Chronic graft-versus-host disease. Part I: Epidemiology, pathogenesis, and clinical manifestations

Abstract

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation and a leading cause of long-term morbidity, non-relapse mortality, and impaired health-related quality of life. The skin is commonly affected and presents heterogeneously, making the role of dermatologists critical in both diagnosis and treatment. In addition, new clinical classification and grading schemes inform treatment algorithms, which now includes 3 FDA approved therapies, and evolving transplant techniques are changing disease epidemiology. Part I reviews the epidemiology, pathogenesis, clinical manifestations, and diagnosis of cGVHD. Part II discusses disease grading and therapeutic management.

Introduction

Hematopoietic cell transplantation (HCT) utilizes hematopoietic progenitor cells to (re)establish hematopoietic and immune function. Indications for HCT include malignant and nonmalignant hematologic diseases, diseases of the immune system, some solid tumors, and inherited disorders of metabolism. Over 1.5 million HCTs have been performed worldwide to date (1) and >21,000 HCTs were performed in the United States (US) in 2018 (2). Due to advances in transplant regimens and supportive care, patients are surviving longer after HCT. The projected prevalence of survivors in the US is expected to double to over 500,000 in the next 10 years (3).

HCT can broadly be divided into autologous HCT, which uses the patient’s own progenitor cells, and allogeneic HCT, which uses donor cells. While graft-versus-host disease (GVHD) can occur rarely following solid organ transplantation, autologous HCT, or blood product transfusions (4), the focus of this CME will be GVHD following allogeneic HCT.

GVHD is classified into acute and chronic forms, which are increasingly recognized as distinct entities (5). In 2005, the National Institutes of Health (NIH) Consensus Development Project established the current classification scheme based on clinical features (Figure 1) (6). Patients with chronic GVHD (cGVHD) are further classified into (1) classic cGVHD (no features of acute GVHD) or (2) overlap cGVHD (concurrent acute GVHD features). The latter has been associated with poorer prognosis (7-10).

Figure 1. Graft-versus-host disease classification.

Acute GVHD is defined by characteristic clinical features of the skin, liver, and gastrointestinal tract and can occur as classic acute GVHD (prior to day 100) or late acute GVHD (after day 100). Chronic GVHD is defined by 2014 NIH Diagnostic Criteria of involved organs and can occur as classic chronic GVHD (without acute GVHD features) or chronic overlap GVHD (with acute GVHD features).

Adapted from Lee SJ Classification systems for chronic graft-versus-host disease, Blood, 2017. 129(1): 30-37

Epidemiology and Risk factors for Chronic GVHD

Key points

• Chronic GVHD is a leading cause of morbidity, non-relapse mortality, and impaired health-related quality of life after HCT

• The skin and mucous membranes are the organ systems most frequently involved in cGVHD

Chronic GVHD is a multisystem syndrome that occurs in 30-70% of allogeneic HCT recipients (11-15). The skin (60-80%), oral (60%) and ocular (50%) mucosal surfaces, and genital area (20-50%) are frequently involved, with the latter likely under-reported (16-19).

Chronic GVHD Morbidity and Mortality

Among long-term (≥ 2 years) allogeneic HCT survivors, cGVHD is a substantial contributor to morbidity and a leading cause of death, exceeded only by relapse of primary disease (14, 20-24). Non-relapse mortality (NRM) in cGVHD patients is 22% at 5 years and 40% at 12 years (25). Higher cGVHD skin scores are associated with an increased risk of NRM (HR 1.9, p=0.002) and this association persists even when controlling for patient age, with cGVHD resulting in a 30-40% increased risk of NRM in all age groups and lower overall survival (OS) (26).

Mortality is attributable to cGVHD complications as well as immunosuppressive therapy. Allogeneic HCT is associated with increased risk of second cancers (27-30), with risk further increased 2.4-fold in patients with cGVHD (30). Keratinocyte carcinomas (10-year cumulative incidence of 15.5% (29, 31)) and squamous cell carcinomas of the lip, tongue, and mouth (13-fold risk (30)) (32) are amongst the highest but lung, liver, brain, soft tissue cancers, and melanoma are also seen (29, 30). Chronic GVHD increases the risk of cardiovascular disease through accelerated arterial disease, dyslipidemia, and hyperglycemia (33), which are further exacerbated by immunosuppressive therapies (24, 33-35). Infections, primarily from bacterial pathogens, are a leading cause of late deaths in adults and children with cGVHD (36), as well as pulmonary complications from bronchiolitis obliterans syndrome (37).

