Chronic graft-versus-host disease (GVHD) is a pleiotropic, multiorgan disorder induced by competent immune cells that have been transferred from the donor to the recipient in the scope of an allogeneic hematopoietic stem cell transplantation (HSCT). Whereas acute GVHD occurs within weeks after the transplantation and primarily affects epithelial tissues, chronic GVHD manifests more than three months after the procedure. It is associated with severe infections, the inflammation of multiple tissues throughout the body, and fibrotic changes often resulting in an irreversible loss of organ function.
Most patients present with skin changes, lesions of the oral mucosa, and dry eyes . Dermatological findings may comprise erythema, papules or plaques, pigmentary changes, atrophic and sclerotic features. They are frequently associated with insufficient lymphatic drainage, ulcers following minor trauma, and poor wound healing. Patients may claim pruritus. Skin changes extend to appendages such as hair follicles and sweat glands, and nails, producing alopecia, intolerance to temperature, and nail dystrophy. With regard to the oral mucosa, mucositis, gingivitis, and other signs related to infections are often observed. However, mucosal lesions are not necessarily restricted to the oral cavity. They may affect other segments of the digestive system and the urogenital tract, thereby triggering symptoms like nausea and vomiting, diarrhea, loss of appetite and weight, and failure to thrive .
Chronic GVHD may also affect other organ systems, namely the liver, respiratory tract, fascia, muscles, and joints. In this context, cholestasis, obstructive lung disease due to bronchiolitis obliterans, restricted joint mobility and eventually joint contractures are to be expected. Disorders of fascia are frequently associated with changes of the overlying skin, e.g., with edema, peau d’orange, or sclerosis . Involvement of the hematopoietic system may cause constitutive symptoms but is more commonly detected by means of laboratory analyses of blood samples. Such analyses typically reveal eosinophilia and increased concentrations of hepatic transaminases . Beyond that, lymphopenia, thrombocytopenia, hyper- or hypogammaglobulinemia, and autoantibodies may be detected .
Entire Body System
Large Pericardial Effusion
CT revealed large pericardial effusion, while echocardiogram was concerning for early tamponade physiology. He underwent emergent pericardiocentesis with pericardial drain placement. [ncbi.nlm.nih.gov]
Involvement of the hematopoietic system may cause constitutive symptoms but is more commonly detected by means of laboratory analyses of blood samples. [symptoma.com]
Rapidly Progressive Glomerulonephritis
The fourth case presented with rapidly progressive glomerulonephritis (RPGN)-like symptoms. The kidney histology in this case was not available. The patient responded well to immunosuppressive therapy, but NS later recurred. [ncbi.nlm.nih.gov]
Jaw & Teeth
Skin changes extend to appendages such as hair follicles and sweat glands, and nails, producing alopecia, intolerance to temperature, and nail dystrophy. [symptoma.com]
Examples of characteristic manifestations include: skin changes - rash, lichenoid changes, sclerodermatous changes, hypopigmentation, hyperpigmentation, loss of appendages (hair follicles, sweat glands), alopecia oral changes - erythema, lichenoid changes [clinicaltrials.gov]
[…] irritation and redness Skin thickening, scaling, hyper- or hypopigmentation (resembling lichen planus ) Loss of skin colour without thickening ( vitiligo ) Hardening of skin ( scleroderma ) may interfere with joint mobility Hair loss (including typical alopecia [dermnetnz.org]
Friable, gray hair and alopecia are common. The nails may be brittle or ridged. Hypo or hyperpigmentation may be present. The skin should be pinched to look for subdermal changes. [cancertherapyadvisor.com]
[…] for chronic GVHD include the following: Lichen planus Lichenoid drug eruption Morphea Lichen sclerosus Scleroderma Nephrogenic systemic fibrosis Vitiligo Postinflammatory hyperpigmentation Postinflammatory hypopigmentation Keratosis pilaris Psoriasis Eczema [visualdx.com]
Skin changes sometimes attributed to chronic GVHD include eczema and ichthyosis. Hypothyroidism may also cause skin changes and hair loss. Adrenal insufficiency in patients after steroid use may cause fatigue and nausea. [cancertherapyadvisor.com]
Other conditions such as eczema, iron overload, hypothyroidism, adrenal insufficiency, infections, or drug effect can be misdiagnosed as chronic GVHD.47 Chronic GVHD generally involves several organs or sites, although manifestations are sometimes restricted [ncbi.nlm.nih.gov]
Oral verruciform xanthoma is an uncommon benign lesion. Although oral verruciform xanthoma occurs in healthy individuals, it has been also reported in association with some inflammatory conditions. [ncbi.nlm.nih.gov]
Graft-versus-host disease-associated angiomatosis (GVHD-AA) is an uncommon manifestation of chronic GVHD consisting of friable vascular proliferations. [ncbi.nlm.nih.gov]
The diagnosis of chronic GVHD is based on anamnestic data and clinical findings. As per definition, chronic GVHD manifests more than three months after HSCT, but the time of onset alone is insufficient to distinguish between acute and chronic GVHD . According to the National Institutes of Health, the diagnosis of chronic GVHD additionally requires the presence of at least one diagnostic clinical sign of chronic GVHD or of at least one distinctive manifestation confirmed by biopsy or other pertinent tests, and the exclusion of other possible causes .
