In the current study, we have reported the second largest series of patients with fascial/articular related cGVHD and performed a narrative review focused on cGVHD related fasciitis. Although literature addressing this complication is scarce, one out of 3 patients evaluated in our multidisciplinary cGVHD consultation developed fasciitis, 13% had isolated joint contractures and 7% severe bone complications. As a result of these events, 35% of patients showed negative impact on physical function.
Studies and reviews specifically of cGVHD-related fasciitis are limited. Most of them are descriptions of isolated cases [21, 27,28,29,30,31,32,33,34,35] or case series with small sample sizes [19, 20, 36,37,38], or uncontrolled series [19, 26]. For this reason, the cohort of our hospital is the second largest series to be reported in the literature after that of the Seattle group [26], whose publication extended the data they published in 2014 [19]. Similar to our series, Inamoto et al. also compared two groups based on the presence or absence of joint/fascia manifestations at the time of enrollment and mainly highlights the need to systematically, objectively, reliably, and simply assess fascia and joint involvement in a clinically meaningful way. However, in contrast to our study, the Inamoto study did not specify how many patients in the cohort presented with EF-like disease.
More than 80% of the patients with fasciitis in our series had some nonspecific symptom before they developed fascial sclerosis. None of these manifestations is considered a diagnostic criterion for GVHD [11, 12] In this regard, our hospital’s series, reported here, reflects a much higher incidence of nonspecific musculoskeletal symptoms. This is probably due to recruitment bias, since these are patients with established cGVHD, most of whom were refractory to first-line treatment, followed in a multidisciplinary consultation that also considered dermatology and rheumatology. On the other hand, inflammatory joint involvement is a very rare, and only exceptionally described entity [40]. Accordingly, only two patients in our series developed arthritis. Sclerotic cGVHD at onset of disease occurs infrequently but long-standing cGVHD is likely to advance to sclerotic so it is necessary that allo-transplanted patients who start with non- specific musculoskeletal symptoms must be evaluated by rheumatologist in order to make an early diagnosis and treatment to prevent irreversible damage and bone complications induced by high dose steroid treatment. Although infrequent at the cGVHD onset, sclerotic manifestation including fasciitis may be developed during the follow-up. Hematologist, rheumatologist and dermatologist should become aware of this post-transplant condition, in order to stablish an early approach to identify and treat this aspect of cGVHD. Allo-HPT transplanted patients with nonspecific and persistent musculoskeletal symptoms such as arthralgias, joint-stiffness, and tendon-rubbing or decrease of joint mobility should be thoroughly evaluated to rule out incipient fibrous disease. Early recognition of chronic GVHD may offer an opportunity to prevent evolution to more severe disease with irreversible damage.
In our cohort, 47% of patients developed fascia involvement during follow-up. The NIH consensus criteria joint/fascia score does not distinguish the contributions to cGVHD severity made by isolated joint involvement compared with joint restriction associated with skin sclerosis [11,12,13]. Although joint/fascia involvement is common in cGVHD, the incidence of isolated joint involvement contracture in the absence of detectable superficial or subcutaneous skin sclerosis is low [41]. It is likely to go unnoticed and be underdiagnosed unless thorough clinical examination of the range of joint mobility is performed as a matter of course (Fig. 1). This entity is considered by some authors, even in the NIH scales, to be the deep cutaneous fibrotic variant. However, there is controversy about its inclusion as part of the skin staging [38, 42].
Additional studies are needed to determine whether joint involvement in the absence of sclerotic skin changes represents involvement of the deep tissues below the limit of clinical detection or if it is a separate clinical process. Several studies have shown a strong correlation between joint and skin symptoms during the course of GVHD [12, 19, 38] According to Vukiç et al [20], joint changes appeared in 83.3% of subjects with superficial/erythematous cutaneous sclerosis and deep sclerosis. These data are consistent with those obtained in our series, in which 89.7% of patients with fascial involvement also had concomitant sclerotic skin involvement.
There is a gap in knowledge and unmet needs regarding sclerotic GVHD, including the need of improving the sclerotic patient’s assessment as reflects NIH 2020 reports [13, 14]. We lack of prognostic biomarkers, we need new approaches for early identification and treatment of fibrotic changes and new tools to objective assess skin sclerosis in cGVHD. Time of intervention (early versus late) is very important to avoid progression and improvement in physical functioning and quality of life.