Chronic GVHD is associated with significant healthcare burden (38). In a US-based claims analysis, patients had a mean of 21 visits in the first year after cGVHD diagnosis and generated costs of nearly $300,000 per patient/year (13). Patients living with cGVHD are almost two-fold more likely to develop another severe or life-threatening illness (39) and also experience poor functional status, psychosocial distress, poor social functioning, anxiety, and less resilience (40-42). Skin severity alone correlates with worse health-related quality of life (hrQoL) (43, 44).

Chronic GVHD Risk Factors

The most important predictor of GVHD is the degree of HLA match between donor and recipient (45-48), but several other important risk factors influence the likelihood of cGVHD (Table 1). Use of peripheral blood stem cells (PBSC) as the graft source significantly increases the risk of cGVHD (19, 49-52). One study reported severe skin cGVHD in one-third of PBSC recipients (52) and two studies have demonstrated PBSC as a risk factor for skin sclerosis (53, 54). Total body irradiation (TBI) is an additional risk factor for cGVHD (55) and the development of sclerosis (53, 54). Vitamin D deficiency has been identified as a possible risk factor for cGVHD with repletion shown to decrease incidence and/or severity in some studies (56).

Table 1:

Risk Factors for Chronic GVHD

	Risk Factor	Reference
Donor-related Factors	PBSCsa	(5, 19, 49-52, 145-147)
	Female donor/male recipient	(5, 145, 148-150)
	Parity of female donor	(5, 149-151)
	HLA mismatch	(5, 45-48, 147)
	Unrelated donor	(5, 145, 152)
	Older donor age	(5, 149, 153)
Recipient-related Factors	Older patient age	(5, 145, 149, 150)
	CML	(149, 150)
	High intensity conditioning	(154)
	TBIa	(53-55)
	Busulfanb	(37)
	Prior acute GVHD	(5, 57, 147, 149, 150)
	DLI	(155)

^aRisk factors for skin cGVHD

^bRisk factor for pulmonary cGVHD

Abbreviations: PBSCs, peripheral blood stem cells; HLA, human leukocyte antigens; CML, chronic myelogenous leukemia; TBI, total body irradiation; GVHD, graft-versus-host disease; DLI, donor lymphocyte infusion

Chronic GVHD Prophylaxis Strategies

There has been significant focus on improving GVHD prophylaxis to reduce GVHD incidence. Facilitating or augmenting graft-versus-tumor effect while minimizing GVHD has been a longstanding, but elusive, goal of allogeneic HCT and is an ongoing research priority (57). Calcineurin inhibitor/methotrexate has been the standard of care for GVHD prophylaxis (58, 59); however, in a recent 3-arm trial compared two calcineurin-free regimens (post-transplant cyclophosphamide [PTCy] alone or CD34 selection) to tacrolimus/methotrexate, CD34-selected grafts led to significantly less cGVHD but higher mortality, while PTCy had similar cGVHD to controls (60). Other forms of T cell depletion (antithymocyte globulin (ATG) (61-63), alemtuzumab (64-66)) have reduced cGVHD, but at the expense of increased relapse and infections. Graft engineering and targeting of specific donor T cell subsets offers the potential for better control of GVHD in the future (a full discussion of these approaches can be found in a recent excellent summary (57)).

Pathophysiology

Key points

• Chronic GVHD pathophysiology can be conceptualized into three phases: 1) tissue injury and early inflammation, 2) dysregulated B and T cell immunity, and 3) fibrosis

• Therapeutic targets are broad in scope; the FDA-approved therapies target B and T cell signaling

Phase 1: Tissue Injury and Early Inflammation

The earliest phase of cGVHD is characterized by activation of the innate immune system following damage to the host tissue (67). Pre-transplantation conditioning regimens, post-transplantation infections, and acute GVHD result in tissue injury, leading to release of damage associated molecular patterns (DAMPs) and pathogen associated molecular patterns (PAMPs) (68, 69). DAMPs and PAMPs activate toll-like receptors (TLR), nucleotide-binding oligomerization domain-like receptors (NOD-R), and the NOD-like receptor 3 (NLRP3) inflammasome. Tissue damage is subsequently amplified by innate immune cells that produce reactive oxygen species and matrix metalloproteinases (70). TLR and NOD-R activation further stimulates antigen presentation, initiating the adaptive immune response that characterizes phase 2. Endothelial cells damaged from tissue injury release von Willebrand factor and activate platelets, resulting in microvascular damage. Intimal arteritis and loss of small and medium-sized arteries have been observed in histopathologic examination of skin (71). TLRs, NLRP3, and NOD-R are current experimental therapeutic targets (67).

