Graft-versus-host disease chronic L99.2-

Complex multi-organ disease that occurs 3-5 months or later after allogeneic hematopoietic stem cell transplantation (see below Graft-versus-Host Disease) The skin is the most frequently affected organ. Clinical morphology shows an overlap between systemic scleroderma, lichen sclerosus, systemic lupus erythematosus and Sjögren's syndrome. The cGVHD can affect different compartments of the skin (epidermis, corium) as well as the subcutaneous fatty tissue. Epidermal or dermal or subcutaneous changes, or a combination of both, may be the main cause. The 2 most frequent manifestations are lichenoid and sclerodermiform cGVHD (Ziemer M 2013).

Classification of chronic GvHD

• Progressive form (about 32% of cases), which directly follows an acute form with the worst prognosis
• Delayed form (quiescent onset; about 36% of cases) occurring after a disease-free interval after acute GvHD
• De novo form (about 30% of cases), without previous acute GvHD, with the best prognosis.

Since allogeneic stem cell transplantations (aSZT) are becoming more and more important therapeutically (expansion of indications), cGVHD will gain in importance in the future. About 50% of patients who survive allogeneic stem cell transplantation in the long term develop cGVHD.

S.u. Graft-versus-host disease.

A distinction must be made between a generalized and a localized form.

• Generalized cGVHD: onset with skin and mucous membrane changes:
  • lichenoid exanthema and hyperpigmentation in the facial area
  • erosive cheilitis
  • Sicca symptoms of the mucous membranes
  • xerophthalmia with keratoconjunctivitis
  • buccal mucositis with extensive erythema and reticular whitish patterns; formation of painful erosions, including ulcers
  • Oesophageal and vaginal strictures
  • Lichen sclerosus-like indurations of the glans penis and prepuce
  • Intestinal infestation
  • Lupoid hepatitis
  • General physical deterioration and pulmonary insufficiency
  • Risk of opportunistic infections.

The lichenoid exanthema can develop into manifestations that resemble (or are identical to) systemic scleroderma.

• Late cGVHD shows poikilodermatic conditions with extensive skin sclerosis and contractures. Complications include a 3-fold increased risk of cutaneous squamous cell carcinoma compared to stem cell transplant patients without GvHd and a 50-fold increased risk compared to the normal population (Zampaola AS et al. 2017).
• Localized cGVHD: Clinical features of lichen sclerosus et atrophicus, also genital lichen sclerosus (w>m) or lichen planus, circumscribed scleroderma (morphea), eosinophilic fasciitis (analogous to Shulman syndrome) or septal panniculitis.
• Images of pityriasis rosea have also been described. The changes can also spread linearly along the Blaschko lines.
• Nail changes appear as nail fold hyperkeratosis, onycholysis, transverse furrows, splinter hemorrhages, hyperpigmentation(melanonychia).

So-called diagnostic signs of cGvHD include the following symptoms:

• Poikiloderma
• Lichen planus-like skin changes
• Lichen sclerosus-like skin changes
• Women: vaginal scarring, agglutination (adhesions) of the clitoris/labia
• Men: phimosis, scarring and stenosis of the orificium urethrae

Clinically difficult to separate from the lichen sclerosus-like skin changes is the GvHD-related fasciitis with fibrosis and sclerosis of the affected fasciae with movement restrictions.

To date, no predictive biomarkers are known that could be used to specifically confirm the diagnosis. The chemokines CXCL9 and CCL17 are being discussed (Chen T et al. 2019).

Depending on its clinical findings, cGvHD is divided into a lichenoid and a sclerotic variant. However, both components are frequently expressed. Permanent phenomena are hyperkeratosis and hypergranulosis. There is usually a strong lymphocytic infiltrate with lichenoid vacuolar interface dermatitis and vacuolar degeneration of the basal epidermal and adnexal epithelia. Keratinocyte necrosis in the surface and deep epithelium is accompanied by pigment incontinence. So-called satellite necroses are also typical (see acute graft-versus-host disease below). With increasing duration of the clinical manifestations, fibrotic changes of the dermis occur, which can take on lichen sclerosus-like features, but also those of circumscribed scleroderma or fasciitis.

In the area of the ulcers, it cleans wounds, promotes granulation and is antiseptic, see below wound treatment.

The indication for systemic immunosuppression depends on the extent of organ involvement. At the latest when two organ systems are affected (e.g. skin and liver, skin and intestine, skin and mucous membrane), an immunosuppressive therapy is useful. The therapy belongs in the hands of experienced colleagues.