Diagnostic clinical signs of chronic GVHD comprise :
- Poikiloderma, lichen planus-like features, sclerotic features, morphea-like features, lichen sclerosus-like features
- Oral lichen-type features, hyperkeratotic plaques, restriction of mouth opening due to sclerosis
- Genital lichen-type features, vaginal scarring or sclerosis
- Bronchiolitis obliterans (diagnosis based on biopsy results)
- Fasciitis, joint stiffness or contractures secondary to sclerosis
Distinctive manifestations of chronic GVHD include :
- Depigmentation of skin
- Nail dystrophy, longitudinal ridging, splitting, or brittle features, onycholysis, pterygium unguis, nail loss
- New onset of scarring or non-scarring scalp alopecia, scaling and papulosquamous lesions
- Xerostomia, mucocele, mucosal atrophy, pseudomembranes, and ulcers
- New-onset dry, gritty, or painful eyes, cicatricial conjunctivitis, keratoconjunctivitis sicca, confluent areas of punctate keratopathy
- Genital erosions, fissures, and ulcers
- Esophageal web, strictures or stenosis in the upper to mid third of the esophagus
- Bronchiolitis obliterans (diagnosis based on lung function tests or diagnostic imaging)
- Myositis or polymyositis
It is beyond the scope of this article to describe the histological criteria for the diagnosis of organ involvement in chronic GVHD, and the interested reader is referred to an excellent review on this topic .
Owing to the chronic, possibly progressive course of the disease, patients should undergo regular follow-ups. An early diagnosis of additional or more severe organ involvement may allow for an adequate therapy before irreversible changes occur. It is not clear to what extent laboratory analyses may facilitate this task. To date, biomarkers of chronic GVHD activity have not been validated . Thus, monitoring relies on clinical examinations. In particular, lung function tests should be repeated quarterly: Bronchiolitis obliterans is a dreaded complication with an insidious onset and devastating effect on life quality .
Standard corticosteroid-based immunosuppression generally suffices to control the initial symptoms of chronic GVHD. In general, topical treatment is preferred over systemic therapy to avoid side effects, but the involvement of multiple organ systems requires a systemic approach . Prednisone at a dose of 0.5-1.0 mg/kg/day is most frequently administered to this end; it is often used in a combined regimen with cyclosporine or tacrolimus. To avoid side effects, doses should eventually be tapered to the lowest possible effective dose. Many patients do well on alternate-day regimens. It should be noted that systemic immunosuppressive therapies predispose to infectious diseases, and this condition requires infection prevention and control measures. Because immunocompromised patients are susceptible to infections with a wide variety of opportunistic pathogens, infection prophylaxis should comprise the application of antibiotics, antiviral compounds, and antimycotics  .