Phase 2: Chronic Inflammation and Dysregulated B and T Cell Immunity

B and T cells are activated via a specific ligand-receptor interaction with antigen presenting cells (APCs). The generation of autoreactive B and T cells is primarily driven by loss of central and peripheral tolerance, and results in reactivity to antigens common to both donor and recipient (72, 73). This process mimics autoimmunity and diverges from acute GVHD, which is driven by alloreactivity. Central tolerance is compromised by thymic injury caused by medications and immune insults (74-76). Malfunction of the thymus allows escape of autoreactive CD4+ T cells (77-80). In humans, thymic production of mature T cells is greatly impaired (81). Loss of peripheral tolerance is driven by impairment in regulatory T cells (Tregs), amongst others (82-90).

Autoreactive T cells differentiate into Th1, Th2, and TH17 subsets, and dysregulated production of cytokines such as IL-17 can drive chronic inflammation (91-93). In skin samples of lichenoid cGVHD, a Th1/Th17 signature is seen, including elevation of cytokine and chemokine transcripts associated with IL-17 producing T cells (94). Activated follicular helper T cells (FhT cells) release IL-21 and lead to B cell somatic hypermutation with germinal center formation and production of immunoglobulins associated with skin cGVHD (95). Indeed, mature autoreactive B cells are necessary for cGVHD development and for autoreactive T and B cell amplification (96-98). The majority of existing therapies for cGVHD, including the three FDA-approved medications, target the adaptive phase (Phase 2) (99).

Phase 3: Aberrant Tissue Repair with Fibrosis

Activated macrophages produce transforming growth factor-beta (TGF-β) and platelet-derived growth factor-alpha (PDGF-α), which stimulate fibroblasts to produce extracellular matrix collagen and biglycan, resulting in tissue fibrosis (67, 100, 101). Th17 cells that escape immune regulation maintain the fibrotic process and are found in higher concentrations in fibrotic human liver tissue (93, 101). B-cell isotype switching and Ig deposition, driven by B-cell activating factor (BAFF), leads to further tissue fibrosis (102-104). Anti-fibrotic therapies include the PDGF-α receptor inhibitor imatinib (105-108) and the TGF-β inhibitor, pirfenidone (109).

Diagnostic Criteria and Clinical Manifestations of Chronic GVHD

Chronic skin GVHD

Key points

• Diagnostic manifestations of skin cGVHD include poikiloderma, lichen planus-like, deep sclerosis, morphea-like, and lichen sclerosus-like features

• Sclerotic cGVHD confers significant morbidity, including impaired mobility and cutaneous ulceration

The 2014 NIH diagnostic criteria divides cGVHD skin manifestations into 1) diagnostic: sufficient for diagnosis and not requiring biopsy, 2) distinctive: insufficient for diagnosis and requiring biopsy, 3) other: acknowledged as a cGVHD feature if diagnosis confirmed elsewhere, 4) common: seen in both acute and cGVHD (Table 2) (6). A survey of 72 transplant centers in 3 countries supported the NIH recommendations that skin biopsy is indicated in suspected skin cGVHD lacking diagnostic features, recommending punch biopsy for nonsclerotic disease and incisional biopsy for sclerotic disease (110). However, in the authors’ experience, a 5-6mm punch biopsy is typically sufficient to render the diagnosis of sclerotic cGVHD when a clinical diagnosis is uncertain. The histology of skin cGVHD evolves over time, is modified by treatment, and can overlap with features of acute GVHD. Histologic criteria for nonsclerotic GVHD include apoptosis in the basilar layer, vacuolar changes, lichenoid inflammation, and lymphocyte satellitosis (Figure 2A), but biopsy may not be diagnostic (111). Sclerosis can present with thickened collagen bundles at any level of the dermis or subcutis (Figure 2B). The common features category assists clinicians in correctly classifying patients with overlap cGVHD (6).