The chronic GVH reaction is also directed against residual leukemia cells. The aim of therapeutic efforts is therefore not the complete suppression of the GVHR.

In addition to systemic immunosuppressive treatment, the following therapies can be attempted in the treatment of scleroderma, erythematous and/or lichenoid skin changes:

• PUVA therapy, systemic: initial 0.5-0.25 J/cm2 at 0.6 mg/kg bw/day of methoxsalene (e.g. meladinine), dose increase up to 8 J/cm2 over several sessions. Maintenance therapy 1-2 times/week over 1-2 years.
• Thalidomide: Briefly 200-400 mg/day p.o., then reduction to 100 mg/day. Cave! Off-Label-Use! Strictest indication for women of childbearing age.
• Extracorporeal photopheresis: Every 4 weeks, good results are reported. Due to its good tolerability, it is an increasing supplement to systemic steropid therapy, especially since ECP does not negatively influence the graft-versus-leukemia effect and does not increase the risk of infection. In a larger retrospective study of 71 patients with steroid-refractory cGvHD the response rate of cutaneous manifestations was >50% (Flowers ME et al. 2008).
• Regarding the success of TNF alpha antagonists, the results of the study are awaited.

Regular intensive physiotherapy exercises are necessary to improve joint mobility.

Chronic GvHD is the main risk factor for significant morbidity and mortality after allogeneic stem cell transplantation. Approximately 15% of patients die as a result. A further 25% suffer significant impairment of their quality of life. The main risk factor for the occurrence of chronic GvHD is a previous acute GvHD and a high recipient age.

1. Aubin F et al. (1995) Phototherapy in the treatment of cutaneous graft-versus-host disease. Our preliminary experience in resistant patients. Transplantation 59: 151-155
2. Barnes DW, Corp MJ, Loutit JF, Neal FE (1956) Treatment of murine leukaemia with X rays and homologous bone marrow; preliminary communication. Br Med J 32: 626-627
3. Barnes DWH, Loutit JF (1957) Treatment of murine leukaemia with X-rays and homologous bone marrow. Br J Haematol 3: 241-252
4. Chen T et al. (2019) The clinical observation of serum specific biomarkers in patients with chronic graft-versus-host disease. Zhonghua Xue Ye Xue Za Zhi 40: 948-952.
5. Cho A et al. (2020) Cutaneous manifestations of acute and chronic graft-versus-host disease. G Ital Dermatol Venereol 155:76-87.
6. Flowers ME et al. (2008) A multicenter prospective phase 2 randomized study of extracorperal photopheresis for treatment of chronic graft versus host disease. Blood 112: 2667-2674
7. Heney D et al. (1990) Thalidomide in the treatment of graft-versus host disease. Biomed Pharm 44: 99-204
8. Jampel RM et al. (1991) PUVA Therapy for chronic cutaneus Graft-vs-Host-Disease. Arch Dermatol 127: 1673-1678
9. Jung AG et al (2010) Unusual chronic sclerodermiform graft-versus-host disease. Dermatologist 61: 514-517
10. Karrer S (2003) Cutaneous graft-versus-host disease. Dermatology 54: 465-480
11. Lee JH et al. (2003) Graft-versus-host disease (GVHD)-specific survival and duration of systemic immunosuppressive treatment in patients who developed chronic GVHD following allogeneic haematopoietic cell transplantation. Br J Haematol 122: 637-644
12. Müller-Serten B et al. (1994) Chronic sclerodermiform graft-versus-host disease (GvHD). Dermatology 45: 772-775
13. Rupec RA, Plewig G (2004) Graft-versus-host-disease: An interdisciplinary problem from the dermatologist's point of view. JDDG 2: 249-259
14. Travnik R et al (2011) Graft-versus-host-disease (GvHD) - an update. Dermatology 62: 139-155
15. Volc-Platzer B (1992) Graft-versus-host reaction (GvHD). Dermatology 43: 669-675
16. Zampaolo AS et al. (2017) Aggressive skin cancers in patients who experienced chronic GvHD after allogeneic bone marrow transplantation. Bone Marrow Transplant 52: 130-131.
17. Ziemer M et al (2020) Skin manifestations of acute and chronic graft-versus-host disease after allogeneic stem cell transplantation. Dermatology 71:557-568.