The treatment of corticosteroid-refractory chronic GVHD poses a major challenge to physicians of all disciplines. About half of all patients develop resistance to corticosteroids at some time during therapy . Ibrutinib, an inhibitor of non-receptor Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells, has recently been approved for the management of refractory chronic GVHD . Furthermore, imatinib, rituximab, mTOR inhibitors, mycophenolate mofetil, and interleukin-2 have been used off-label as second-line immunosuppressants. If the patient's response remains poor, their inclusion in ongoing clinical trials may be their best chance for improvement . Additional tyrosine kinase inhibitors and anti-CD20 monoclonal antibodies, immune checkpoint modulators, and proteasome inhibitors are currently assessed for their efficacy in patients suffering from chronic GVHD. Furthermore, cell therapy agents with immunomodulatory properties, namely regulatory T cells and mesenchymal stromal cells, are considered in this context. The identification of additional therapeutic targets is to be expected as soon as our understanding of the pathogenesis of chronic GVHD improves .
Despite all efforts, recurrence is common after the complete cessation of therapy  . Cure of chronic GVHD is only achieved upon the development of immunological tolerance by the host. It is currently not known how this process can be accelerated. The aforedescribed therapies aim at providing symptomatic relief and avoiding irreversible damage as long as this process doesn't come to its natural conclusion . This may take several years. Meanwhile, supportive care should be provided by a multidisciplinary team. Supportive care may comprise, but is not limited to, the use of topical antimicrobials, the provision of wound care, dental hygiene, artificial tears, and dietary supplementation, the application of bronchodilators, immunoglobulins, and growth factors, as well as physical therapy. Patients may also benefit from psychological support .
Chronic GVHD is a major cause of reduced quality of life, morbidity, and mortality after allogeneic HSCT. Nevertheless, half of patients are cured within 7 years after the beginning of therapy. About 10% of those suffering from chronic GVHD require pharmacotherapy for more than 7 years, and the remainder of patients dies as a result of their primary disorder, GVHD, or non-related diseases . The involvement of multiple organ systems, decreased clinical performance, hyperbilirubinemia or thrombocytopenia at the time of diagnosis have been identified as unfavorable prognostic factors that augment the likelihood of GVHD-related death. Similarly, survival rates are lower among patients who develop chronic GVHD from acute GVHD .
The etiology and pathogenesis of chronic GVHD remain incompletely understood. Accordingly, current knowledge doesn't allow for a reliable prediction of chronic GVHD in an individual patient. Notwithstanding, several risk factors have been identified and may be used to carry out a personalized risk assessment:
- Patients of old age and those who undergo HSCT for chronic myeloid leukemia are more likely to develop chronic GVHD.
- HLA disparity between recipient and donor as well as the transplantation of grafts from female donors to male recipients predisposes to chronic GVHD .
- The transplantation of granulocyte-colony stimulating factor-mobilized peripheral blood stem cells increases the likelihood of chronic GVHD .
- Those who have previously been diagnosed with acute GVHD are at higher risks of developing chronic GVHD, but de novo chronic GVHD is also observed .
Data regarding the incidence of chronic GVHD among patients who have undergone an allogeneic HSCT range between 30 and 70%, rendering it the most common long-term complication of the procedure  . The majority of patients is diagnosed with chronic GVHD within one year of HSCT, but the onset of symptoms may be delayed even longer .
Chronic GVHD is caused by the replacement of the host’s immune system with immunocompetent donor cells. This condition is referred to as active alloimmunity and comprises disturbances in innate and adaptive cell-mediated immunity, humoral immunity, immune regulation, and inflammation  . Any of these aspects may make a significant contribution to chronic GVHD in an individual patient, but there is considerable interpatient variability. The efficacy of preventive measures taken before or shortly after HSCT demonstrates that the events leading to chronic GVHD are initiated by the procedure. These circumstances suggest the involvement of (patho-)physiological and possibly environmental factors in the pathogenesis of the disease, but little is known about them.
