J Kenderian 5, Julia S Lehman 1
PMCID: PMC8719782  NIHMSID: NIHMS1756796  PMID: 34107339

Abstract

Background:

Chronic graft-versus-host disease (cGVHD), a potentially debilitating complication of hematopoietic cell transplantation, confers increased risk for mortality. While treatment decisions rely on an accurate assessment of disease activity/severity, validated methods of assessing cutaneous cGVHD activity/severity appear to be limited.

Objective:

We aimed to identify and evaluate current data on the assessment of disease activity/severity in cutaneous cGVHD

Study Design:

Using modified PRISMA methods, we performed critical literature review for relevant articles.

Results:

Literature search identified 1741 articles, of which 1701 were excluded as duplicates or failure to meet inclusion criteria. Of all included studies (n=106), 39 (37%) addressed clinical and/or histopathologic parameters, 53 (50%) serologic parameters, 8 (7.5%) imaging parameters and 6 (5.5%) computer-based technologies.

Conclusions:

The only formally validated metric is the NIH consensus scoring system. The currently validated measure of disease activity/severity assessment in cutaneous cGVHD is founded on clinical assessment alone. Lack of an objective marker for cGVHD necessitates further studies. The potential contributions of serologic, imaging and/or computer-based technology are warranted.

Keywords: Graft-versus-host disease, GVHD, sclerotic GVHD, monitoring, disease activity

Introduction

Graft-vs-host disease (GVHD), a common complication of allogeneic hematopoietic cell transplant (HCT), confers substantial risk for morbidity, mortality and diminished quality of life.1 Typically developing a few months after HCT, chronic GVHD (cGVHD) most frequently involves the skin and mucosal surfaces, although multiple organs may be affected, including the eyes, lungs, liver and GI tract.2,3 Cutaneous cGVHD can be classified clinically as sclerotic or non-sclerotic (Fig 1, 2).3 Although sclerotic cGVHD (ScGVHD) is not acutely life-threatening, widespread involvement may lead to considerable functional disability. In addition, skin sclerosis can be associated with ulceration,4 poor wound healing, and increased risk of infection.5 Scarring alopecia or nail dystrophy also can result.6

Figure 1. Dyspigmentation, brawny erythema, and sclerosis in a patient with sclerotic chronic graft-versus-host disease.

Figure 1.

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Figure 2. Induration and erythema of the arm in a fasciitis-like presentation of chronic graft-versus-host disease.

Figure 2.

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ScGVHD can be difficult to manage, not only due to lack of effective treatments along with their potential adverse effects and high costs, but also due to difficulty with assessing disease activity. Differentiation of active disease versus inactive sequelae can be challenging.7,8 Ideally, medication titration would be guided by reliable, reproducible measures of disease activity.

We aimed to critically evaluate the current literature to assess the utility of various methods, including clinical, histopathologic, serologic, imaging, and computer-based parameters, of accurately measuring disease activity and severity in cutaneous cGVHD.

Methods

We used modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform a critical literature review of disease activity assessment in chronic GVHD affecting the skin. An electronic search of MEDLINE and Embase databases was performed in April 2021, using the following key words: “graft-versus-host disease”, “GVHD”, “stem cell transplant”. Each term was searched individually and in combination with terms including, “disease activity”, “disease severity”, and “monitoring”. In addition, relevant literature cited in identified articles was reviewed for possible inclusion. All article abstracts were reviewed manually by a dermatologist (HS) for relevance. Inclusion criteria included availability of full-text versions through our institution’s electronic library or interlibrary exchange and being written in English. Due to the nature of available literature, findings were reported descriptively. For the purposes of this study, we defined disease activity to mean evidence of ongoing inflammation and severity to indicate the intensity of disease activity.

Results

Literature search identified 1741 articles, of which 1701 were excluded as duplicates or failure to meet inclusion criteria. Of all included studies (n=106), 39 (37%) addressed clinical and/or histopathologic parameters, 53 (50%) serologic parameters, 8 (7.5%) imaging parameters and 6 (5.5%) computer-based technologies. Defining disease activity and severity in cutaneous cGVHD can be challenging. For instance, erythema is regarded as sign of active disease whereas pigmentary changes are not. Disease severity refers to intensity of disease activity and can be inferred from patient-reported outcomes like Lee symptom scale.9,10

Table 1 outlines previously reported methods for assessing disease activity and severity.