Table 2:

Criteria for Mucocutaneous Chronic Graft-versus-host Disease^a

Organ Site	Diagnosticb	Distinctivec	Other featuresd	Commone
Skin	Poikiloderma Lichen planus-Sclerosis Morphea-like Lichen sclerosus	Depigmentation Papulosquamous lesions	Sweat impairment Ichthyosis Keratosis pilaris Hypopigmentation Hyperpigmentation	Erythema Maculopapular rash Pruritus
Nails		Dystrophy Longitudinal ridging Onycholysis Pterygium unguis Nail loss (symmetric, most nails)
Scalp and hair		Scarring or nonscarring alopecia Loss of body hair Scaling	Thinning scalp hair Premature gray hair
Mouth	Lichen planus	Xerostomia Mucoceles Mucosal atrophy Ulcers Pseudomembranes		Gingivitis Mucositis Erythema Pain
Eyes		Dry eye Cicatricial conjunctivitis Keratoconjunctivitis sicca Confluent areas of punctate keratopathy	Photophobia Periorbital hyperpigmentation Blepharitis
Genitalia	Lichen planus Lichen sclerosus Females: vaginal scarring or clitoral/labial agglutination Males: Phimosis or urethral scarring	Erosions Fissures Ulcers

^aJagasia MH. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-host Disease: The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015,21:389-401

^bSufficient to establish a diagnosis of chronic GVHD

^cSeen in chronic GVHD but insufficient to establish diagnosis. Must exclude infection, drug reaction, malignancy, and other causes with confirmatory testing.

^dAcknowledged as part of chronic GVHD if diagnosis confirmed

^eSeen in acute and chronic GVHD

Figure 2: Histologic features of chronic skin graft-versus-host disease.

A) Nonsclerotic-type in a patient with lichen planus-like involvement (see Figure 3B for clinical pathologic correlation) demonstrating vacuolar interface changes at the dermal-epidermal junction, with scattered apoptotic basal epidermal keratinocytes, and focal detachment of the epidermis from the subjacent dermis (hematoxylin and eosin, 20x). B) Sclerotic-type in a patient with deep-seated involvement resembling eosinophilic fasciitis demonstrating thickening of collagen bundles in the deep reticular dermis near the border with the subcutaneous fat and marked thickening of the fat septae. The epidermis and papillary dermis appear relatively normal (hematoxylin and eosin, 2x).

Significant efforts are underway to identify early disease. Candidate diagnostic biomarkers are in early discovery and include soluble B cell activating factor (sBAFF), chemokine (C-X-C motif) ligand 9/10 (CXCL9/10), and suppression of tumorigenicity 2 (ST2) (112, 113). Clinician and patient education, telehealth, and electronic reporting tools have been implemented to improve diagnostic accuracy (15). The skin presents early in the disease course of cGVHD and dermatologists play a critical role in establishing the diagnosis of cGVHD.

Nonsclerotic chronic GVHD

Nonsclerotic cGVHD refers to all skin manifestations without superficial or deep tissue fibrosis (Table 2). Nonsclerotic cGVHD presents earlier and is more common than sclerotic disease, and carries prognostic significance (17, 114). Lichenoid changes at presentation (115), extent of erythema (116), and patient-reported pruritus (117) have been associated with worse OS. It remains unclear whether nonsclerotic disease is a direct driver of mortality or merely a marker of overall disease activity. Regardless, early recognition and diagnosis of nonsclerotic disease can risk stratify patients for early referral to clinical trials.

Lichen planus (LP)-like GVHD has long been recognized as a diagnostic manifestation of nonsclerotic cGVHD (6) and involves atypical areas such as the face, neck, palms, soles and may have a blaschkoid appearance (Figure 3A,B) (118, 119). Papulosquamous lesions, although common in GVHD, are considered distinctive (not diagnostic) and, therefore, require biopsy for confirmation. Patients may present with eczematous features, ichthyosis, exfoliative dermatitis, keratosis pilaris-like involvement or pruritus (120-122). Dyspigmentation has been reported in up to 96% of patients with skin cGVHD and may cause significant psychological impact (123) (Figure 3C) (124). Skin of color patients with a history of skin cGVHD reported more skin bother from dyspigmentation than from active sclerosis (125).

