A hematopoietic stem cell transplant (HSCT) is a life-saving procedure often used to treat cancers like leukemia and lymphoma. This process involves infusing healthy blood-forming cells from a donor into a patient following high-dose chemotherapy or radiation to rebuild the immune system. However, this transplant carries the risk of graft-versus-host disease (GVHD). GVHD occurs when the transplanted immune cells, the “graft,” recognize the patient’s body, the “host,” as foreign and attack it. Chronic graft-versus-host disease (cGVHD) is a long-term, multi-system inflammatory disorder that significantly impacts a patient’s recovery and quality of life.
Defining Chronic Graft-versus-Host Disease
Chronic graft-versus-host disease is a complex syndrome distinguished by its clinical features and duration. Historically, cGVHD was defined as GVHD occurring more than 100 days post-transplant, but this arbitrary cutoff is now less emphasized. The disease is identified by clinical manifestations that often resemble autoimmune disorders. It can emerge de novo without prior acute GVHD, develop progressively from an acute form, or follow successful treatment of acute GVHD. Unlike the acute form, cGVHD is a persistent condition that can last for years and requires long-term management.
The Underlying Mechanism
The root cause of cGVHD is a prolonged, misdirected immune response by the donor’s T-cells and B-cells against the recipient’s healthy tissues. Initially, donor T-cells become activated and proliferate, attacking host cells perceived as foreign due to differences in human leukocyte antigens (HLA). This damage sets the stage for a chronic phase involving a shift toward an autoimmune-like process. Donor B-cells also produce autoantibodies that target host tissues, mimicking diseases such as lupus or scleroderma.
This sustained immune assault drives chronic inflammation and subsequent fibrosis, which is the hallmark of cGVHD. Continuous inflammation leads to the abnormal deposition of collagen and other connective tissues, causing hardening or scarring of affected organs. This fibrotic process explains symptoms like skin tightening, joint stiffness, and lung damage. The condition represents the donor immune system failing to achieve tolerance, maintaining chronic immune dysregulation.
Systemic Manifestations and Symptoms
Chronic GVHD is a systemic disorder that can affect almost any organ, most commonly targeting the skin, mouth, and eyes. Skin involvement is frequently seen, presenting as a rash that can evolve into lichen planus-like lesions (purple, itchy bumps) or scleroderma-like changes. These changes cause the skin to become thick, hard, and taut. This tightening, sometimes described as “hidebound,” can severely restrict joint mobility. Patients may also experience changes in pigmentation, hair loss, and nail abnormalities.
Ocular cGVHD, often an early sign, results in severe dry eye syndrome, or keratoconjunctivitis sicca. Patients report a gritty or burning sensation, persistent irritation, and light sensitivity, which can lead to blurred vision due to corneal damage. The oral cavity is also frequently affected, with symptoms ranging from persistent dryness and pain to painful ulcers and white, lace-like patches on the cheeks, resembling oral lichen planus. This involvement can make eating and speaking difficult and increase the risk of oral infection.
Involvement of the musculoskeletal system manifests as fasciitis or myositis, causing pain, muscle weakness, and cramps. Inflammation and fibrosis in the fascia (the connective tissue surrounding muscles) can lead to joint contractures and limited movement. Lung involvement, presenting as bronchiolitis obliterans syndrome (BOS), is a serious internal complication. BOS causes inflammation and scarring in the small airways, leading to a persistent cough and progressive shortness of breath. Other affected organs include the liver (causing cholestasis and elevated liver enzymes) and the gastrointestinal tract (leading to diarrhea and nausea).
Diagnosis and Disease Scoring
Diagnosing cGVHD requires a thorough clinical assessment combined with specific laboratory and imaging tests to confirm organ involvement and rule out other post-transplant complications. The diagnostic process relies on the National Institutes of Health (NIH) Consensus Criteria, which standardize the clinical features required to establish the diagnosis and assess severity. A diagnosis requires at least one diagnostic manifestation, such as characteristic skin sclerosis, or one distinctive manifestation confirmed by a biopsy or specific test.
Suspected lung involvement requires pulmonary function tests, and ocular cGVHD must be confirmed by an ophthalmologist. Biopsies of affected tissues (skin, liver, or oral mucosa) are performed to identify characteristic inflammatory and fibrotic changes. The NIH criteria provide a standardized scoring system to quantify the severity of the disease in each affected organ on a scale of 0 to 3. This score determines an overall global severity score: mild, moderate, or severe. This scoring is crucial for guiding treatment decisions and monitoring a patient’s response to therapy.
Management and Treatment Approaches
The primary goals of cGVHD management are to suppress the immune reaction and halt the progression of tissue damage and fibrosis. Systemic corticosteroids, such as prednisone, are the standard first-line therapy for moderate to severe disease. They are often used in combination with a calcineurin inhibitor like cyclosporine or tacrolimus. This combined approach aims to dampen the immune system and control inflammation. The goal is to taper the steroid dose to the lowest effective level to minimize long-term side effects, such as bone loss and diabetes.
When disease progresses despite initial therapy or patients cannot tolerate high-dose steroids, the condition is classified as steroid-refractory. This prompts the use of second-line treatment options. The Janus kinase (JAK) inhibitor Ruxolitinib has been approved for cGVHD treatment after the failure of one or two lines of systemic therapy. This agent works by blocking the activity of JAK enzymes involved in immune cell signaling, reducing the production of inflammatory cells. Other second-line options include extracorporeal photopheresis (ECP) or other immunosuppressive agents.
Supportive care is an integral component of management, focusing on organ-specific relief and maintaining function. This includes specialized physical therapy to combat joint contractures and skin tightening, meticulous dental care, and prescription eye drops for oral and ocular symptoms. Given the long-term nature of the disease, comprehensive, multidisciplinary care is necessary to address the affected organ systems and improve the patient’s quality of life.