Table 1.

Possible serum biomarkers in chronic graft-versus-host disease.

Parameter/Technique Level of Evidence Reference
Clinical parameters
2014 NIH skin scoring system Expert opinion 8,9,11–16
Itching as a part of patient-reported score Prospective study (575 patients) 12
Lee cGVHD Symptom Scale Prospective study (107 patients) 12,17
Vienna Skin Score Prospective study (16 patients) 18
Skin erythema Cross-sectional (193 patients) 9
Adnexal involvement Retrospective, case-controlled study (36 patients) 19,20
original Rodnan total skin thickness score Prospective study (147 scleroderma patients) 21
modified Rodnan total skin thickness score Prospective study 22
Periorbital pigmentation Case series (7 patients) 23
Grip strength Prospective study (584 patients) 24
2-minute walk test Prospective study (584 patients) 24
Durometer Prospective, case-controlled studies (13 patients) 25–28
Myoton device Cross-sectional study (10 patients) 28,29
Histopathological parameters
Histolopathological grading Retrospective study (120 skin biopsies) 30
Serological parameters
Eosinophilia Retrospective studies (237 patients), (142 patients) 31–33
Autoantibodies Retrospective studies (>200 patients) 34
Platelet-derived growth factor Cross-sectional study (39 patients)
CXCL9 Prospective studies (17, 67, 211 patients) 35–37
CXCL10 Prospective studies (170, 115 patients) 38–40
CXCL11 Prospective study (49, 115, 211 patients) 36,39,41
CXCR3+CD4+ T cells Prospective study (46 patients) 42
BAFF Retrospective and prospective studies (104, 115 patients) 39,43–47
CD19+CD21low B Cells Prospective study (70 patients) 47–50
ST2 Prospective study (67 patients) 37
Elafin Prospective study (22 patients) 51
Matrix metalloproteinase Prospective study (67 patients) 37
Osteopontin Prospective study (67 patients) 37,52
soluble CD163 Prospective study (167 patients) 53
MICA Prospective study (116 patients) 54
TNF-α Prospective study (30 patients) 55
TGF-beta Prospective study (66, 31 patients) 56,57
AIF-1 Prospective study (31 patients) 57
n-10 Prospective study (57 patients) 58
n-15 Prospective study (153 patients) 59
n-17 Retrospective study (51 patients) 60,61
n-6 Retrospective study (51 patients) 37,61,62
IL1ra Prospective study (98 patients) 63,64
Soluble IL-2R Prospective study (27 patients) 65
Adiponectin Prospective study (34 patients) 66,67
lactoperoxidase, lactotransferrin Case series (10 patients) 68
Prolactin Prospective study (236 patients) 69
Branched-chain amino acids:
leucine, isoleucine and sulfur-containing metabolite (cystine) 		Prospective study (18 patients) 70
Imaging parameters
20-MHz ultrasonography Case series (5 patients) 71
Acoustic radiation force impulse (ARFI) and shear wave elasticity imaging (SWEI) Case report (5 patients) 72
Magnetic resonance imaging (MRI) Case series (16 patients) 73
MRI with PET Case series (6 patients) 74
optical coherence tomography (OCTA) Case series (1 patient) 75,
Computer-based technologies
Assessing erythema in 3D photography Case report (1 patient) 76
Crowdsourcing for assessing extent of skin involvement Case report (1 patient) 77
Machine-learning for patient stratification, based on phenotype severity Retrospective study (339 patients) 78
eGVHD App Prospective study (78 physicians) 79
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Clinical Parameters

