Introduction: The Divergent Lens of Therapeutic Assessment
Chronic graft-vs-host disease (cGVHD) remains a formidable challenge in the landscape of allogeneic hematopoietic cell transplantation (HCT). As a multisystemic alloimmune disorder, its manifestations are diverse, but the skin is the most frequently affected organ, appearing in approximately 75% of cases. In clinical trials and routine practice, determining whether a treatment is working often relies on two distinct sources of information: the clinician’s objective assessment and the patient’s subjective experience. However, these two perspectives do not always align.
Recent evidence, published in JAMA Dermatology, highlights a significant gap in how clinicians and patients perceive treatment response in cutaneous cGVHD. This discordance is not merely a matter of differing opinions; it has profound implications for therapeutic decision-making, drug approval processes, and, most critically, patient survival. Understanding the factors that drive this misalignment is essential for advancing evidence-based care in this complex population.
Highlighting the Clinical Disconnect
Among the key findings of this multicenter longitudinal cohort study are several critical insights for the transplant community:
1. Over one-third (34.4%) of patients with cutaneous cGVHD experience a discordance between their own assessment of treatment response and that of their clinician.
2. Sclerotic cGVHD is a primary driver of discordance. Patients with skin sclerosis are significantly more likely to have clinicians either overestimate or underestimate their treatment progress compared to non-sclerotic cases.
3. While both clinician-reported and patient-reported outcomes (PROs) are associated with nonrelapse mortality (NRM) in the general cohort, the patient’s voice is the only significant predictor of survival in the high-risk sclerotic subgroup.
4. The findings suggest that current clinical metrics may fail to capture the deep-tissue changes and functional limitations that define the patient experience in fibrotic cGVHD.
Background: The Burden of Cutaneous cGVHD
Cutaneous cGVHD is categorized into two main phenotypes: inflammatory (erythematous, lichenoid) and fibrotic (sclerotic). While inflammatory lesions are often visible and easier to quantify via Body Surface Area (BSA) measurements, sclerotic disease involves the deep dermis, fascia, and sometimes the muscle. Sclerosis leads to skin tightening, joint contractures, and significant morbidity.
Traditionally, the NIH Consensus Criteria have guided response assessment, focusing heavily on clinician-measured BSA and skin features. However, these metrics often correlate poorly with patient-reported symptoms like pruritus, pain, and restricted mobility. As the FDA and other regulatory bodies increasingly prioritize PROs in clinical trial endpoints, understanding why clinicians and patients disagree becomes a priority for drug development and clinical validation.
Study Design and Methodology
This study was a multicenter longitudinal cohort analysis involving 489 adults with cutaneous cGVHD. The participants were drawn from three major sources: two observational studies and one randomized clinical trial. The demographic profile was balanced, with a median age of 55 and a slight male predominance (60.7%).
Measuring Response
The primary measure was a global 8-point cutaneous cGVHD treatment response scale. On this scale, 1 indicated ‘resolved’ and 8 indicated ‘very much worse.’ Assessments were collected 3 to 6 months after study enrollment. To simplify the analysis, responses were grouped into three categories: improved, stable, and worse.
Defining Discordance
Discordance was defined as any difference in the categorized response between the clinician and the patient.
– Positive clinician discordance: The clinician reported a better response (e.g., ‘improved’) than the patient (e.g., ‘stable’ or ‘worse’).
– Negative clinician discordance: The clinician reported a worse response than the patient.
The researchers also evaluated the association of these responses with nonrelapse mortality (NRM), providing a hard clinical endpoint to validate the importance of these subjective measures.
Key Findings: The Prevalence and Impact of Discordance
The study found that 65.6% of patient-clinician pairs were in agreement, leaving 34.4% in discordance. This level of disagreement is substantial enough to potentially skew the results of clinical trials if only one perspective is utilized.
The Sclerosis Factor
The most striking finding related to the type of skin involvement. Patients with sclerotic cGVHD had significantly higher odds of discordance. Specifically, clinicians were more likely to report a better response than the patient (adjusted odds ratio [aOR], 3.14; 95% CI, 1.41-6.95) and also more likely to report a worse response (aOR, 2.33; 95% CI, 1.19-4.56). This ‘double-edged’ discordance suggests that sclerotic disease is inherently difficult for clinicians to assess accurately using standard visual or palpation-based tools.
Survival and Nonrelapse Mortality
The study established a clear link between perceived worsening and mortality. When either a clinician or a patient reported that the skin condition was worsening, the risk of NRM increased:
– Clinician-reported worsening: Adjusted hazard ratio (aHR), 2.28; 95% CI, 1.46-3.54.
– Patient-reported worsening: aHR, 1.86; 95% CI, 1.12-3.08.
However, in the sclerotic subgroup, the clinician’s assessment lost its predictive power for survival, while the patient’s assessment remained significant (aHR, 2.00; 95% CI, 1.02-3.90). This suggests that for patients with fibrotic disease, their internal perception of disease progression is a more sensitive indicator of systemic health and mortality risk than a physical exam.
Expert Commentary: Why Do We Disagree?
The discordance in sclerotic disease likely stems from the limitations of the physical exam. Sclerosis is a three-dimensional process. A clinician might see a stable area of skin, but the patient feels increasing ‘tightness’ or a loss of range of motion in a joint that isn’t easily captured on a 2D skin assessment. Furthermore, patients may prioritize ‘invisible’ symptoms like deep-seated pain or the psychological burden of skin changes, which clinicians may overlook in favor of objective signs like redness or scaling.
From a mechanistic perspective, sclerosis represents a late-stage, often irreversible fibrotic process. If a clinician misses early signs of worsening because they are looking only at the surface, the window for adjusting immunosuppression or introducing anti-fibrotic agents may close. The fact that patient-reported worsening in sclerosis is so strongly tied to mortality emphasizes that the patient is often the ‘canary in the coal mine’ for systemic graft-vs-host progression.
Clinical and Policy Implications
For clinicians, these findings are a call to integrate PROs more formally into every visit. Relying solely on a physical exam for skin cGVHD, especially in sclerotic cases, is insufficient and potentially dangerous. The 8-point global assessment used in this study is a simple, low-burden tool that could be implemented in clinics to facilitate better communication.
For researchers and health policy experts, the data reinforces the necessity of dual endpoints. Clinical trials that rely only on clinician-reported NIH scores may fail to capture the true efficacy (or lack thereof) of a drug. Regulatory bodies should consider patient-reported worsening as a valid and critical endpoint for determining the success of new therapies, particularly in fibrotic diseases where objective clinical tools are lacking.
Conclusion: A Call for Integrated Assessment
Discordance in treatment response is not a failure of the clinician or the patient; it is a reflection of the complexity of cutaneous cGVHD. This study proves that the patient’s perspective is not just a ‘quality of life’ measure—it is a survival measure. In the high-stakes environment of post-transplant care, bridging the gap between clinical observation and patient experience is essential. By valuing the patient’s voice, particularly in the face of sclerotic disease, we can better predict outcomes, tailor treatments, and ultimately improve the survival of those living with this challenging condition.
References
1. Babu V, Shin DB, Onstad L, et al. Discordance in Treatment Response Assessment Between Clinicians and Patients With Skin Chronic Graft-vs-Host Disease. JAMA Dermatol. 2026 Jan 21:e255545. doi: 10.1001/jamadermatol.2025.5545.
2. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2015;21(3):389-401.
3. Lee SJ, Onstad L, Chow EJ, et al. Patient-reported outcomes and survival at 1 year after diagnosis of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2013;19(11):1600-1605.
