Graft-versus-host disease (GVHD) — cutaneous manifestations

Meet the patient

A 42-year-old man is on day 28 after a matched-unrelated-donor stem cell transplant for leukaemia. He arrives with a rising rash that began on his palms and earlobes, now spreading up his trunk, accompanied by cramping diarrhoea and a bilirubin that has crept from 20 to 60. The team that cured his leukaemia now has a new enemy, and it is the donor's immune system.^[1][4]

The two questions that decide his next week are the two that decide every GVHD case: is this acute or chronic, and how severe? (timing plus stage set the whole ladder) and will steroids be enough, or do I need the second-line drug ready? Roughly half do not respond to steroids — so the refractory pathway is not the exception, it is the plan.^[3]

The graft turns on the host — the Billingham three

GVHD can only happen when three conditions line up at once. Memorise them, because the third is the one examiners probe — it is the difference between GVHD and plain transplant rejection.^[19]

1. The graft carries immunocompetent cells — donor T-lymphocytes able to mount a response. (Solid organs come without a T-cell army; stem cell grafts arrive with one.)
2. The host cannot reject them — the recipient is immunocompromised, the conditioning having cleared the native immune system. This is the inverse of solid-organ rejection, where the host attacks the graft.
3. There is histoincompatibility — HLA mismatch, or disparity at minor histocompatibility antigens. This is why even HLA-identical sibling transplants still get GVHD: minor antigens like HA-1 and HY differ.^[5]

The clinician's confession: the conditioning regimen does not just prepare space for the graft — it damages host tissues, releasing danger signals (DAMPs, gut-derived LPS) that prime the very immune attack you are about to fight. The harder the conditioning, the worse the GVHD tends to be. The treatment is also the trigger.^[18] The three-phase cascade of acute GVHD is the mechanism every stem must hang on:^[18]

^[5]

Why skin, gut, and liver? They share rapidly dividing epithelia preferentially injured by conditioning, they express the minor histocompatibility antigens donor T-cells target, and the gut — once breached — leaks LPS that amplifies the whole fire. One broken barrier feeds the next.^[1]

The graft-versus-leukaemia (GVL) balance is the catch examiners love: the same donor T-cells that cause GVHD also clear residual leukaemia. Aggressive T-cell depletion stamps out GVHD and lets the leukaemia back — so the aim is control, never total abrogation. Regulatory T-cells (Tregs) hold the leash; conditioning depletes them, and their slow reconstitution tracks with disease control.^[1]

Acute GVHD — read the rash where it starts

Acute cutaneous GVHD is a graded maculopapular rash that begins acrally — palms, soles, ears — and the acral onset is the single sign that separates it from a drug eruption. Drug rashes are truncal and symmetrical; GVHD creeps in from the edges. That distinction is worth a viva mark every time.^[1][3][4]

The skin stage is the one every candidate reproduces — it tracks the rash from trivial to lethal:^[1]

^[1]

The classic trap: a post-transplant patient on ten drugs gets a truncal maculopapular rash and is labelled "drug eruption." If it started on the palms and soles, and the diarrhoea and bilirubin are climbing too, that triad is acute GVHD until proven otherwise — biopsy it, do not just stop an antibiotic.^[3][4]

The companion organs define the syndrome: gut involvement is anorexia, nausea, watery or bloody diarrhoea, abdominal pain, and ileus (endoscopy with biopsy confirms and excludes CMV and C. difficile); liver involvement is cholestatic, with rising bilirubin and alkaline phosphatase — distinct from sinusoidal obstruction syndrome, which is painful hepatomegaly and weight gain. Onset is typically 2–6 weeks post-transplant; a rash before day 14 is hyperacute GVHD — fulminant and treatment-refractory, with a grim prognosis.^[3]

Chronic GVHD — when the attack turns to fibrosis

Chronic GVHD is a different disease, not a late acute GVHD. The cytokine milieu flips from Th1 cytotoxicity to a Th2/B-cell/TGF-beta fibrotic process — autoimmunity tangled with alloimmunity — and the skin changes from an inflamed rash to lichenoid and sclerodermoid patterns. Roughly 30–70 percent of allogeneic recipients develop it, and it is a leading cause of long-term morbidity, non-relapse mortality, and impaired quality of life.^[1][6][20]

The cutaneous patterns fall into two faces, and the sclerodermoid face is the one that cripples:^[1][6]