In 2005, the National Institutes of Health (NIH) Consensus Conference developed criteria and a practical worksheet to assist with the diagnosis and scoring of cGVHD of all major organ systems.80 After several years of implementation of original criteria, these guidelines were refined in 2014.8 Regarding documentation of cutaneous involvement, the scoring system evaluates extent of involvement by body surface area (BSA) and degree of sclerosis, with a mechanism to account for immobility or ulceration. Other skin features, including hyperpigmentation, hypopigmentation, poikiloderma, severe or generalized pruritus, hair involvement or nail involvement, are documented without BSA estimation.9 Assessment of joint and fascial involvement from ScGVHD was added, with photographic range-of-motion (ROM) included as an exploratory measure. While this scoring system represents a useful attempt to quantify disease severity in cutaneous cGVHD, the ability of the tool to distinguish between active, ongoing inflammation and inactive sclerosis has been challenged.81 For example, although erythema, a proxy for inflammation, is included in the BSA skin score calculation, it can be challenging to assess erythema in patients with poikiloderma due to admixed pigmentary changes. Even more challenging can be evaluation of dermal, subcutaneous or fascial disease only, when determination of activity relies on acute edema, loss of range of motion, involvement of new anatomic sites, and/or other organ involvement.

The ability of the 2014 NIH scoring system to reliably identify patients with severe cGVHD was validated in subsequent studies. Specifically, Moon et al. demonstrated in a cohort study of 425 patients that the NIH scoring correctly identified high-risk patients (i.e. lower overall survival) using the method. Subsequently, the authors successfully validated the NIH global scoring system of cGVHD in severe disease.14

The Chronic GVHD Consortium evaluated patient-reported skin scores and outcomes, such as the 2005 NIH skin scoring scale, 2006 NIH skin response scale, Vienna Skin Scale, Johns Hopkins sclerosis and fasciitis scales, and the Lee Symptoms skin subscale. This large, multicenter study included a prospectively assembled cohort of 458 patients.15 Results demonstrated that an NIH skin score of 3 (most severe) correlated with increased risk for mortality and non-relapse mortality. Also, patients who experienced worsening of their NIH skin score had worse overall mortality than those with stable skin disease.15 In addition, another study compared NIH criteria and other tools to clinician- and patient-reported response measures in a cross-sectional prospective study of 193 patients with moderate-to-severe cGVHD. This study noted that the presence and extent of erythema was associated with active disease and poor survival. 81 The authors cautioned that the degree and extent of scored erythema can be affected by topical medications; hence, the effect of skin-directed treatment should be taken into account.81

Inter-rater agreement of the 2005 NIH scoring system was tested in several studies. Mitchell et al. evaluated 34 hemato-oncologists who received standardized training in skin scoring (2.5 hours) then assessed 25 cGVHD patients in an ambulatory clinic.16 Results were then compared with transplant experts’ ratings. Results showed a fair level of inter-rater agreement on skin manifestations, with regards to erythema and sclerosis. While this study demonstrated the feasibility of NIH for clinical application, it also required standardized training of raters. However, these findings were limited by lack of control group. 16 Another study involved assessment by 6 HCT transplant physicians and 4 dermatologists of 8 patients using NIH scoring system skin-specific variables, ROM severity grading, and a body site skin sclerosis grade (SSG); with a sclerosis score ranging from 0 to 3. Results were correlated with patient-reported severity scores and quality-of-life metrics.13 This study demonstrated reasonable inter-rater agreement for ROM, a finding attributed to the incorporation of a detailed visual aid with the 2014 NIH scoring sheet. Limitations of this study included a small number of patients, lack of information regarding the experience level of assessors, few details regarding the training guides provided to them, and lack of validation of the SSG grading used.

Other cGVHD scoring systems have been proposed previously. Specifically, Lee et al. developed a symptom scale of 30 items in a patient self-administered questionnaire to evaluate the effects of cGVHD on skin, vitality, pulmonary status, nutritional status, psychological functioning, ocular symptoms, and oral symptoms.17 It also predicted overall survival and non-relapse mortality.12 While shown to be easily understood and accepted by patients, the Lee cGVHD Symptom Scale emphasizes patient-reported symptoms rather than disease activity. The Vienna Skin Score was found to have reasonable reproducibility in a pilot validation study involving 16 patients examined by 4 physicians 3 separate times over 2 days.18 However, this scoring system also does not differentiate active disease from disease sequelae. In a large scale-study performed on 575 patients, Palmer et al demonstrated that itching could be a predictor of disease activity and treatment outcome. 12

A recent systematic review of patient-reported outcome measures (PROM) revealed that Human Activity Profile, Lee Symptom Scale and NIH Eleven Point Scale were the most reliable in cGVHD.82

The Rodnan total skin thickness score, which assesses skin thickness by palpation, is validated for use in systemic sclerosis and has since been modified for use in morphea.21,22 The utility of this scoring system in the assessment of ScGVHD is not well explored.