Janin et al. [38] published a retrospective study in 1994 of a series of 14 patients diagnosed with cGVHD who developed fasciitis during their follow-up. They presented with sudden painful swelling of the skin on their extremities and some on their flanks. Seven of these 14 patients (50%) had a history of strenuous or unusual physical exertion, as in the case described by Ustun et al [32]. In our series, we documented in only one patient the presence of exertion as a trigger for fascial involvement in the abdomen and proximal region of the upper limbs.
Patients with sclerotic cGVHD experience negative effects on their physical function, due to decreased joint mobility, and a reduced quality of life [3]. In our series, more than 15% of the patients studied had an ECOG score greater than 1, and up to 70% of those with fasciitis had some limitation on their joint mobility.
Unfortunately, the clinical, genetic, and biological factors that are specifically linked to musculoskeletal and joint involvement in patients with GVHD are unknown [18, 19, 42]. The search for serum biomarkers in this fibrosing entity, such as specific autoantibodies (anti-sclerosis) has so far proved unsuccessful [43]. In our series of patients with fasciitis, positive antinuclear antibodies were detected in 25% of patients, with the nucleolar pattern being the most frequent.
Chu et al [29] concluded in their work that patients with clinical manifestations suggestive of EF-like cGVHD should undergo a full-thickness biopsy consisting of skin, muscle and fascia and, in some cases, an additional MRI study to detect the pattern of involvement and monitor the response to treatment. Fasciitis in the NIH consensus is included as a diagnostic entity of cGVHD, and biopsy confirmation is not necessary [11, 12], which is why neither biopsy nor advanced imaging tests were routinely requested for patients in our cohort. Few studies have analyzed the usefulness of advanced imaging techniques, such as magnetic resonance imaging or high-resolution soft-tissue ultrasound [44, 45], in patients with cGVHD with nonspecific prodromal musculoskeletal symptoms such as arthralgias, joint-stiffness, and tendon-rubbing. In our patients, imaging tests were occasionally performed, because they had an established diagnosis of cGVHD and the information that such tests could provide was considered unlikely to change any aspect of their therapeutic management. Nevertheless, it would undoubtedly be worthwhile designing a study that included imaging tests in the initial stages of the disease, to try to detect the inflammatory phases in the initial stages, and to analyze whether early treatment improves the functional prognosis of this fibrosing entity, such as the development of sclerosis joint contracture.
The assessment of active joint mobility as an objective measure to evaluate response to treatment has the limitations of requiring time and a properly trained professional who can carry out standardized, reproducible measurements. In this setting, the P-ROM scale offers an alternative for clinical use, since any clinician can complete the assessment adequately in 1–2 min. However, this scale does not detect patient-related outcomes (PROs) as well, probably because it does not take stiffness or limitations in performing activities of daily living into account, as does the NIH joint/fascial scale. Incorporating a measure of musculoskeletal symptoms similar to Lee's subscale (0–10) into the P- ROM scale would capture changes in PROs and would carry weight in the overall GVHD assessment score [9]. In addition, some studies have recommended that the dominant hand grip strength be measured with a dynamometer or sphygmomanometer and a 2-min gait test carried out [46]. These measurement indices have not been subsequently replicated and the NIH consensus group does not recommend their use in clinical practice, although they are required in some clinical trials.
This disease entity remains a therapeutic challenge due to the lack of knowledge about its pathogenesis and the need to use rescue therapy due to cortico-refractoriness and the frequent adverse effects, such as bone complication morbidities (7% in our series), related to steroid treatment. Since the patients treated in our multidisciplinary cGVHD clinic are mainly corticosteroid-refractory or corticosteroid-intolerant, most of them required several lines of treatment. Although no clear conclusion can be drawn about specific agent response due to the limitations of our study, it is important to emphasize that the majority of them experienced improvement, and 41% of them achieved complete resolution of their signs and symptoms. The usefulness of non- pharmacological measures such as physiotherapy and other physical therapies to prevent disease progression is also extensively reported [16, 47].
