Cutaneous Graft-Versus-Host Disease (Graft-Versus-Host Disease)
Are You Confident of the Diagnosis?
Allogeneic hemopoietic stem cell transplantation (AHSCT) is a therapeutic tool that is being used with increasing frequency. The number of centers that perform AHSCT and the number of transplant patients is rising, with more than 20,000 transplants performed yearly worldwide. The main complication of AHSCT is the development of graft versus host disease (GVHD). The result is an increased exposure of dermatologists to these patients in their clinics.
GVHD is divided into two forms: acute GVHD and chronic GVHD.
Acute GVHD (AGVHD) usually appears in the first 2 to 6 weeks after the transplant, but cases of late AGVHD are more frequent with the increased use of nonablative AHSCT. AGVHD is similar to a drug eruption. It has five target organs: skin, gastrointestinal tract, liver, lung, and lymphoid tissue. AGVHD is similar to a drug eruption. The dermatological clinical spectrum is from morbilliform exanthema to epidermal necrolysis (
Acute GVHD with some erosions suggesting evolution to stage IV.
Chronic GVHD (CGVHD) usually occurs a few months after the transplant, but may happen earlier in patients after a second (or more) AHSCT, or after donor lymphocyte infusions. It is similar to an autoimmune connective tissue disease. CGVHD may occur as a progression from active AGVHD, quiescent (when there is a disease-free interval between AGVHD and CGVHD) and de novo (in patients without previous AGVHD).
The target organs for CGVHD are the skin, liver, eyes, upper respiratory tract, esophagus, lower gastrointestinal tract, and skeletal muscle. Dermatologically, CGVHD is divided into two clinical forms: lichenoid GVHD, which appears early in the evolution (
Lichenoid chronic GVHD.
What you should be alert for in the history
In AGVHD, the skin is often the first and most commonly involved organ. The patient may have a prodrome of an itchy and burning sensation, followed by a maculopapular exanthem that appears at 2-6 weeks after the AHSCT. Hyperacute GVHD appears in the first 14 days, but always after engraftment has commenced; while late AGVHD may be observed as late as 192 days after AHSCT.
AGVHD may begin on the pinnae, cheeks, lateral neck, upper back, and palms and soles. The erythematous macules may coalesce to cover the whole body. Eventually, the skin desquamates and leaves postinflammatory pigmentary changes.
Extracutaneous involvement includes:
- Liver (second most affected organ)—jaundice, pruritus
- Gastrointestinal (GI) tract (third most affected organ)—anorexia, nausea, vomiting, abdominal pain, and diarrhea. Rarely, paralytic ileus and intestinal bleeding; the patient presents with an acute abdomen
- Lungs—cough with hemoptysis, shortness of breath, and chest pain
- Hematolymphoid organs—increased risk of serious infections
- Heart—clinically expressed by bradycardia
CGVHD is the most common complication after transplantation, described in 60%-80% of patients. Lichenoid CGVHD appears before the first year in more than 50% of the patients. Sclerodermatous lesions usually appear after day 500 following AHSTC.
Extracutaneous manifestations include:
- Ocular symptoms—burning, irritation, and pain due to xerophthalmia
- GI tract—xerostomia, diarrhea, dysphagia, odynophagia, and weight loss
- Liver—cholestatic symptoms such as jaundice and pruritus
- Lungs—wheezing, dyspnea, and chronic cough that is unresponsive to bronchodilator therapy
Characteristic findings on physical examination
The general condition will depend on the stage of GVHD. Maculopapular exanthem with early lesions centered on hair follicles (clue to the diagnosis) is the most common presentation. Sometimes the exanthem may evolve into erythroderma (stage III). Approximately 2% of cases develop vesicles, epidermal necrosis with positive Nikolsky sign, and general erythroderma, resembling toxic epidermal necrolysis (stage IV disease).
Other rare forms include scarlatiniform, varicelliform, and ichthyosiform eruptions.
Extracutaneous clinical signs will depend on the organ involved. The severity of AGVHD is graded by measuring skin, liver, and gastrointestinal involvement.