• Lichenoid — violaceous, polygonal, flat-topped papules indistinguishable from lichen planus on the wrists, forearms, trunk, and oral mucosa (Wickham-striae-like white reticulate patches). May leave hyperpigmentation and atrophy.
• Sclerodermoid — indurated, bound-down, fibrotic plaques like morphea or systemic sclerosis, localised or generalised. Deep fasciitis produces restricted joint mobility and contractures, peau d'orange skin, and a "groove sign" where superficial veins are buried.
• Poikiloderma, nail dystrophy (pterygium, ridging, anonychia), and scarring alopecia complete the cutaneous picture.^[6]

The sicca flag everyone forgets: dry eyes and dry mouth from lymphocytic destruction of the lacrimal and salivary glands is often the earliest and most disabling chronic GVHD symptom, and it is the one patients suffer in silence. Ask about it; sicca plus oral lichenoid lesions plus genital erosions or vaginal stenosis is the hidden morbidity of this disease.^[1]

The systemic reach is what makes chronic GVHD a multisystem disease, not a skin disease: bronchiolitis obliterans (the lethal lung complication), myasthenia gravis, autoimmune cytopenias, polymyositis, peripheral neuropathy, and oesophageal webs. And the dark late sequel — squamous cell carcinoma of the skin and oral mucosa, at increased risk after chronic GVHD, often multiple and aggressive, demanding lifelong surveillance.^[1][6]

Histopathology — the two signs that close the diagnosis

Skin biopsy is not always needed when the classic triad follows transplant, but two signs confirm it when the picture is ambiguous. In acute GVHD: basal vacuolar degeneration with apoptotic keratinocytes (dyskeratotic cells, Civatte bodies) and lymphocytic satellitosis — lymphocytes sitting beside dying keratinocytes. Severe disease shows full-thickness epidermal necrosis with subepidermal blistering, the TEN-like picture.^[7]

Chronic GVHD mirrors its two faces histologically: a lichenoid band-like lymphocytic infiltrate obscuring the dermo-epidermal junction, or a sclerodermoid pattern of dermal sclerosis with loss of adnexal structures and thickened collagen bundles — indistinguishable from morphea on a blind slide. Deep biopsies of fasciitis show an eosinophilic-fasciitis-like infiltrate.^[7]

Grading — the skin stage is only one column

Overall acute GVHD grade combines skin, liver, and gut, and it is the grade — not the rash alone — that predicts survival. The Glucksberg/IBMTR system is the one to reproduce:^[1][18]

^[1]

Grade IV — any organ at stage 4 — is life-threatening; the skin alone rarely kills, but skin stage 4 with gut or liver failure does. High stool volume predicts poor prognosis independently, which is why severe diarrhoea escalates urgency.^[3]

Chronic GVHD uses the NIH 2025 consensus severity score across eight organs (skin, mouth, eyes, GI, liver, lungs, joints/fascia, genital tract), classifying disease as mild (at most 2 organs, none over score 1, no lung), moderate (at least 3 organs, or any single organ at score 2, or lung score 1), or severe (any organ at score 3, or lung score 2–3). The NIH moved the field past the 100-day clock — chronic GVHD is defined by features, not just timing.^[9]

Acute versus chronic at a glance

The split that earns the marks is the cytokine flip — Th1 cytotoxicity becomes Th2/B-cell fibrosis — and the skin pattern that follows.^[1]

^[1]

The discriminator line: a rash on the palms within six weeks is acute cytotoxic GVHD; lichenoid papules, bound-down skin, and a dry mouth after three months is chronic fibrotic GVHD. The cytokine milieu flips, and so does the morphology.^[1]

Management — steroids first, the refractory pathway ready

Every patient starts with systemic corticosteroids, and roughly half will need more — so plan the second line before you need it. For grade II–IV acute GVHD, methylprednisolone 2 mg/kg/day IV is the standard starting dose (1 mg/kg/day may be tried in milder grade II disease to cut toxicity); response rates run roughly 40–70 percent, and about half of patients ultimately fail steroids. Steroid-refractory disease — progression despite several days of treatment or no response after 5–7 days — calls for ruxolitinib (JAK1/2), validated in the REACH-2 trial (62% vs 39% overall response at day 28 versus best available therapy), with extracorporeal photopheresis, anti-TNF agents, and mesenchymal stromal cells as alternatives.^[3][13][18]