A clinical clue reported to correlate with increased severity of overall cGVHD is involvement of the hair follicle or nails,19 sites that are usually sequestered from the immune system and that, when affected, may indicate more aggressive skin disease.20 In an analysis of 7 patients with ScGVHD, periorbital pigmentation was observed as an initial manifestation in 3 cases, and so it has been proposed as a predictor for extensive ScGVHD; 23 however, larger validation studies are required.

Several attempts have been made to quantitatively measure the severity of skin and soft tissue sclerosis. Myotonometry is a non-invasive method to study soft tissue mechanical properties that works by delivering a brief mechanical impulse and measuring dampening of oscillatory tissue response. In a study of 14 cGVHD patients compared to 10 healthy controls, myotonometry proved to be effective in measuring skin stiffness, and thereby degree of sclerosis.29 A durometer is a non-invasive handheld device used to determine surface hardness by measuring the amount of force required to produce an indentation, to evaluate skin hardness.25–28 In a study of 7 cGVHD patients, both myotometry and durometry exhibited high inter-observer reproducibility.28 However, performance between the two modalities varied based on anatomic site of measurement.28 Larger studies involving serial measurements over time and correlation with other measures of clinical disease activity are required.

While dermoscopy, a rapid non-invasive tool, is extensively employed in the diagnosis of many dermatologic diseases, its utility in GVHD remains limited. One study correlated dermoscopic findings with histopathologic features in 15 patients with cGVHD. The most common findings in cGVHD were granularity, scaling, linear vessels, and white patchy areas. Granularity corresponds to melanophages whereas the white areas are related to increased dermal collagen.83 Further studies are needed to establish the dermoscopic features of GVHD along with the potential use for monitoring disease activity and severity.

Other reported disease activity assessment methods include hand grip strength (HGS) and 2-minute walk test (2MWT)11,24 pertain more to extracutaneous manifestations of cGVHD. The recent 2021 NIH consensus criteria emphasized on the patients’ role in monitoring and reporting their symptoms which would be helpful in determining the disease activity, severity as well as response to treatment.84 This can be facilitated using mobile application or online platforms.85

Histopathological parameters

Microscopic features of cGVHD can include pandermal sclerosis with periadnexal lymphoplasmacytic aggregates and vacuolar interface changes, considered helpful to support a clinical diagnosis of cGVHD.8 In a recent study, no correlation was observed between histopathological grading of GVHD and survival.30

Imaging parameters

Several studies involving the measurement of skin thickness radiographically in ScGVHD have been performed.71,72,74,86,87 One study found an inverse correlation between skin thickness, as quantified by two-dimensional 20-MHz B-mode B-scan ultrasonography, and clinical response to therapy in 5 patients with cGVHD.71 Another study using acoustic radiation force impulse (ARFI) and shear wave elasticity imaging (SWEI), a method allowing for simultaneous assessment of tissue thickness and stiffness, showed increased skin stiffness in sclerotic compared to unaffected skin in a patient with localized ScGVHD.72

In a study of 16 patients with cGVHD, magnetic resonance imaging (MRI) was employed to evaluate subcutaneous or fascial involvement.73 MRI was able to detect deeper and more extensive involvement than could be appreciated by physical examination alone. Another group of investigators combined MRI with fluorodeoxyglucose (FDG)-positron emission tomography (PET) to monitor disease activity in 6 patients with ScGVHD.74 The study found that MRI could detect pathological changes in the deep soft tissues, and the addition of contrast allowed estimation of the degree of inflammation. 74

