Effect of cGVHD

• Immunological activation leads to ocular surface inflammation and lacrimal gland fibrosis in oGvHD.
• Self-reactive T cells (CD4+ and CD8+) from the donor persist due to defective central and peripheral tolerance mechanisms.
• T cell-mediated immune response targets host antigens, including major (MHC) and minor (miHAG) histocompatibility antigens, driven by differences in host and donor antigen expression, such as HLA mismatch and polymorphic minor histocompatibility antigens.
• Imbalance between effector and regulatory T cell functions triggers inflammatory cascades.
• Donor T cells play a predominant role in systemic and ocular disease orchestration, although B cells and antigen-presenting cells are also involved.
• In oGvHD, APC activation, donor T cell differentiation, proliferation, and activation, along with B cell activation and pro-inflammatory cytokine release, induce and maintain ocular surface inflammation and activate fibroblasts and dendritic cells in the lacrimal gland, ultimately leading to lacrimal tissue fibrosis.
• Tissue damage in oGvHD extends beyond the ocular surface and lacrimal gland, involving ocular adnexa, with Meibomian gland and ocular surface damage correlating with each other.

Pathophysiology of ocular GvHD

• Immunological activation leads to ocular surface inflammation and lacrimal gland fibrosis in oGvHD.
• Self-reactive T cells (CD4+ and CD8+) from the donor persist due to defective central and peripheral tolerance mechanisms.
• T cell-mediated immune response targets host antigens, including major (MHC) and minor (miHAG) histocompatibility antigens, driven by differences in host and donor antigen expression such as HLA mismatch and polymorphic minor histocompatibility antigens.
• Imbalance between effector and regulatory T cell functions triggers inflammatory cascades.
• Donor T cells play a predominant role in systemic and ocular disease orchestration, although B cells and antigen-presenting cells are also involved.
• In oGvHD, APC activation, donor T cell differentiation, proliferation, and activation, along with B cell activation and pro-inflammatory cytokine release, induce and maintain ocular surface inflammation and activate fibroblasts and dendritic cells in the lacrimal gland, ultimately leading to lacrimal tissue fibrosis.
• Tissue damage in oGvHD extends beyond the ocular surface and lacrimal gland, involving ocular adnexa, with Meibomian gland and ocular surface damage correlating with each other.

This image was obtained from an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY). APC: Antigen-Presenting Cells; CD4+:

Cluster of Differentiation 4; CD8+: Cluster of Differentiation 8; HLA: Human Leukocyte Antigen; MHC: Major Histocompatibility Complex; miHAG: Minor Histocompatibility Antigens; oGvHD: Ocular Graft-versus-Host Disease

1. Tappener C et al. Front Med (Lausanne). 2023.10;1133381.

Diagnosis

Characteristics of cGvHD: Eyes

Eyes: Distinctive KCS

• New onset of dry, gritty or painful eyes
• Cicatricial conjunctivitis
• KCS
• Confluent areas of punctate keratopathy

Eyes: Other^2,3

• Photophobia
• Periorbital hyperpigmentation
• Blepharitis (i.e., erythema and edema of eyelids, telangiectasia of eyelid margin)
• Scoring of cGvHD: Eyes⁴

Eyes⁴

	SCORE 0	SCORE 1	SCORE 2	SCORE 3
EYES Keratoconjunctivitis sicca (KCS) confirmed by ophthalmologist:     ☐ Yes     ☐ No     ☐ Not examined	☐ No symptoms	☐ Mild dry eye      symptoms not      affecting ADL     (requirement of     lubricant eye     drops ≤ 3 x per     day)	☐ Moderate dry eye     symptoms partially     affecting ADL     (requiring lubricant     eye drops > 3 x per     day or punctal     plugs),     WITHOUT new     vision impairment     due to KCS	☐ Severe dry eye     symptoms significantly     affecting ADL (special     eyeware to relieve pain)     OR unable to work     because of ocular     symptoms OR loss of     vision due to KCS
☐ Abnormality present but explained entirely by non-GVHD documented cause (specify):

‡To be completed by specialist or trained medical providers.

cGvHD, chronic graft-versus-host disease; KCS, keratoconjunctivitis sicca; ADL, activities of daily living.

1. Nassiri N et al. J Ophthalmic Vis Res. 2013;8(4):351-358; 
2. Screening eyes for chronic GvHD. BetheMatchClinical.org. Accessed April 11, 2022. https://bethematchclinical.org/post-transplant-care/chronic-gvhd/eyes/;
3. Smith Knutsson E et al. Acta Obstet Gynecol Scand. 2018;97(9):1122-1129. doi:10.1111/aogs.13366;
4. Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001.

The figures are included from the article Nair S et al. Indian J Ophthalmol. 2021 May;69(5):1038-1050; which is under the copyright license of CC-BY-NC that permits the non-commercial use.

