Chronic Graft-versus-Host Disease
Sclerodermatous Chronic Graft-versus-Host Disease in Focus
Sclerodermatous graft-versus-host disease (GVHD) is a less common manifestation of chronic GVHD (cGVHD) that can be extremely debilitating. Cutaneous features may include sclerosis, atrophy, and contractures, and complications such as skin ulceration, hair loss, and nail changes are possible.
Sclerodermatous cGVHD typically involves the deeper layers of the skin with scarring or the induration of subcutaneous tissues. It can also potentially affect sites such as the eyes and the mouth, presenting with dry eye or dry mouth, because scar tissue has obliterated the tear-producing or salivary glands. Scleroderma generally refers to sclerotic skin (ie, an inability to move the skin normally). Our normal skin is quite stretchy and flexible. The loss of the skin’s normal elasticity from scleroderma is similar to what is observed in the skin of burn victims: where people with deep burns can have contractures or locked-down areas of scar tissue that restrict joint movement and the elasticity and mobility of the skin.
Therefore, the damage from scleroderma is not so much in the superficial skin, which is relatively intact, but rather is the result of a deeper inflammatory and fibrotic reaction. A deeper fibrotic scar tissue is formed in the dermis and the subcutaneous tissues, and this can lead to damage of the accessory structures such as hair follicles and sebaceous glands, nail changes, and, potentially, ultimately erosion of the skin and the development of ulcers, all from this underlying process. Although the pathophysiology of sclerodermatous cGVHD is not well understood, alterations in pathways such as the WNT signaling pathway or CSF1-dependent macrophages are being investigated for their potential involvement in the development and management of sclerodermatous cGVHD.
Sclerodermatous cGVHD can have a significant impact on patient quality of life in that the tighter and stiffer the skin becomes, the more limited the patient becomes in their ability to move across joints. If someone is not able to straighten their joint (eg, to lift their hand above their shoulder to reach something in a cupboard or to bend down to tie their shoe), then that is a significant impairment to their quality of life.
Thankfully, the development of sclerodermatous cGVHD is not very common. Skin is very commonly impacted in patients who develop cGVHD, but only a subset of those with skin GVHD progress to include sclerodermatous involvement. If scleroderma is extensive, if it crosses important joints, and/or if it leads to a lockdown and a breakdown of secondary structures in the skin, then it really does start to become a major cause of morbidity and, potentially, even mortality.
I do not believe that there are many patient trials that are specifically focused solely on sclerodermatous GVHD, but cGVHD treatment trials necessarily often include a significant proportion of patients with sclerodermatous skin involvement. In fact, patients in these studies who are defined has having severe cGVHD per the National Institutes of Health cGVHD consensus criteria often have sclerodermatous skin involvement. Although it was initially thought that sclerodermatous manifestations in cGVHD might be irreversible, recent studies of newer agents describe responses in all organs, including sclerodermatous cGVHD, with skin softening, potentially more tear formation, and dry mouth relief. So, I do believe that scarring in sclerodermatous cGVHD is a dynamic process that constantly undergoes remodeling. If you are able to shut down the development of the scar, then perhaps the natural process of clearing the scar continues with an improvement in sclerodermatous cGVHD, as observed in recent trials.
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