Optical coherence tomography (OCTA), a non-invasive imaging modality using near-infrared light, has been explored in various dermatological diseases.88 It has been employed to visualize capillary-level vascular and structural features within skin in vivo, a function that has shown to correlate with vascular and structural changes in morphea75 and cGVHD.87 Recently, Chen et al. investigated the utility of OCTA in 7 patients with cGVHD, where they described hyperkeratosis, epidermal hyperplasia as well as reduced depth of light transmission in those patients. These findings correlated with the severity of cutaneous cGVHD when measured by the Vienna Skin Scale. The decrease in the depth of light transmission was attributed to inflammatory cellular infiltrate with more severe disease. Of note, these findings varied with body sites which may necessitate the need for body site-specific criteria when assessing patients with cGVHD. Authors also followed up one patient after receiving treatment and detected improvement by OCTA paralleling the clinical improvement. 89 However, larger scales studies are warranted to evaluate its utility in monitoring cGVHD.

Serologic parameters

In 2014, the cGVHD Biomarker Working Group gave recommendations regarding identification and validation of potential biomarker candidates prior to qualification for clinical application.90 Several attempts have been made to identify clinically useful diagnostic and prognostic serologic biomarkers for cGVHD (Supplementary Table). However, none is specific to cutaneous cGVHD activity.

Evidence for the prognostic value of serum eosinophilia, a marker of Th2 immunity, in cGVHD has been mixed.31–33 C-reactive protein, a marker of overall inflammation, was found to be elevated in patients with active and severe cGVHD in a cohort of 189 patients.91 The relationship between platelet count and disease activity appears unclear. Specifically, complications and treatment-related mortality have been reported with thrombocytopenia92 while more severe forms of cGVHD were associated with thrombocytosis.91

Several studies have noted an association between certain chemokines, particularly CXCL10 and its biologic mediators, and the presence and severity of cGVHD.35,38,40,93 Given the role of B-cells in the development of cGVHD, researchers have investigated B-cell-activating factor (BAFF) as a biomarker for cGVHD.41,43,45,46 In a study of 104 patients, BAFF levels were higher in patients with active cGVHD. Another study of 46 patients showed reduction in serum BAFF levels after treatment with high-dose prednisone 43 and extracorporeal electrophoresis.45 In addition, BAFF levels seem to correlate directly with non-relapse mortality.94 Larger prospective validation studies of the most promising predictors of cGVHD disease activity are required.

The clinical relevance of circulating of autoantibodies, such as anti-nuclear antibodies, in patients with cGVHD has been investigated. A cohort study of 121 patients found that the presence of autoantibodies conferred more favorable survival outcomes.95 Though another study of 65 patients showed no correlation with cGVHD activity and outcomes.34 In addition, two larger studies, each involving over 200 patients, found no association with autoantibodies specific cGVHD disease manifestations.96 Among the most commonly studied autoantibodies were antinuclear antibody (ANA) and rheumatoid factor (RF).

Elafin, a serine protease inhibitor, secreted by keratinocytes. It has immunomodulatory and antiproliferative function favoring the development of a Th1response. While increased levels of epidermal elafin is associated with poor prognosis of lichenoid cGVHD, elafin was not detectable in sclerotic cGVHD.51 When measured on days 15 and 30 post-transplant, elafin was not associated with occurrence of cGVHD, non-relapse mortality, therapy-resistant GVHD, or overall survival. However, levels of elafin were elevated in patients with severe skin acute GVHD.97

Another potential biomarker for cGVHD is prolactin, a polypeptide hormone, not only secreted by pituitary gland but also by T lymphocytes with various immunoregulatory functions.98 Salas and colleagues studied prolactin in 255 patients with cGVHD and they found that patients with elevated prolactin levels were 6.4 times more likely to have active cGVHD compared to patients with normal levels. However, prolactin levels did not correlate with overall survival.69 Although these results support the use of prolactin as an indicator for activity in cGVHD, no solid association can be made owing to the retrospective design of this study. Larger prospective studies are warranted to prove the reliability of prolactin.

While the use of serologic biomarkers to assess disease activity would be attractive, there are several practical limitations, including: (a) clinical heterogeneity, (b) laboratory assay variation, (c) inadequate patient numbers included in studies, and (d) variable effect of immunosuppressive therapy or infection on biomarker levels.99

Clinical trials of preemptive interventions or novel drugs based on GVHD biomarkers are warranted.