The stages of AGVHD are summarized in
The stages of AGVHD.
|Organ||Stage I||Stage II||Stage III||Stage IV|
|Skin||Maculopapular rash involving 25% of the body||Maculopapular rash involving 25%-50% of the body||Generalized erythroderma||Toxic epidermal necrolysis appearance|
|Bilirubin levels (umol/L)||34-51||51-101||101-256||>256|
|Diarrhea||500-1000mL/day||1000-1500mL/day||>1500mL/day||>2000mL/day or severe abdominal pain with or without diarrhea|
The physical findings of CGVHD depend on the clinical form.
Lichenoid CGVHD presents with lichen-planus-like lesions. These may include erythematous or violaceous papules or plaques, sometimes able to form larger confluent areas. They are usually not well-defined. The periorbital region, ears, axillae, and flexures (especially axillary and inguinal regions) are the most commonly affected sites. In some cases, lichenoid papules can occur around hair follicles. Lichenoid CGVHD can also affect the nails and the genital organs.
Sclerodermatous CGVHD presents with lichen sclerosus, morphea, fasciitis, and systemic scleroderma-like lesions. These may include indurated sclerotic shiny white-yellow plaques of poorly defined contours, usually with the early development of patchy hyperpigmentation or a poikilodermatous patches. Although more common on the abdomen, and the proximal and inner parts of the limbs, the lesions may cover the limbs, thorax, neck, and head.
The severity of CGVHD is graded on the extent of skin and other organ involvement following the criteria from the National Institutes of Health consensus.
Expected results of diagnostic studies
Diagnosis is based on the history and physical examination in a bone marrow transplant recipient, supported by histopathology.
In AGVHD, the histopathological findings have been classified into four grades, according to the epidermal damage:
Grade I—Focal or diffuse vacuolar degeneration of the basal cell layer. Mild spongiosis with exocytosis of lymphocytes and lymphocytes surrounding a necrotic keratinocyte (satellitosis)
Grade II—Eosinophilic degeneration (dyskeratosis) of epidermal or follicular keratinocytes
Grade III—Subepidermal cleft or microvesicle formation (see
Histopathology changes in GVHD (H&E): vacuolar degeneration of the basal cell layer, subepidermal clefting, dyskeratosis, exocytosis.
Grade IV—Complete dermo-epidermal separation (TEN-like histology).
In CGVHD, the findings depend on the clinical forms:
Lichenoid GVHD—histology similar to classic lichen planus: hyperkeratosis, hypergranulosis, acanthosis, and dyskeratotic keratinocytes with basal vacuolar change. Sometimes, sawtoothed rete ridges and dermal melanophages are found. A bandlike infiltrate along the dermal-epidermal junction, occasionally extending to the deep dermis, is essential for the diagnosis, as basal vacuolar changes are a common, long-lasting finding in patients after AHSCT.
Sclerodermoid GVHD—histology indistinguishable from other forms of sclerosis, including lichen sclerosus, morphea, and systemic sclerosis. It may involve the dermis and subcutaneous tissue, and may affect the fascia. The normal tissue is replaced by thick sclerotic collagen fibers and hyalinization of the collagen occurs with loss of the appendage structures.
Drug reactions are mainly due to conditioning chemotherapy in early stages. They could be related to any medication when it appears later in the evolution.
There is a need to combine evaluation of histopathological findings with the clinical presentation to reach a diagnosis. The absence of an inflammatory infiltrate or the presence of eosinophils would suggest a drug reaction, while the presence of hair follicle damage or satellitosis would make the diagnosis of GVHD more likely. It is most difficult to distinguish between toxic epidermal necrolysis and stage IV AGVHD.
- Palmoplantar erythrodysesthesia syndrome can be distinguished only by its clinical presentation: acral dysesthesia, followed by tender erythematous swelling of the palms and soles, which can be bullous, erosive, or ulcerating. It is a frequent and localized side effect related to antineoplastic chemotherapies, most commonly doxorubicin, doctaxel, fluorouracil, and cytarabine.
Histology will show a toxic keratinocyte reaction with sub-basal edema, a tendency to bullae, dilated blood and lymph capillaries, and usually only a mild perivascular lymphocytic infiltration.
Palmoplantar erythrodysesthesia syndrome appears early after the AHSCT due to conditioning therapy. Treatment includes cold compresses or baths.