Figure 3. Nonsclerotic features of chronic skin graft-versus-host disease.

A) Lichen planus-like, back, B) Lichen planus-like, forehead, C) Dyspigmentation, D) Nail dystrophy, pterygium

Vitiligo and alopecia areata have been reported in 5-20% of patients (123, 126, 127). The use of a female donor for male recipient was an independent risk factor in multivariable regression models. Cutaneous lupus erythematosus (128), dermatomyositis (129), and epidermolysis bullosa acquisita-like presentations have also been described (130). While autoantibodies were previously implicated as a risk factor for cGVHD, two recent large cross-sectional studies found no association between the presence of autoantibodies and cGVHD (54, 131). Nail dystrophy (Figure 3D) and diffuse alopecia are also common, reported in up to 20% of patients with skin cGVHD. In a case-control study, hair and nail involvement were associated with oral and ocular involvement (132).

Sclerotic chronic GVHD

Sclerotic cGVHD encompasses all cutaneous disease manifestations with superficial and/or deep sclerosis (Table 2). In a cohort of 977 patients with cGVHD, sclerotic cGVHD was present in 7% of patients at initial diagnosis and increased to 20% at 3 years after transplant (53). Sclerotic disease can occur de novo, concurrently with nonsclerotic disease, or following prior nonsclerotic disease (17, 53). In a cohort of 423 allogeneic HCT patients, only 36.4% of patients with sclerotic GVHD had a history of nonsclerotic disease (133). In 2 large observational studies, sclerotic cGVHD was not associated with OS, NRM, or malignancy relapse (53, 54).

Lichen sclerosus (LS)-like lesions of cGVHD occur most commonly on the neck and upper back (Figure 4A) (134). Morphea-like cGVHD can cause contractures of overlying joints (Figure 4B) and can localize to sites of skin injury (isomorphic response) including ultraviolet radiation, radiotherapy, viral infection (e.g. herpes zoster) and pressure (Figure 4C) (135, 136). Deep sclerosis and fascial disease (Figure 4D) (134, 137) resembles subcutaneous morphea and eosinophilic fasciitis and may be insidious in onset. Joint contractures may develop without epidermal skin changes. The presence of new onset limb edema in HCT patients, particularly in the absence of other potential etiology, should prompt evaluation for new onset skin sclerosis. In contrast to systemic sclerosis, sclerotic cGVHD often clinically spares acral skin. Sclerotic cGVHD confers significant morbidity and is often refractory to treatment. Standard photographic range of motion (PROM) assessment can help monitor for worsening joint mobility (Figure 4E) (6). Chest wall restriction may reductions lung vital capacity (Figure 4F) (54). Sclerosis predisposes patients to poorly healing wounds (Figure 4G). Vascular proliferations (GVHD-associated angiomatosis) (Figure 4H) (138) and cutaneous calcifications may also develop (Figure 4I).

Figure 4. Sclerotic features of chronic skin graft-versus-host disease.

A) Lichen sclerosus-like, B) Morphea-like, overlying joint causing contracture, C) Isomorphic (lichen planus-like and morphea-like), buttocks at area of pressure, D) Fasciitis groove sign, E) Sclerosis causing hand contracture, F) Sclerosis causing chest wall restriction, G) Leg ulcers, H) GVHD-associated angiomatosis, I) Cutaneous calcifications

Chronic oral GVHD

Key Points

• Oral cGVHD is often preceded by new-onset dry mouth and oral sensitivity to spicy foods

• Oral cGVHD initially resemble mucositis, but may evolve into tissue fibrosis

Chronic GVHD affects the oral cavity in three domains: (1) oral mucosa, (2) exocrine salivary gland, and (3) reduced oral opening (139). A diagnosis of oral cGVHD may be made clinically or through biopsy of the oral mucosa (Table 2) (6). Histologic diagnosis may be confounded by immunosuppressive therapy as well as intra-oral infection. The oral mucosa can be examined using a light source, tongue blade and a gauze square to manipulate the tongue. Reduced oral opening is often secondary to perioral skin fibrosis or, less frequently, fibrotic banding of the oral mucosa or involvement of the temporomandibular joint (6).

Symptoms of oral cGVHD include oral sensitivity, particularly to spice, mint, carbonation, acidic, and hard foods, oral pain, difficulty eating, and xerostomia. New-onset xerostomia and sensitivity to spicy foods are frequently the first changes reported by patients.