Computer-based technologies

Computer assisted estimation of BSA involvement, a crucial component of the 2014 NIH skin score, has been recognized as a practice gap.8,81 Tkaczyk et al. investigated an objective means to assess the extent and severity of erythema in 3D photographs, a method that offered the potential to increase accuracy of BSA estimation over that from 2D photographs. After undergoing standardized training, 6 raters were asked to delineate areas of erythema in 3D photos of one patient. Annotated images were evaluated by software that could calculate BSA. While this method was shown to be efficient in tracking erythema, raters disagreed on extent and degree of erythema, likely due to the indistinct margins of erythema and/or differences in visual perception.76 Application on larger scale is required to fully understand the utility of this technology. The same group of investigators studied crowdsourcing, or employment of multiple non-expert individuals to complete independent tasks, to assess the extent of skin involvement by cGVHD.77 Crowdsourcing was shown to be an efficient method in delineating the extent of skin involvement in cGVHD patients. Machine-learning has also been used to risk-stratify patients with cGVHD based on phenotype.100. Based on the subcomponents of the NIH Consensus Criteria, disease manifestations were divided into 7 clusters based on every organ involvement. Then, computer analysis classified 339 patients into various clusters, which could then subsequently predict clinical outcomes. 100

Aiming to easily assess severity of cGVHD among health care providers, an online application has been used eGVHD App (www.uzleuven.be/egvhd). Using this low-cost, readily available tool encourages clinicians to systematically evaluate patients and score the disease severity.79,101,102 The recent 2021 NIH consensus criteria suggested the incorporation of such tools in the electronic health record for better disease assessment.84

Measures used in Clinical trials

The use of the 2005 and 2014 NIH consensus criteria proved to be useful for developing better structured clinical trials. they helped in approving a novel drug, ibrutinib by the FDA in 2017.103 When compared, the 2014 NIH consensus criteria were better than the 2005 criteria in classification of organ involvement in 284 patients with cGVHD.104 Therefore, recent clinical trials employed the 2014 NIH response criteria as primary end-point to measure overall survival. For example, these measures were used in trials for ibrutinib103 and pomalidomide for resistant cases of cGVHD.105 In addition to the most recent drug belumosudil (KD025) which showed substantial improvement in overall survival rate and quality-of-life with reduced corticosteroids doses and limited toxicity. 106 This highlights the necessity of having a valid tool to measure disease activity and severity as it helps in clinical trials and discovering novel therapies.

Conclusion

This critical literature analysis revealed several prior efforts to use clinical, histopathologic, imaging, serologic, or computer-based methods to assess disease activity and severity of cGVHD. However, the only well-validated method is the NIH clinical scoring system, which depends on clinical information only. While currently used by dermatologists in clinical practice, the 2014 NIH criteria are helpful for assessing skin disease yet the need for a more objective marker is warranted. As per the 2021 NIH recommendation for clinical trials, the use of optical coherence tomography and myoton device was highly supported. 84

Future studies may evaluate the additive value of incorporating other biomarkers, whether histopathologic, imaging, serologic, or computer-based, into clinical scoring systems to optimally assess disease activity and severity in cGVHD.

Supplementary Material

1

Figure 3. Flowchart indicating article inclusion/exclusion, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Figure 3.

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Highlights.

  • Cutaneous chronic graft-versus-host disease (cGVHD) can be difficult to manage, not only due to lack of effective treatments along with their potential adverse effects and high costs, but also due to difficulty with assessing disease activity.

  • There is unmet need for reliable and reproducible measures of disease activity/severity which will affect treatment plan.

  • This study found that the NIH consensus scoring system, based entirely on clinical data, is the only well-validated metric of disease activity/severity.

  • The potential value of imaging, serologic, and/or computer-based methods of disease activity/severity assessment requires further exploration.

Acknowledgments

Funding source: This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.

Dr. Tkaczyk was supported by a Career Development Award from the United States Department of Veterans Affairs Clinical Sciences R&D Service (IK2 CX001785).

Footnotes

Conflicts of interest: Authors have no conflicts of interest to declare.

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