- Eruption of syringometaplasia develops in patients with AHSCT treated with high-dose chemotherapy regimens. Eruption begins within 2-39 days of initiation of chemotherapy. Well-defined elevated erythematous macular areas develop on the axillae, groin, palms, and soles, and discrete papular lesions form on the trunk or extremities.
Histology will show syringometaplasia. Eruption is asymptomatic and resolves spontaneously without scarring in 7-10 days.
- Toxic epidermal necrolysis is a severe exfoliative adverse drug reaction that is characterized by fever with rapid and extensive epidermal necrolysis. Skin eruptions begin as poorly defined erythematous macules with darker purpuric centers that tend to coalesce and form blisters, leading to extensive epidermal necrosis and detachment. Distribution is usually symmetrical, primarily affecting the face and upper trunk, with mucosal involvement in up to 90% of patients.
The histology will show necrotic keratinocytes and confluent epidermal necrosis with vacuolar alteration of the dermoepidermal junction and subepidermal blisters.
Clinically, toxic epidermal necrolysis may be indistinguishable from stage IV or hyperacute GVHD.
Herpes viruses have a tendency to remain latent in the body after primary infection and periodically reactivate in immunocompromised hosts, including patients after AHSCT.
Infection with herpes simplex virus may occur 1-2 weeks after transplantation, while cytomegalovirus (CMV) infection tends to occur at a median of 38 days after transplantation.
Cutaneous manifestations of viral infections are variable and often indistinguishable from GVHD. Human herpes virus 6 can cause cutaneous symptoms by itself or favor the development of cutaneous AGVHD. Herpes simplex virus may induce erythema multiforme-like lesions in the early days after AHSCT.
Other skin findings include maculopapular eruption, petechiae, vesicullobullous lesions and ulcerations involving the oropharynx and genital tract. Cutaneous disease is a rare manifestation of reactivated CMV, EBV or parvovirus B19 disease but they should be considered.
Clinicopathological correlation is important, as herpes viruses persistently infect peripheral blood mononuclear cells. Measurement of viral load by real-time polymerase chain reaction (PCR) can distinguish between latent and active viral infections.
Changes of acute or chronic radiodermatitis following AHSCT are unusual because of the lower doses of irradiation used in conditioning regimens.
Engraftment syndrome was first described in patients after autologous hemopoietic stem cell transplantation and after ablative chemotherapy without transplant at the time of neutrophil recovery. It is characterized clinically by fever, rash, and pulmonary injury. Bone marrow engraftment usually occurs between days 12 and 13 after AHSCT.
The clinical findings for engraftment syndrome are very similar to AGVHD. The speed of neutrophil recovery has been seen to be predictive of engraftment syndrome. Major criteria include a temperature greater than 38°C with no identifiable infectious etiology, erythematous exanthem involving more than 25% of body surface area, pulmonary edema, and hypoxia. This eruption usually responds well to corticosteroids.
Differential diagnoses for CGVHD include drug reactions, viral infections, chronic dermatitis, systemic autoimmune diseases (systemic lupus erythematosus, scleroderma, Sjögren's syndrome, rheumatoid arthritis, polymyositis, dermatomyositis), and lichen planus in lichenoid GVHD.
Systemic sclerosis is in the differential for sclerodermatous GVHD. Histologically, they are indistinguishable, but there is no Raynaud's phenomenon, no Scl-70/anticentromere antibodies, and patients do not present with an edematous phase before the sclerosis in CGVHD.
Who is at Risk for Developing this Disease?
GVHD occurs when immunocompetent donor lymphocytes become sensitized by recipient antigens and react against tissue of the immunosuppressed host.
Requirements of GVHD (Billingham 1966) are that the graft must contain immunologically competent cells, the tissue antigens of the recipient differ from those of donor, and the recipient is immunocompromised.
This condition appears in patients after allogeneic stem cell transplantation. It may occur after solid organ transplantation if a sufficient number of donor cells are in the transplanted organ.