Management

Treatment of ocular cGvHD^1,2

• Lubrication: Intensive lubrication for dry and inflamed ocular surface is an essential parameter for the treatment of ocular cGvHD. Several artificial tears, viscous eye drops and ointments are available with limited data.
• Topical anti-inflammatory agents: Topical corticosteroids have been used with limited data on efficacy. However, cyclosporine eye drops have been used to treat refractory eye disease.
• Increase teat and mucin production: Oral muscarinic agonist such as pilocarpine or cevimeline can be used as an adjuvant treatment approach. Other medication include secretagogue eye drop (diquafosol or rebamipide)
• Reducing train drainage: Using collagen or silicone punctual plugs can be inserted into lacrimal ducts
• Scleral lenses: Using scleral lenses can be pivotal in reducing ocular symptoms including ocular pain and promote visual activity by forming a uniform surface
• Systemic treatment: High dose corticosteroids (methylprednisolone 1 mg/kg) is the first line treatment with options for second-line and third-line treatments
• Surgical management of complications
• Lid care/warm compress/humidified environment
• Bandage contact lens (used with caution)

• GvHD related Dry Eye Disease is often overlooked due to lack of subjective symptoms and reliable testing in children. Schirmer’s test is difficult for children because it is painful and take 5 minutes to complete. Routine ophthalmological screening should be done periodically post-HSCT.
• Although severe ocular sicca is uncommon in children with cGvHD, measured tear production is reduced, and surveillance for keratoconjunctivitis sicca is necessary.
• Ocular sicca generally responds to ancillary measures in conjunction with systemic immunosuppression.
• Experience is limited and dosing is not established for many of the topical and oral medications for ocular GvHD.

cGvHD, chronic graft-versus-host disease; GvHD, graft-versus-host disease; HSCT, hematopoietic stem-cell transplantation.

1. Tappeiner C et al. Front Med. 2023;10:1133381.
2. Carpenter PA et al. Biol Blood Marrow Transplant. 2015;21(7):1167-87.

Effects

Pathophysiology of cGvHD: Mouth¹

 

Phase 1: Active inflammation is initiated by conditioning toxicity, resulting in mucous membrane disruption, aGvHD, and viral reactivation. DAMPs, chemokines, and cytokines are released from endothelial, epithelial, and innate immune cells, leading to T cell activation. Initially, Th17 cells support epithelial maintenance and acute inflammation.

Phase 2: Plasmocytic dendritic cells (pDCs) with type 1 IFN secretion attract Th1/Tc1 response, which drives the chronic inflammatory phase.

Phase 3: IFN-γ secretion promotes activated macrophages (M1) with TNF-α. Tc cells secrete perforin and granzyme B, inducing apoptosis, which leads to the secretion of BAFF, affecting B cells, although this requires further confirmation in oral mucosal cGvHD pathophysiology. Many cell types, including anti-inflammatory macrophages, secrete TGF-β as the inflammatory response transitions to a fibrotic stage.

 

Phase 1 cGvHD

Active inflammatory manifestations (phase 1) and increased pathological features are common within the first year after HCT, but a patient-dependent association should be considered. Effector mechanisms in oral cGvHD resemble but are not identical to those in patients with OLP or Sjogren’s Syndrome. Th1, Tc1, and Th17 cells are predominant in oral mucosal and salivary gland cGvHD, aggregating near the mucosal epithelium, ducts, and acini units. Dendritic cells, primarily Langerhans cells (CD1a), and plasmacytoid-like dendritic cells are involved in oral cGvHD. Th1 cells may play a role in early disease phases, but their elevation is not as pronounced as Tc cells and macrophages with increasing cGvHD severity. Th cells persist steadily over time in active and severe cGvHD, while Tc cells increase.

 

Phase 2 cGvHD

During cGVHD propagation into phase 2, persistent clinical ulcerations may become visible due to dysregulated immunity. Tc cells appear to decrease, while Th cell infiltration remains frequent, and the macrophage immune profile predominates compared to healthy individuals. Although no study has examined the characterization of cell populations with respect to biological phases, progression into distinctive erosive features suggests a Th2-polarized response. Th2 cells typically exhibit a cytokine profile of IL-4 and IL-5, along with C-C chemokine receptor 4, which have been associated with oral mucosal and salivary gland cGvHD infiltration.

 

Phase 3 cGvHD

Phase 3 of cGvHD, the fibrotic stage, manifests as mucosal scleroderma and degenerated acinar structures in salivary gland cGvHD. Salivary gland cGvHD leads to fibroplasia and functional impairment of saliva secretion. Clinical fibrotic components may be less prominent in oral mucosal cGvHD, but reports describe oral lichenoid-sclerodermatous plaque, erosions, and oromandibular parafunctions. Aberrant healing in phase 3 may represent the transition into non-typical lichenoid clinicopathological features, such as frictional/factitial keratosis, non-reactive, or dysplastic leukoplakia.

aGvHD, acute graft-versus-host disease; B cells, bursa-derived cells; cGvHD, chronic graft-versus-host disease, T cells, thymocyte cells.

1. Tollemar V et al. Front Immunol. 2023. 14:1151493

These images was obtained from an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY)

Diagnosis

Characteristics of cGvHD: Mouth
Lichen planus-like changes¹

• Lichen planus-like changes that are characterized by hyperkeratotic white lines and lacy-appearing lesions on the oral mucosa
• Changes are typically observed on the buccal mucosa and tongue

Mouth: Distinctive
Ulcers²

• Xerostomia (dryness)2
• Mucosal atrophy2
• Ulcers2
• Mucoceles2
• Pseudomembranes

The mouth is a predominant site in pediatric patients with cGvHD3

• Lichenoid changes
• Hyperkeratotic plaques
• Circumoral restriction
• Impaired enamel
• Ageusia (loss of taste)

Scoring of cGvHD: Mouth⁴

Mouth⁴

	SCORE 0	SCORE 1	SCORE 2	SCORE 3
MOUTH Lichen planus–like features present: by ophthalmologist:     ☐ Yes     ☐ No	☐ No symptoms	☐ Mild symptoms      with disease signs      but not limiting      oral intake       significantly	☐ Moderate      symptoms with      disease signs with      partial limitation      of oral intake	☐ Severe symptoms with      disease signs on      examination with major      limitation of oral intake
☐ Abnormality present but explained entirely by non-GVHD documented cause (specify):

cGvHD, chronic graft-versus-host disease.