Clinical signs of oral cGVHD include LP-like changes on the buccal mucosa, vermillion lip and labial mucosa, tongue, palate, or gingiva. Lichenoid oral cGVHD is characterized by white reticular streaks that resemble Wickham’s striae (Figure 5A-B) (6). These can be accompanied by oral ulcers that may be covered by a pseudomembrane, mucosal erythema (Figure 4C), patchy hyperkeratosis including diffuse or dense flat white plaques (Figure 4D), or papillary atrophy of the tongue (Figure 4E). Edema associated with mucosa inflammation can restrict the ductal opening from the minor salivary glands into the oral cavity, which induces mucoceles (Figure 4F).

Figure 5. Chronic oral graft-versus-host disease.

A) Lichen planus-like, vermillion lips, B) Lichen planus-like, buccal mucosa, C) mucosal erythema, gingiva, D) Patchy hyperkeratosis with associated erythema, E) Papillary atrophy and hyperkeratosis of the dorsal tongue, F) Palatal mucoceles

Infectious entities may mimic oral cGVHD and should be ruled out and/or sufficiently treated prior to establishing a diagnosis. Viral pathogens include recrudescent herpes simplex virus, human papillomavirus, cytomegalovirus, and adenovirus. Viral-induced oral lesions are often smaller and more painful than cGVHD-related ulcers, but confirmatory testing should be performed with polymerase chain reaction, histopathology or in situ hybridization. Fungal overgrowth can present as soft white hyperkeratotic material that may be scraped away, erythematous, tender mucosa or superficial oral ulcers. These infections often are accompanied with a burning sensation on the tongue and mucosa.

Chronic Genital GVHD

Key points

• Genital cGVHD presents as discomfort, dyspareunia, or vaginal or penile adhesions

• Genital cGVHD consists of lichen sclerosus and lichen planus-like features, adhesions and scarring.

Diagnosis of genital cGVHD is based on diagnostic and distinctive features (Table 2) (6). Biopsy can assist in diagnosis if features are non-diagnostic, particularly if cGVHD has not been confirmed at another anatomic site (140), and is also indicated if there is suspicion for neoplasia. However, biopsy may be nondiagnostic even with diagnostic examination findings and healing is often difficult (141). At minimum, external genital involvement can be examined during the dermatology visit by spreading the labia majora and touching the vestibular gland openings, labia minora and majora gently with a cotton swab. If provider and patient are comfortable, palpation of the vaginal walls with a single digit can screen for bands, shortening, narrowing or other signs of vaginal scarring.

Vulvovaginal cGVHD typically presents with pain, burning, dyspareunia, dysuria, or vaginal obstruction, but may also be asymptomatic and found incidentally on examination. Patients may report difficulty with penetration or other vaginal insertion (e.g. sexual intercourse, medication applicators). Moderate to severe pain in the absence of sexual activity suggests more severe disease.

Vulvovaginal cGVHD primarily affects mucosal surfaces, including the medial aspects of the labia majora, labia minora, clitoral hood, and vagina. LS-like (Figure 6A) or LP-like findings may be present, including white patches, hyperkeratosis, or Wickham’s striae. In our experience, cGVHD is not associated with severe vulvar pruritus, severely thickened plaques, or hemorrhagic or bullous lesions, in contrast with idiopathic LS and LP.

Figure 6. Chronic vulvovaginal graft-versus-host disease.

A) Lichen sclerosus-like with hypopigmented, thickened, adhesed left labium minus; fissures at right labium minus and posterior fourchette, B) Vulvar patchy erythema and erosions.

Vulvovaginal cGVHD also shares features with genitourinary syndrome of menopause (GSM), in which hypoestrogenism causes vulvovaginal atrophy and urinary tract changes. Premature ovarian failure occurs in more than 95% of women following HCT and many patients have concurrent GSM and genital cGVHD (142). Erythema (Figure 6B) and fissures (Figure 6A) can occur in both GSM and genital cGVHD; however, erosions (Figure 6B) and ulcers are characteristic of cGVHD. Architectural changes such as resorption or agglutination of the labia minora, adhesions of the clitoral hood, or mild introital narrowing or vaginal shortening can be seen in GSM and genital cGVHD. Dense scarring, tissue retraction, or the presence of intravaginal adhesions favors cGVHD. Vaginal adhesions can preclude access to the cervix for pelvic examination or cervical cancer screening. Vulvovaginal cGVHD has been observed infrequently in prepubertal girls (143).