Early-phase epithelial damage is related to an activation of antigen-presenting cells, to the release of inflammatory cytokines, and the initiation of an enhanced inflammatory response . Increased counts of active B cells, low counts of regulatory B and T cells and accordingly low levels of anti-inflammatory cytokines like interleukin-10 have all been proposed to account for the inflammation, namely by favoring the proliferation of immune cells and inhibiting the apoptosis of lymphocytes in patients after HSCT . The dysfunction of regulatory mechanisms contributes to the perpetuation of inflammation, which has been shown to cause thymic injury, to interfere with positive and negative selection, and to ultimately induce a loss of peripheral tolerance . Finally, chronic inflammation is followed by tissue repair with fibrosis.
According to the risk factors mentioned above, the use of bone marrow instead of peripheral blood stem cells should be considered to lower the risks of chronic GVHD. Beyond that, prophylactic measures against acute GVHD may also help to decrease the incidence of chronic GVHD. In vivo and ex vivo T-cell depletion and the administration of cyclophosphamide after HSCT shall be mentioned as examples for such measures . Close monitoring after HSCT is recommended to guarantee an early diagnosis of chronic GVHD .
HSCT is carried out to cure a variety of benign and malignant hematological disorders, such as immune deficiency syndromes, myelodysplastic syndromes, distinct types of leukemia and lymphoma. Unfortunately, HSCT remains a high-risk procedure, with acute and chronic GVHD being among its most dreaded complications. Even though prophylactic measures are taken, about half of all patients develop acute GVHD and/or chronic GVHD. The former is characterized by dermatitis, enteritis, and cholestatic liver disease . The latter is an even more complex disorder affecting the skin, gastrointestinal tract, and liver, but also the mucous membranes of the oral cavity and genital tract, the lungs, fascia, muscles, and joints .
Both forms of GVHD are known to be mediated by the transplanted immune system, but the underlying mechanisms remain largely elusive. Accordingly, GVHD therapy is based on prolonged immunosuppression and supportive care. The side effects of the former add to the debilitating consequences of the primary disease and increase the overall risk of infection, inflammation, and irreversible organ damage. These conditions reduce the patients' quality of life and may ultimately be fatal . Fortunately though, the majority of survivors develops immunological tolerance and overcomes chronic GVHD after years of therapy .
For many patients suffering from hematological disorders, allogeneic hematopoietic stem cell transplantation (HSCT) constitutes the only chance for cure. Unfortunately though, remains a high-risk procedure. For instance, complications may arise due to the activity of transplanted immune cells that aren't able to distinguish between "self" and "foreign" in the recipients' body. This may lead to what is called graft-versus-host disease, i.e., the donor's immune cells attack distinct tissues and organs of the recipient. Graft-versus-host disease may occur shortly after HSCT and is then referred to as acute graft-versus-host disease. In other patients, symptoms don't manifest until months or even years after the procedure. This variant is referred to as chronic graft-versus-host disease. It is a multisystem disorder associated with a wide variety of skin changes, mucosal lesions, dry eyes, obstructive lung disease, joint stiffness and contractures, among others. In order to prevent irreversible organ damage, treatment should be initiated in a timely manner. In this context, it is of utmost importance to comply with follow-ups scheduled after HSCT.
- Lee SJ. Classification systems for chronic graft-versus-host disease. Blood. 2017; 129(1):30-37.
- Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005; 11(12):945-956.
- Shulman HM, Cardona DM, Greenson JK, et al. NIH Consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 Pathology Working Group Report. Biol Blood Marrow Transplant. 2015; 21(4):589-603.
- Ren HG, Adom D, Paczesny S. The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease. Expert Rev Clin Immunol. 2018:1-16.
- Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015; 125(4):606-615.
- Hill L, Alousi A, Kebriaei P, Mehta R, Rezvani K, Shpall E. New and emerging therapies for acute and chronic graft versus host disease. Ther Adv Hematol. 2018; 9(1):21-46.
- Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017; 130(21):2243-2250.
- Couriel D, Carpenter PA, Cutler C, et al. Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2006; 12(4):375-396.
- Zeiser R, Blazar BR. Pathophysiology of Chronic Graft-versus-Host Disease and Therapeutic Targets. N Engl J Med. 2017; 377(26):2565-2579.
- Bacigalupo A, Sica S, van Lint MT. Failure to effectively treat chronic graft-versus-host disease: a strong call for prevention. Haematologica. 2016; 101(5):e214-215.