• Margaix-Muñoz M et al. J Clin Exp Dent. 2015;7(1):e138-e145. doi:10.4317/jced.51975;
• Mawardi H et al. Oral Dis. 2019;25(4):931-948. doi:10.1111/odi.12936;
• Yanik G. Pediatric transplant: issues. Lecture presented at: The Pediatric Blood and Marrow Transplant Program; April 2022;
• Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001.

The figures are included from the article Rodrigues S K et al. Am J Clin Dermatol. 2018 Feb;19(1):33-50; which is under the copyright license of CC-BY-NC that permits the non-commercial use.

Management

Treatment of oral cGvHD¹

• Behavioural: Children often don’t communicate symptoms of impaired speech, oral dryness or sensitivities, taste alteration, and dysphagia; reduced oral intake and increased drinking during eating or at night may be presenting symptoms. Specific approaches to help parents assist children with oral topical therapies may improve compliance.
• Secondary infections with viruses (especially herpes simplex) and yeasts are common; therefore, using a local antifungal preparation in combination with the steroid rinse is recommended.
• Developmental: Fibrosis and limited mouth opening may contribute to the disruption of craniofacial growth.
• Pharmacologic considerations: While oral mucosal cGvHD generally responds well to topical steroids or calcineurin inhibitors, these agents may produce clinically relevant systemic drug levels in infants and small children. Viscous lidocaine may reduce the gag reflex, compromise swallowing and should be used with caution. Sialagogue use has been limited in children and dosing is not established.
• Orthodontic: Fixed braces should only be used after healing of acute inflammation. Specific guidelines for optimal force and pace of orthodontic management in cGvHD remain undefined.

cGvHD, chronic graft-versus-host disease.

1. Carpenter PA et al. Biol Blood Marrow Transplant. 2015;21(7):1167-87

Types of BOS: Lungs

• BOS is the lung manifestation of cGvHD that is clinically characterized by the development of fixed new-onset airflow obstruction and pathologically characterized by progressive fibrosis targeting the terminal bronchioles.¹
• BOS clinically presents as obstructive lung disease detected as a decline in FEV1. BOS is the predominant phenotype of chronic lung allograft dysfunction, which remains a major cause of morbidity and mortality.²
• One challenge in diagnosing BOS in pediatric patients is the inability to accurately measure FEV1 in children aged >8 years.³
• BOS can occur secondary to cGvHD or secondary to lung transplantation.4 The following slides will discuss BOS secondary to cGvHD.

Proliferative BOS^5,6

Air-space opacification and intraluminal exudates; much more common and likely to respond to therapy.

 

Constrictive BOS^3,5

Alterations in the walls of the bronchioles ranging from inflammation to fibrosis and, ultimately, to complete obliteration of the lumen.5 One challenge in pediatric patients is recognizing this type of BOS.3

 

BOS is a progressive disease that is associated with high morbidity and mortality rates.⁴

• Among 2859 patients with cGvHD, the incidence of BOS was 6% at 1 year and 7% at 3 years after transplantation.⁷
• Patients affected by BOS have a 2-year survival rate of 44% and a 5-year survival rate of 13%.⁸

Overview of BIOS in cGvHD

Epidemiology1,8

Risk factors associated with the development of BOS after allo-HCT include8 Low immunoglobulin G (IgG) levels Use of peripheral blood stem cells Use of busulfan or methotrexate (MTX) during the transplant process Intensity of the conditioning regimen Poor pretransplant lung function and respiratory infection during the first 100 days post transplantation Risk factors found to be significantly associated with cGvHD include1 Lower baseline FEV1/forced vital capacity (FVC) ratio Non-Caucasian race Lower circulating IgG level

cGvHD, chronic graft-versus-host disease; BOS, bronchiolitis obliterans syndrome; FEV1, forced expiratory volume at 1 second. alloHCT, allogeneic hematopoietic cell transplant; FEV1, forced expiratory volume at 1 second.

1. Au BKC et al. Biol Blood Marrow Transplant. 2011;17(7):1072-1078. doi:10.1016/j.bbmt.2010.11.018;
2. Pilewski J. Chronic lung allograft dysfunction: bronchiolitis obliterans syndrome. UpToDate. Accessed April 11, 2022. https://www.uptodate.com/contents/chronic-lung-allograft-dysfunction-bronchiolitis-obliterans-syndrome
3. . Yanik G. Pediatric transplant: issues. Lecture presented at: The Pediatric Blood and Marrow Transplant Program; April 2022;
4. Williams KM et al. Transplant Cell Ther. 2022;S2666-6367(22)00049-5. doi:10.1016/j.jtct.2022.01.021;
5. Smith KJ, Fan LL. Thorax. 2006;61(6):462-463. doi:10.1136/thx.2005.052670;
6. Jamkhana Z. Bronchiolitis obliterans. Cancer Therapy Advisor. Published January 17, 2019. Accessed April 11, 2022. https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/hospital-medicine/bronchiolitis-obliterans/;
7. Dudek AZ et al. Biol Blood Marrow Transplant. 2003;9(10):657-666. doi:10.1016/S1083-8791(03)00242-8;
8. Chien JW et al. Biol Blood Marrow Transplant. 2010;16(1 suppl):S106-S114. doi:10.1016/j.bbmt.2009.11.002;