Risks for AGVHD include:
HLA mismatch donor
Matched unrelated donor
Sex-mismatch with donor being female
Older age of donor or recipient
Diagnosis of chronic myeloid leukemia
Increased number of AHSCT procedures
Use of total body radiotherapy
Use of prophylactic treatments other than cyclosporine and methotrexate
More than one stem cell transplant
High IL-3 (Th2 cytokine) levels in donor
Polymorphism of cytokine genes
Ineffective GVHD prophylaxis
Risks for CGVHD include:
Past history of AGVHD, especially greater than grade II
Increased donor or recipient age (age greater than 20 years)
Lack of T cell depletion of the donor stem cells
Female donor to male recipient (previous donor pregnancies)
Transfusion of donor buffy coat
Use of blood stem cells
TBI as conditioning regimen
What is the Cause of the Disease?
The pathophysiology of AGVHD is divided into three phases:
Conditioning regimen causes tissue damage to the intestinal mucosa (with translocation of microbial products to the circulation) and liver, which leads to activation of host cells and release of inflammatory cytokines. These cytokines upregulate major histocompatibility complex antigens, thus enhancing their recognition by donor T cells.
Donor T cells reactivate and proliferate in response to host antigens, fueled by the inflammatory cytokines.
Activated monocytes secrete interleukin (IL-1) and tumor necrosis factor (TNF)-alpha, which leads to tissue damage. In addition, cytotoxic T cells and natural killer cells cause more damage.
Pathophysiology of CGVHD
Chronic GVHD is the result of autoreactive T cells, from donor-derived stem cells. Donor lymphocytes mature in the host thymus and some host-reactive T cells escape from the elimination mechanisms, resulting in persistent alloreactive and autoreactive T-cell clones. These immune dysregulations result in immunodeficiency and autoimmunity. Most patients have evidence of B cell dysregulation with a high prevalence of autoantibodies.
Systemic Implications and Complications
Cutaneous GVHD is usually part of a syndrome with multi-organ involvement, although there are cases of pure cutaneous acute or chronic GVHD.
Complications of generalized erythroderma (stage III) and toxic epidermal necrolysis-like disease (stage IV) include temperature dysregulation, electrolyte imbalance, protein-losing enteropathy, increased risk of infection, high cardiac output failure, paralytic ileus, GI tract involvement, diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, and bronchiolitis obliterans organizing pneumonia.
Mortality is up to 50% in moderate to severe cases of AGVHD.
Complications are due to pigmentary changes, ulcerations, sclerosis with joint retraction and diminished mobility, strictures in the ano-genital area, and pain.
Poor prognostic factors include older age, resistant disease, persistent thrombocytopenia, hyperbilirubinemia, lichenoid histologic findings, and inability to achieve a response after 9 months of therapy.
Skin severity score is independently associated with the risk of nonrelapse mortality (HR 5.2) and with overall mortality (HR 3.4).
Treatment options in GVHD are an active area of research, as no optimal treatment has been found and morbidity and mortality due to the procedure is relatively high. Most patients will develop multisystemic diseases that require management by multidisciplinary teams.
Treatment focuses on prevention, minimization of risk factors, and the use of AGVHD prophylaxis. A calcineurin inhibitor plus methotrexate or mycophenolate mofetil is the recommended GVHD prophylaxis. Other modalities have been proposed, including total lymphoid irradiation, sirolimus, maraviroc (a CCR5 inhibitor), bortezomib, or vorinostat. New regimens are being developed and tested worldwide in clinical trials.
For systemic disease, supportive treatments include:
Reverse isolation, intensive care
Skin care (avoid soaps, maintain cutaneous hygiene, minimize the use of topical antiseptics, liberal applications of emollients)
Antimicrobial prophylaxis (antibiotics, antifungals, antivirals)
Other treatments include:
Monoclonal antibodies (anti-TNF, anti-IL-2 receptors, anti-CD52, anti-IL6 receptor, anti-CD20)
Monoclonal antibody conjugates (Denileukin diftitox, brentuximab vedotin)
Expanded mesenchymal stromal cells
Extracorporeal photophoresis (ECP)
For cutaneous involvement, topical corticosteroids (medium- to high-potency triamcinalone 0.1% or clobetasol cream or ointment), emollients (50% emulsifying ointment, liquid paraffin), type B ultraviolet light (broad or narrow band), psoralen and ultraviolet light (PUVA), ECP, or systemic treatment as used in systemic disease.
For systemic disease, treatments include:
For cutaneous involvement, treatment depends on the clinical form.