In penile cGVHD, the glans penis, urethra or meatus may be involved (142), with signs including noninfectious balanoposthitis (Figure 7A), LS-like or LP-like features (Figure 7B), phimosis, or urethra or meatus scarring (Table 2) (144).

Figure 7. Chronic male genital graft-versus-host disease.

A) Noninfectious balanitis with erythema and erosion of the coronal sulcus, B) Lichen planus-like with flat-topped papules with overlying scale

Evaluation of multi-system chronic GVHD

Once a diagnosis of mucocutaneous cGVHD has been established, a thorough review of systems with appropriate specialist referral and diagnostic testing should be performed to evaluate the presence of cGVHD in other organs (Table 3).

Table 3:

Evaluation of Multi-system Chronic Graft-versus-host Diseasea^a

Organ	ROS	Positive ROS	Negative ROS
Skin	Skin feels tight or hard, increased dryness, pruritus, rash, discoloration?	Dermatology consultation: clinical evaluation, biopsy, photographs, every 3 months or more often	Dermatology consultation: yearly
Sweat glands	Inability to sweat or to keep body warm?
Skin appendages	Loss of hair or nail changes?
Fasciae/joints	Stiffness or pain in the wrists, fingers, or other joints?	Assessment of range of motion: every visit Physical therapy consultation: every 3 months or more often	Assessment of range of motion: every visit
Eyes	Eye dryness, sensitivity to wind or dry environments, pain?	Ophthalmology consultation: every 3-6 months or more often	Ophthalmology consultation: 100 days after transplant, yearly
Mouth	Oral dryness, taste alterations, sensitivities (spicy, carbonate drinks, toothpaste), sores, pain?	Dental or oral medicine consultation: every 3-6 months or more often	Dental or oral medicine consultation: yearly or at symptom onset
Esophagus	Food or pills get stuck upon swallowing?	GI consultation for endoscopy
Lungs	Cough, shortness of breath, wheezes?	PFTs: 100 days after transplant, monthly for at least 3 months	PFTs: 100 days after transplant, every 3 months for 1 year, then as needed
Genital tract	Vaginal or penile pain, dyspareunia, dysuria, or sense of obstruction?	Gynecology/urogynecology consultation (female), Urology consultation (male)	Gynecology consultation: yearly or at symptom onset
Weight loss	Unexplained weight loss or inability to gain weight?	Weight every visit	Weight: every visit

^aAdapted from Flowers ME. How we treat chronic graft-versus-host disease. Blood. 2015, 125(4):606-615 Abbreviations: Review of systems, ROS; Gastroenterology, GI; pulmonary function tests, PFTs

Learning Objectives.

After completing this learning activity, participants should be able to identify patient and transplant-related risk factors for chronic graft-versus-host disease, diagnose cutaneous, oral, and genital chronic GVHD, and screen patients for multi-system involvement.

Abbreviations and Acronyms

HCT

Hematopoietic cell transplantation

US

United States

GVHD

Graft-versus-host disease

MHC

Major histocompatibility complex

cGVHD

Chronic graft-versus-host disease

NRM

Non-relapse mortality

OS

Overall survival

PBSC

Peripheral blood stem cells

TBI

Total body irradiation

PAMPs

Pathogen associated molecular patterns

DAMPs

Damage associated molecular patterns

TLR

Toll like receptor

NOD-R

Nucleotide-binding oligomerization domain-like receptors

NLRP3

NOD-like receptor 3

Ig

Immunoglobulin

APCs

Antigen presentation cells

Tregs

T regulatory cells

FhT cells

Follicular helper T cells

ATG

Anti-thymocyte globulin

PTCy

Post-transplant cyclophosphamide

TGF-B

Transforming growth factor beta

PDGF-a

Platelet derived growth factor alpha

BAFF

B cell activation factor

hrQoL

Health-related quality of life

LP

Lichen planus

PROM

Photographic range of motion

LS

Lichen sclerosus

GSM

Genitourinary syndrome of menopause

sBAFF

Soluble B cell activating factor

CXCL9/10

Chemokine (C-X-C motif) ligand 9/10

ST2

Suppression of tumorigenicity 2