Diagnosis

Characteristics of cGvHD: Lungs

Lungs: Diagnostic – Partial obstruction of bronchioles in BOS¹

• Bronchiolitis obliterans²
• BOS²
• Characterized by peribronchiolar fibrosis, intraluminal fibrous obliteration and circumferential narrowing of the terminal small airways
• Clinical presentation shows airflow obstruction.³

Lungs: Distinctive²

• Air trapping and bronchiectasis

Lungs: Other²

• Cryptogenic organizing pneumonia
• Restrictive lung disease

Complete obstruction of bronchioles in BOS¹

Scoring of cGvHD: Lungs⁴

Lungs⁴

LUNGS** Symptom Score	☐No symptoms	☐ Mild symptoms  (shortness of breath after     climbing one flight of steps)	☐ Moderate symptoms (shortness of breath after      walking on flat ground)	☐ Severe symptoms  (shortness of breath at         rest; requiring O2)
Lung Score	☐ FEV1 ≥ 80%	☐ FEV1 60–79%	☐ FEV1 40–59%	☐ FEV1 ≤ 39%
Pulmonary function tests ☐ Not performed ☐ Abnormality present but explained entirely by non-GVHD documented cause (specify): _______________

**Lung scoring should be performed using both the symptoms and FEV1 scores whenever possible. FEV1 should be used in the final lung scoring where there is discrepancy between symptoms and FEV1 scores.

cGvHD, chronic graft-versus-host disease; FEV1, forced expiratory volume at 1 second.

• Dudek AZ et al. Biol Blood Marrow Transplant. 2003;9(10):657-666. doi:10.1016/S1083-8791(03)00242-8;
• Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001;
• arrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001; 3. Bergeron A, Cheng G-S. Clin Chest Med. 2017;38(4):607-621. doi:10.1016/j.ccm/2017.07.003;
• Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001

Management

BOS secondary to cGvHD: Lungs

Patient path to therapy1,2,3

Diagnosis1,2,3 BOS often occurs within first 2 years of HCT with other manifestations of cGvHD3 Procedures used to diagnose BOS include lung biopsy, transbronchial lung biopsy, as well as pulmonary function test1,2 General guidelines for treatment1,3 Upon ruling out infection, evaluate the patient’s eligibility for inclusion in a clinical trial for BOS and initiate (or increase) prednisone dose to 1 mg/kg/d1 Start standard cGvHD prednisone taper at 2 weeks Consider continuing inhaled corticosteroids throughout prednisone therapy · Studies have shown that gastroesophageal reflux disease (GERD) may be associated with BOS genesis and progression3 Maximizing GERD therapies may diminish progression of BOS Fungal infection is a common cause of morbidity and mortality in patient with lung GvHD. Antifungal prophylaxis in those on steroid >0.5 mg/kg/day is recommended.

Current treatment options1,4

Immunosuppressive agents, which comprise the backbone of treatment to decrease the rate of progression of BOS, include Inhaled corticosteroids (fluticasone or fluticasone/salmeterol) as initial treatment Azithromycin Montelukast High-dose systemic corticosteroids (1 mg/kg/d)

• Formal spirometry, lung volumes, and diffusing capacity are not measurable reliably in children <7 years, but negative plethysmography is an option. The PFT screening can be tried beginning at 6 years of age, but results should take into consideration the child’s compliance with PFT instructions and proper technique, so it requires discussion with a pulmonologist.
• Actual measured PFT values must be carefully considered in pediatric patients because predicted normal values vary with age, weight, and height. Therefore, per cent predicted values might spuriously show a serial decrease over time without a substantive decline in absolute values.
• Recipients of total body or chest wall irradiation may not have proportional chest wall growth, and this is particularly relevant for growing children. A drop in the percent-predicted value may reflect poor lung growth rather than a physiologic drop in lung function.

BOS, bronchiolitis obliterans syndrome; cGvHD, chronic graft-versus-host disease; HCT, hematopoietic stem cell transplant; PFT, Pulmonary function test.

1. Flowers MED, Martin PJ. Blood. 2015;125(4):606-615. doi:10.1182/blood-2014-08-551994;
2. Dudek AZ et al. Biol Blood Marrow Transplant. 2003;9(10):657-666. doi:10.1016/S1083-8791(03)00242-8;
3. Williams KM. Blood. 2017 Jan 26;129(4):448-455. doi: 10.1182/blood-2016-08-693507;
4. Au BKC et al. Biol Blood Marrow Transplant. 2011;17(7):1072-1078. doi:10.1016/j.bbmt.2010.11.018;
5. Carpenter PA et al. Biol Blood Marrow Transplant. 2015;21(7):1167-87

How GvHD affects Liver

Hepatic GvHD presents with abnormal liver function tests, along with elevated levels of bilirubin and alkaline phosphatase in the serum.

Donor lymphocytes target bile duct epithelial cells, leading to endotheliitis, pericholangitis, and the destruction of bile ducts through apoptosis.

Liver GvHD causing bile duct involvement and resulting in severe hyperbilirubinemia is less common, there is a rising incidence of hepatitis-like cGvHD as another, albeit less harmful, liver complication.

cGvHD, chronic graft-versus-host disease.