For lichenoid CGVHD, treatments include:
Topical medium- to high-potency corticosteroids
PUVA, UVB (broad or narrow band)
Systemic immunosuppressive treatment
For sclerodermatous CGVHD, treatments include:
High-potency topical corticosteroids
Optimal Therapeutic Approach for this Disease
Treatment of CGVHD should always be discussed by a multidisciplinary team. They are led by hematologists and include other medical, and sometimes surgical, specialties. Patients usually have multisystemic disease and develop a wide variety of side effects.
It is critical in AGVHD to reach a consensus in the diagnosis of the disease. This usually takes place in an acute/subacute setting, often with only clinical information and minimal laboratory or pathology results. Frequently, therapy is started before a definitive diagnosis can be reached. It is important to exclude infections and drug reactions as causes for the disease.
For systemic disease, the main treatment is to increase the immunosuppressive treatment, initially with corticosteroids. Second-line treatment or salvage therapy is started if disease progresses after 3 days, if there is no change after 7 days, or if the response is incomplete after 14 days of corticosteroid therapy.
As a first-line therapy, add or increase systemic corticosteroids (up to 2 mg/kg/day of methylprednisolone). Combine a second-line therapy if the patient is already getting high doses of prednisone.
As a second-line therapy, use cyclosporin (10 mg/kg, maintain serum levels 150-300 ng/mL), tacrolimus (0.12-0.15 mg/kg/day, maintain serum levels 5-10 ng/mL), sirolimus (4-5 mg SQM daily, maintain serum levels 7-12 ng/mL), mycophenolate mofetil (1-3 g/day), or anti-thymocyte globulin (ATG) (5-30 mg/day of horse ATG or 1-5 mg/kg of rabbit ATG for 5 days).
Third Line For Refractory Cases
For third-line therapy, use monoclonal antibodies, Anti-TNF-alpha (infliximab, etanercept), anti CD25 (daclizumab, basiliximab), anti CD-3 (OKT3, visilizumab), anti-CD52 (alentuzumab), alefacept, denileukin diftitox, anti CD147 (ABX-CBL), desferoxamine mesylate, pentostatin, brentuximab vedotin, ECP. Expanded mesenchymal stromal cells may also be used.
Limited Skin Disease
For limited skin disease, use topical corticosteroids (medium-high potency) such as methylprednisolone aceponate, bethametasone dipropionate, or clobetasol. Systemic steroids (as in systemic AGVHD), other immunosuppressants, ECP, PUVA, and UVB (broad or narrow band) may also be used.
For systemic disease, a combination of corticosteroids (1 mg/kg) and cyclosporine (10 mg/kg, maintain serum levels 150-300 ng/mL) is the recommended first line of therapy.
Tacrolimus(0.075-0.15 mg/kg, maintain serum levels 5-10 ng/mL), sirolimus (4 mg loading dose followed by 2 mg/day, maintain serum levels 7-12 ng/mL), and mycophenolate mofetil (0.5-3 g) are recommended as second line.
Salvage therapy includes ECP, pentostatin, thalidomide, etanercept, infliximab, rituximab, etretinate, ketotifen, and pentostatin.
For limited skin disease in CGVHD, treatment depends on the clinical form.
For lichenoid CGVHD, use topical medium- to high-potency corticosteroids such as methylprednisolone aceponate, bethametasone dipropionate, or clobetasol. Use systemic immunosuppressive treatment (as in systemic disease), ECP, phototherapy (PUVA or UVB [broad or narrow band]). Increased risk of progression to sclerodermatous disease has been reported.
For sclerodermatous CGVHD, use topical high-potency corticosteroids (clobetasol or betamethasone dipropionate in optimized vehicles), systemic steroids and cyclosporin (systemic immunosuppressive treatment as used in systemic disease), methotrexate, imatinib, azathioprine, etretinate, ECP, PUVA, bath PUVA (or UVA1), or thalidomide.
A multidisciplinary team should manage patients.
Patients with AGVHD are usually inpatients, and should be reviewed very often to assess clinical changes.
Patients with CGVHD are followed in outpatient clinics. Regular follow-ups (every 4-8 weeks) are required to assess clinical changes. Involvement of other organs (joints, eyes, liver, lungs, gut, etc.) should be assessed on a regular basis.