1. Ghimire S et al. Front Immunol. 2017. 10.3389/fimmu.2017.00079.

Diagnosis

Characteristics of cGvHD: Liver¹

Liver: Common for both aGvHD and cGvHD

• Increased LFTs (i.e., total bilirubin, alkaline phosphatase [AP], alanine transaminase [ALT])
• Total bilirubin, ALP or ALT >2 x upper normal liimt

Scoring of cGvHD: liver²

liver²

	SCORE 0	SCORE 1	SCORE 2	SCORE 3
LIVER	☐ Normal total     bilirubin and     ALT or AP     < 3 × ULN	☐ Normal total      bilirubin with ALT      ≥ 3 to 5 × ULN or      AP ≥ 3 × UL	☐ Elevated total      bilirubin but      ≤3 mg/dL or      ALT > 5 ULN	☐ Elevated total      bilirubin > 3 mg/dL
☐ Abnormality present but explained entirely by non-GVHD documented cause (specify):

cGvHD, chronic graft-versus-host disease; GI, gastrointestinal; LFTs, liver function tests; ALT, alanine aminotransferase; AP, alkaline phosphatase; ULN, normal upper limit.

1. Zeiser R, Blazar BR. N Engl J Med. 2017;377(26):2565-2579.doi:10.1056/NEJMra1703472. 
2. Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001.

Management

Treatment of Liver¹

• Surveillance for infection (viral, bacterial, fungal, parasites)
• Rule out other potential etiologies
• Dietary modification for carbohydrate, fat malabsorption
• Pancreatic enzyme replacement for insufficiency
• Ursodeoxycholic acid if cholestasis
• Bile acid binding resins if bile salt malabsorption (e.g., cholestyramine)
• Lactase tablets or lactase-containing dairy products
• Topical glucocorticoid formulations for late acute GVHD
• Limitation of ethanol intake
• Avoidance of hepatotoxins

• Children with cGvHD may have varied GI complaints consisting of nausea, anorexia, abdominal pain, weight loss, cramping or diarrhea.
• Weight loss and malnutrition (as reflected by a decrease in BMI) are clinically significant issues in children with multisystem cGvHD and are likely systemic manifestations of the disease.
• Maintaining adequate nutrition is essential and careful evaluation of growth and head circumference in infants is required.

BMI, body mass index; cGvHD, chronic graft-versus-host disease; GI, gastrointestinal.

1. Carpenter PA et al. Biol Blood Marrow Transplant. 2015;21(7):1167-87.

How GvHD affects skin
 

Figure 1: Normal Skin

cGvHD involves complex mechanisms such as thymic injury, disordered T cell selection, loss of regulatory cells, disrupted B cell homeostasis, and abnormal tissue repair leading to fibrosis.¹

Figure 2: aGvHD process

During aGvHD, tissue injury triggers the production of IFN-γ inducible chemokines, attracting CXCR3+ alloreactive T cells to the skin. These T cells interact with host Langerhans cells, becoming pathogenic and producing IFN-γ. They then destroy Lgr5+ epidermal stem cells, impairing skin repair and causing cell degeneration, separation, and necrosis. Additionally, changes in the local microbiome due to treatment can exacerbate skin inflammation.

Figure 3: cGvHD process

During chronic GvHD, donor T cell-derived IL-17 recruits Ly6Clow monocytes to the skin, which become macrophages. These macrophages produce TGF-β, leading to fibroblast differentiation into myofibroblasts that deposit collagen. Allo- or auto-antibodies further polarize macrophages to produce more TGF-β, enhancing collagen production. IL-21 from follicular helper-like cells also affects fibroblast differentiation, resulting in thickened and homogenized collagen bundles in the dermis.

aGvHD, acute Graft-Versus-Host Disease; CXCR3, C-X-C Motif Chemokine Receptor 3; cGvHD, chronic Graft-Versus-Host Disease; IFN-γ, Interferon Gamma; IL-17, Interleukin 17; IL-21, Interleukin 21; Lgr5, Leucine-rich repeat-containing G-protein coupled receptor 5; Ly6Clow, Low Ly6C Expression; TGF-β, Transforming Growth Factor Beta.

1. Pedro Santos e S et al. Front Immunol. 2018;9:00963.

Diagnosis

Characteristics of cGvHD: Skin

Skin: Diagnostic Poikiloderma¹

• Poikiloderma (i.e., atrophy, pigmentary changes, telangiectasia)²
• Lichen planus-like eruption (i.e., erythematous flat-topped papules/plaques with/without a shiny appearance)²
• Deep sclerotic features (i.e., smooth, waxy, thickened/tight skin due to deep and diffuse sclerosis over a large area limiting joint mobility)²
• Morphea-like features (i.e., localized patchy areas of moveable smooth/shiny skin with leather-like consistency that often has dyspigmentation)²

Papulosquamous lesions³

• Depigmentation (vitiligo)
• Papulosquamous lesions
• Sclerosis
• Morphea-like
• Lichenslcerosis-like

Skin: Other Hyperpigmentation⁴

• Sweat impairment and intolerence to temperature change due to loss of sweat glands
• Keratosis pilaris
• Ichthyosis
• Hypopigmentation
• Hyperpigmentation

Scoring of cGvHD: Skin, nails, and hair⁵

Skin⁵

	SCORE 0	SCORE 1	SCORE 2	SCORE 3
PERFORMANCE SCORE: KPS  ECOG  LPS	☐ Asymptomatic and     fully active (ECOG     0; KPS or LPS     100%)	☐ Symptomatic,     fully ambulatory,     restricted only in     physically     strenuous activity    (ECOG 1, KPS    or LPS 80–90%)	☐ Symptomatic,     ambulatory, capable of     self-care, >50%     of waking hours out     of bed (ECOG 2,    KPS or LPS 60–70%)	☐ Symptomatic,      limited self-care,     >50% of waking     hours in bed (ECOG    3–4, KPS or LPS    <60%)
SKIN: SCORE % BSA GVHD features to be scored by BSA: Check all that apply: ☐Maculopapular rash/erythema ☐ Lichen planus–like features ☐Sclerotic features ☐Papulosquamous lesions or ichthyosis ☐Keratosis pilaris–like GVHD	☐ No BSA involved	☐  1 - 18% BSA	☐ 19-50% BSA	☐  >50% BSA
SKIN FEATURES: SCORE :	☐ No sclerotic      features		☐ Superficial      sclerotic features      "not hidebound"      (able to pinch)	Check all that apply   ☐ Deep sclerotic       features ☐ "Hidebound"      (unable to pinch) ☐ impaired mobility ☐ Ulceration
Other skin GVHD features (NOT scored by BSA) Check all that apply: ☐Hyperpigmentation ☐Hypopigmentation ☐Poikiloderma ☐Severe or generalized pruritus ☐ Hair involvement ☐ Nail involvement ☐ Abnormality present but explained entirely by non-GVHD documented cause (specify):

†Skin scoring should use both percentage of BSA involved by disease signs and the cutaneous features scales. When a discrepancy exists between the percentage of total body surface (BSA) score and the skin feature score, OR if superficial sclerotic features are present (Score 2), but there is impaired mobility or ulceration (Score 3), the higher level should be used for the final skin scoring.

cGvHD, chronic graft-versus-host disease; BSA, body surface area; ECOG, Eastern Cooperative Oncology Group; KPS, Karnofsky Performance Status; LPS, Lansky Performance Status.

1.  Hymes SR, et al. Biol Blood Marrow Transplant. 2006. https://doi.org/10.1016/j.bbmt.2006.08.043;12(11):1101-13;
2. Pavletic SZ et al. Bone Marrow Transplant. 2006;38(10):645-651. doi:10.1038/sj.bmt.1705490;
3. Jang S et al. Ann Dermatol. 2016;28(1):90-93. doi:10.5021/ad.2016.28.1.90;
4. Gray AN, et al. JAAD Case Rep. 2023;36:82-88. doi: 10.1016/j.jdcr.2023.03.023;
5. Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001.

The figures are included from the article Rodrigues S K et al. Am J Clin Dermatol. 2018 Feb;19(1):33-50; which is under the copyright license of CC-NC that permits the non-commercial use

Management

Treatment of skin GvHD¹

Preventive measures

Photoprotection: UVA and UVB blockade including:

• Avoidance of sun exposure (especially between 10:00 am and 4:00 pm)
• Use of sunscreens (> SPF 20 with broad-spectrum UVA and UVB protection)
• Protective clothing
• Avoidance of photosensitizing agents

Treatment

Intact skin

• Symptomatic treatment with emollients and antipruritic agents
• Topical corticosteroids
• Light therapy (PUVA, UVA1, UVB, narrow-band UVB)
• Topical calcineurin inhibitors (pimecrolimus, tacrolimus)

Sclerotic manifestations with joint stiffness or contractures

• Deep muscle/fascial massage (Heller works) to improve range of motion
• Stretching exercises to improve range of motion

Erosions and ulcerations

• Topical or oral antimicrobials
• Wound dressings and debridement
• Control of edema

• Systemic side effects of topical steroids and calcineurin inhibitors may occur more frequently in young children because of the larger skin surface area to body weight ratio.
• Less potent steroids [Hydrocortisone 1-2.5%] should be used for thinner areas [face, neck, axillae, and groin]and higher potency steroids [Betamethasone 0.1%] are recommended for rest of the areas. For sclerotic form of cGvHD clobetasol 0.05% can be used. It should be applied twice daily.
• Topical tacrolimus is commonly used as an adjunct treatment in practice and applied twice a day with at least 1 hour gap from steroid application. [0.03% strength for face and genitalia and 0.1% strength for rest of the body]. It should be considered before increasing the dose of systemic immune suppressants or to reduce exposure to steroids.
• Topical steroids under occlusive dressings are not recommended.
• Avoid urea or menthol containing products in young children because they may cause skin irritation.
• Skin care include topical moisturizers, antipruritic agents, and strict photoprotection

cGvHD, chronic graft-versus-host disease; GvHD, graft-versus-host disease; PUVA, Psoralen plus ultraviolet A; SPF, Sun Protection Factor; UVA, Ultraviolet A; UVB, Ultraviolet B.

Carpenter PA et al. Biol Blood Marrow Transplant. 2015;21(7):1167-87

 

How GvHD affects GI tract¹

The base of intestinal crypts, housing epithelial stem cells and Paneth cells, is a key target for GvHD due to its role in epithelium regeneration. Loss of Paneth cells at GI GvHD onset suggests their sensitivity to the condition.¹

Histological features such as single cell apoptosis, patchy ulcerations, apoptotic bodies in crypt bases, loss of surface epithelium can be reported.

This mechanism results in secretory diarrhea, severe abdominal pain, vomiting, and anorexia.

GVHD development in the gut is associated with a disturbed microbiome. In cGvHD decreased microbial diversity with reduced Faecalibacterium and increased Akkermansia and Streptococcus species are reported, whereas high abundance of Lachnoclostridium is protective.²

cGvHD, chronic graft-versus-host disease; GI, gastrointestinal.