Unusual Clinical Scenarios to Consider in Patient Management
Clinicians must be mindful of the differential diagnosis of acute GVHD prior to establishing this diagnosis.
It has been suggested that systemic corticosteroid therapy should be started as soon as possible, regardless of the histopathology result.
What is the Evidence?
Penas, PF, Zaman, S. "Many faces of graft-versus-host disease". Australas J Dermatol. vol. 51. 2010. pp. 1-10.(This comprehensive review provides a synopsis of clinical manifestations of acute, lichenoid, and sclerodermatous phases of GVHD with a look at the current evidence surrounding its differential diagnosis and the new manifestations of GVHD.)
Ringden, O, Le Blanc, K. "Allogeneic hematopoietic stem cell transplantation: state of the art and new perspectives". APMIS. vol. 113. 2005. pp. 813-30.(This review describes established state-of-the-art stem cell transplantation. Some new developments include peripheral blood stem cell compared to bone marrow enhanced engraftment and the role of reduced conditioning.)
Ferrara, JL, Deeg, HJ. "Graft-versus-host disease". N Engl J Med. vol. 324. 1991. pp. 667-74.(This article outlined the mechanism of GVHD and proposed that future attempts at prophylaxis and treatment will target specific subsets of immunocompetent donor cells.)
Penas, PF, Fernandez-Herrera, J, Garcia-Diez, A. "A dermatologic treatment of cutaneous graft-versus-host disease". Am J Clin Dermatol. vol. 5. 2004. pp. 403-16.(This article reviews the effect of different therapies in the cutaneous manifestations of GVHD. It emphasizes that dermatologists should be deeply involved in the diagnosis and treatment of GVHD.)
Holtan, SG, Pasquini, M, Weisdorf, DJ. "Acute graft-versus-host disease: a bench-to-bedside update". Blood. vol. 124. 2014. pp. 363-373.(Treatment of acute GVHD remains a clinical challenge. This paper reviews new treatments.)
Arora, M. "Therapy of chronic graft-versus-host disease". Best Pract Res Clin Haematol. vol. 21. 2008. pp. 271-9.(This paper summarizes the treatment of the chronic phase of GVHD.)
Filipovich, AH, Weisdorf, D, Pavletic, S. "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. vol. 11. 2005. pp. 945-56.(A coordinated effort to promote new diagnostic criteria and staging techniques to improve clinical research in CGVHD.)
Shulman, HM, Kleiner, D, Lee, SJ. "Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. Pathology working group report". Biol Blood Marrow Transplant. vol. 12. 2006. pp. 31-47.(A review of the histologic changes in CGVHD.)
Jacobsohn, DA, Vogelsang, GB. "Acute graft versus host disease". Orphanet J Rare Dis. vol. 2. 2007. pp. 35.(Updated information about AGVHD from diagnostic criteria and etiology to management and prognosis.)
Lee, SJ. "New approaches for preventing and treating chronic graft-versus-host disease". Blood. vol. 105. 2005. pp. 4200-6.(This review covers potential new approaches to the prevention and treatment of CGVHD based on a better understanding of the immunoregulation.)
Sundram, U. "A review of important skin disorders occurring in the posttransplantation patient". Adv Anat Pathol. vol. 21. 2014 Sep. pp. 321-9.(Good review of the histopathological changes in GVHD and differential diagnoses.)
Zhang, L, Chu, J, Yu, J, Wei, W. "Cellular and molecular mechanisms in graft-versus-host disease". J Leukoc Biol. vol. 99. 2016 Feb. pp. 279-87.(Update of the pathogenic mechanisms in AGVHD.)
Tong, LX, Worswick, SD. "Viral infections in acute graft-versus-host disease: A review of diagnostic and therapeutic approaches". J Am Acad Dermatol. vol. 72. 2015 Apr. pp. 696-702.(Review of viral infections after AHSCT.)
Garbutcheon-Singh, KB, Fernandez-Penas, P. "Phototherapy for the treatment of cutaneous graft versus host disease". Australas J Dermatol. vol. 56. 2014 Oct 10. pp. 93-9.(Review of phototherapy as treatment for GVHD.)
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