1. Ghimire S et al. Front Immunol. 2017. 10.3389/fimmu.2017.00079.
2. Gail LM et al. Front Immunol. 2023:14:1199422.

Diagnosis

Characteristics of cGvHD: GI tract¹

GI tract: Common for both aGvHD and cGvHD

• Anorexia
• Nausea
• Vomiting
• Diarrhea
• Weight loss

GI tract: Diagnostic

• Sclerotic mucosa of the esophagus1
• Esophageal webs, strictures or concentric rings documented by endoscopy or barium contrast radiograph

GI tract: Other

• Exocrine pancreatic insufficiency

Scoring of cGvHD: GI tract²

GI tract²

	SCORE 0	SCORE 1	SCORE 2	SCORE 3
GI Tract Check all that apply: ☐ Esophageal web/ proximal stricture or ring ☐ Dysphagia ☐ Anorexia ☐ Nausea ☐ Vomiting ☐ Diarrhea ☐ Weight loss ≥5%* ☐ Failure to thrive	☐ No symptoms	☐ Symptoms without  significant weight loss* (<5%)	☐ Symptoms associated with  mild to moderate weight loss* (5–15%) OR  moderate diarrhea without significant interference with daily living	☐ Symptoms associated with significant weight loss* >15%, requires nutritional  supplement for most calorie needs OR esophageal dilation OR  severe diarrhea with significant interference with daily living
☐ Abnormality present but explained entirely by non-GVHD documented cause (specify):

*Weight loss within 3 months.

cGvHD, chronic graft-versus-host disease; GI, gastrointestinal.

1. Zeiser R, Blazar BR. N Engl J Med. 2017;377(26):2565-2579.doi:10.1056/NEJMra1703472;
2. Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001

Management

Treatment of GI tract¹

• Surveillance for infection (viral, bacterial, fungal, parasites)
• Rule out other potential etiologies
• Gastroesophageal reflux management
• Esophageal dilation for webs or stricture
• Dietary modification for carbohydrate, fat malabsorption
• Pancreatic enzyme replacement for insufficiency
• Ursodeoxycholic acid if cholestasis
• Bile acid binding resins if bile salt malabsorption (e.g., cholestyramine)
• Lactase tablets or lactase-containing dairy products
• Topical glucocorticoid formulations for late acute GVHD
• Limitation of ethanol intake

• Children with cGvHD may have varied GI complaints consisting of nausea, anorexia, abdominal pain, weight loss, cramping or diarrhea.
• Weight loss and malnutrition (as reflected by a decrease in BMI) are clinically significant issues in children with multisystem cGvHD and are likely systemic manifestations of the disease.
• Maintaining adequate nutrition is essential and careful evaluation of growth and head circumference in infants is required.

GvHD, graft-versus-host disease; BMI, body mass index; cGvHD, chronic graft-versus-host disease; GI, gastrointestinal.

1. Carpenter PA et al. Biol Blood Marrow Transplant. 2015;21(7):1167-87.

How cGvHD affects Genitalia¹

• Genital cGvHD presents at a median of 7–10 months after HCT, but signs and symptoms can also develop late, over a year post-HCT.
• GVHD of the genital tract is often associated with oral cGvHD. Genital examination is recommended, even in asymptomatic patients, especially if signs of cGvHD are present in the mouth.
• Symptoms of genital cGvHD in women are due to estrogen deficiency and include vulvovaginal dryness, pruritis, burning, pain, dysuria, dyspareunia and at times, bleeding. Patients who are sexually active may experience pain and post-coital bleeding and thus report symptoms earlier.
• Acute and chronic inflammation within the subepithelial stroma and epithelium, with vacuolar degeneration of the basal layer, apoptotic keratinocytes and superficial perivascular lymphohistiocytic infiltrates.
• Typical signs such as erythema of the vulva, tenderness of vestibular gland openings, mucosal erosions or fissures, lace-like leukokeratosis or vulvar architecture changes such as labial resorption or clitoral hood agglutination are seen.
• Male genital lesions post-transplant include lichenoid, lichen sclerosis, phimosis, and contracture secondary to Peyronie’s disease, which may lead to penile deformity, pain, and erectile dysfunction.

cGvHD, chronic graft-versus-host disease; GvHD, graft-versus-host disease; HCT, hematopoietic cell transplantation

1. Hamilton BK et al. Bone Marrow Transplant. 2017;52(6):803-810

Diagnosis

Characteristics of cGvHD: Genitalia

Genitalia: Diagnostic
Labial agglutination^1-3

• Lichen planus-like and lichen sclerosis-like features
• Females: vaginal scarring or clitoral/labial agglutination
• Males: phimosis and urethral scarring or stenosis

Genitalia: Distinctive

• Erosion
• Fissure
• Ulcers

Scoring of cGvHD: Genitalia⁴

Genital tract⁴

	SCORE 0	SCORE 1	SCORE 2	SCORE 3
GENITAL TRACT (See Supplemental figure)     ☐ Not examined Currently sexually active     ☐ Yes     ☐ No	☐ No signs	☐ Mild signs and      females with or      without discomfort      on exam	☐ Moderate signs and      may have      symptoms with      discomfort on exam	☐ Severe signs with      or without      symptoms
☐ Abnormality present but explained entirely by non-GVHD documented cause (specify):

‡To be completed by specialist or trained medical providers.

cGvHD, chronic graft-versus-host disease; KCS, keratoconjunctivitis sicca; ADL, activities of daily living.

1. Nassiri N et al. J Ophthalmic Vis Res. 2013;8(4)::351-358;
2. Screening eyes for chronic GvHD. BetheMatchClinical.org. Accessed April 11, 2022. https://bethematchclinical.org/post-transplant-care/chronic-gvhd/eyes/;
3. Smith Knutsson E et al. Acta Obstet Gynecol Scand. 2018;97(9):1122-1129. doi:10.1111/aogs.13366
4. Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001.

The figures are included from the article Nair S et al. Indian J Ophthalmol. 2021 May;69(5):1038-1050; which is under the copyright license of CC-BY-NC that permits the non-commercial use

Management

Treatment of genitalia¹

• Early gynecology consultation
• Water-based or silicone lubricants
• Topical estrogens
• Topical corticosteroids or calcineurin inhibitors
• Dilators or vibrators
• Surgery for extensive synechiae or obliteration
• Surveillance for estrogen deficiency, infection (HSV, HPV, yeast, bacteria) and malignancy
• Avoid glycerin, paraben, fragrance, and other additive products

• Examine for evidence of phimosis and glans dryness/ulceration periodically post-HSCT. Pre-BMT exam should document if patient has preexisting phimosis or not.
• Vulvar or vaginal GvHD needs to be considered as soon as physical development has progressed beyond thelarche and into pubarche.
• Vulvovaginal GvHD has been observed infrequently in prepubertal girls.
• Evaluation by an adolescent gynecologic practitioner is recommended when a diagnosis of vulvovaginal GvHD is being considered.

HPV, Human Papillomavirus; HSV, Herpes Simplex Virus; BMT, Bone marrow transplant; GvHD, graft-versus-host disease; HSCT, hematopoietic stem-cell transplantation.

1. Carpenter PA et al. Biol Blood Marrow Transplant. 2015;21(7):1167-87.

How cGvHD affects Fascia and joints¹

• Joint and fascial involvement is relatively common and can cause significant functional impairment
• Fasciitis due to inflammation of the fascia with an eosinophilic component may manifest as joint stiffness, erythema, edema, restricted range of motion, arthralgia, and rarely arthritis or synovitis
• Joint and fascial manifestations can be clinically detectable when inflammation and fibrosis arise in deep tissues (deep sclerosis/fasciitis) or skin overlying joints (superficial sclerosis)
• Widespread sclerosis may result in joint contractures and severe limitation of function, and common sites of involvement include the hands/wrists, shoulders, elbows, and ankles

1. Calleja CH et al. Reumatol Clin (Engl Ed).2023;19(5):235-243.

Diagnosis

Characteristics of cGvHD: Fascia and joints

Fascia and joints: Diagnostic
Subcutaneous and fascial fibrosis^1,2

• Fasciitis
• Joint stiffness or contractures secondary to fasciitis or sclerosis

Joint contractures²

Fascia and joints:
Distinctive polymyositis³

• Myositis or polymyositis

Other

• Edema
• Muscle cramps
• Arthralgia or arthritis
• Scoring of cGvHD: Fascia and joints4

Scoring of cGvHD: Fascia and joints⁴

Joints and Fascia⁴

	SCORE 0	SCORE 1	SCORE 2	SCORE 3
JOINTS AND FASCIA P-ROM score (see below) Shoulder (1-7): Elbow (1-7): Wrist/finger (1-7): Ankle (1-4):	☐ No symptoms	☐ Mild tightness of      arms or legs      normal or mild     decreased range of     motion (ROM)     AND not affecting    ADL	☐ tightness of arms or      legs OR joint     contractures,     erythema thought     due to fasciitis,     moderate decrease     ROM AND mild to     moderate limitation     of ADL	☐ Contractures WITH     significant decrease     of ROM AND significant     limitation of ADL     (unable to tie shoes,     butoon shirts, dress self     etc.)
☐ Abnormality present but explained entirely by non-GVHD documented cause (specify):

cGvHD, chronic graft-versus-host disease.

1. Martires KJ et al.Blood. 2011;118(15):4250-4257. doi:10.1182/blood-2011-04-350249; 
2. Hidalgo Calleja C, et al. Adv Rheumatol. 202;62(1):33. doi: 10.1186/s42358-022-00262-3; 
3. Meng L et al. Clin Case Rep. 2018;6(9):1723–1726.doi:10.1002/ccr3.1709; 4. Jagasia MH et al. Biol Blood Marrow Transplant. 2015;21(3):389-401.e1. doi:10.1016/j.bbmt.2014.12.001

Treatment of joints

Polymyositis: Can be treated with the standard line therapies of steroids adjuvant with rituximab, only if there is a presence of B-cell infiltration.¹

Systemic first line and second-line therapy: As per the NIH treatment guidelines it is essential to initiate the first line steroid treatment.²

Adjuvant treatment can be used based on the clinical presentation of the patient.²

• It is often challenging to examine the ROM of all joints in young kids. Particular attention should be paid to development and active trends at home, and parents should be instructed to observe this.
• Children should be monitored for complications of prolonged steroid therapy like avascular necrosis and osteoporosis.

NIH, National Institutes of Health; ROM, range of motion.

1. Chinello M et al. Mediterr J Hematol Infect Dis. 2020;12(1):e2020002.
2. DeFilipp Z et al. Transplant Cell Ther. 2021. 27(9):729-737.
3. Carpenter PA et al. Biol Blood Marrow Transplant. 2015;21(7):1167-87