^{[1] [20]}

For chronic GVHD, first-line is prednisone (or prednisolone) 0.5–1 mg/kg/day, often combined with a calcineurin inhibitor for moderate-to-severe disease. Approximately 50 percent of patients respond to initial therapy; the remainder become steroid-refractory (progression on prednisone 1 mg/kg/day beyond a week, or no response on 0.5 mg/kg/day after 4 weeks) or steroid-dependent — and it is this population the three targeted drugs were built for. A fellowship candidate must name each one's class, dose, and trial.^[8][9][20]

The three drugs that carry steroid-refractory chronic GVHD:^[8][20]

^{[10] [11] [12]}

Beyond the three targeted drugs: rituximab (anti-CD20) — in the Dana-Farber phase I/II study of steroid-refractory chronic GVHD, 21 patients treated with 38 cycles achieved a 70 percent response rate confined to cutaneous and musculoskeletal disease, with the median prednisone dose falling from 40 to 10 mg/day over a year; extracorporeal photopheresis (ECP) — leukapheresis with ex vivo 8-methoxypsoralen plus UVA irradiation, given on 2 consecutive days, tapering from weekly to every 2 weeks as disease settles; steroid-sparing and infection-light, used for sclerodermoid and refractory cutaneous disease; mycophenolate mofetil; and low-dose methotrexate for joint and fascia disease.^[8][16]

Organ-specific therapy — systemic alone never controls chronic GVHD

The recurring junior error is to escalate only the systemic drug and leave the sicca, the mouth ulcers, and the lungs untreated. Organ-specific topical, intralesional, and inhaled therapy runs in parallel with the systemic regimen from the start — the NIH 2025 consensus insists on it.^[9]

^{[1] [6] [14] [15]}

Bronchiolitis obliterans deserves its own warning. It is the leading non-cutaneous cause of chronic GVHD death — progressive dyspnoea with an obstructive, irreversibly declining FEV1 — and by the time it is symptomatic the lung is already scarred. The FAM regimen slows but rarely reverses it; recognise and treat early, not late.^[6]

^{[1] [10] [11] [12] [16]}

Prophylaxis — the regimen that sets the risk

Prophylaxis is decided before the transplant and is the single biggest determinant of whether GVHD happens at all. The standard is a calcineurin inhibitor (tacrolimus or cyclosporine) plus short-course methotrexate. Post-transplant cyclophosphamide (PTCy) — with tacrolimus and mycophenolate in the BMT CTN 1703 regimen — beat tacrolimus/methotrexate for GVHD-free, relapse-free survival and is now favoured for haploidentical transplants; it depletes alloreactive T-cells while sparing regulatory T-cells. Ex vivo T-cell depletion (CD34+ selection) cuts chronic GVHD but raised transplant-related mortality in the same platform, an honest trade-off.^[1][14]

Differential diagnosis — the post-transplant rash trap

Three mimics account for most mislabels; the discriminator is distribution plus the accompanying organs.^[1]

• Drug eruption — morbilliform, truncal and symmetrical, from antibiotics or conditioning drugs; temporal relationship to a new drug. Acral onset favours GVHD.
• Viral exanthem — CMV, adenovirus, HHV-6 reactivation post-transplant; often with the virus detectable in blood.
• Morphea or systemic sclerosis — indistinguishable from sclerodermoid chronic GVHD histologically; the transplant history settles it.^[1]

The classic trap: calling Stage IV acute GVHD "TEN from a drug" in a recent transplant. The timing, the acral onset, the rising bilirubin and diarrhoea, and satellitosis on biopsy separate true GVHD from a drug reaction — and the management overlaps (steroids, supportive care) but the prognosis and escalation pathway differ.^[4]

How GVHD patients come to harm — the preventable list

• Stage III–IV acute GVHD read as "a bad drug rash", delaying steroids in a TEN-like dermatological emergency.^[3]
• A chronic sinus or non-healing oral ulcer left unbiopsied in chronic GVHD — squamous cell carcinoma, often metastatic at diagnosis.^[6]
• Sicca syndrome never asked about — corneal scarring and a destroyed mouth from untreated ocular and oral disease.^[1]
• Fasciitis and joint contractures left without physiotherapy and belumosudil — permanent immobility that was preventable.^[6]
• Progressive dyspnoea attributed to "deconditioning" when it is bronchiolitis obliterans — the FAM regimen started too late.^[6]
• A non-irradiated blood product given to an immunocompromised host — transfusion-associated GVHD, fatal in over 90 percent of cases.^[17]
• Steroid-refractory acute GVHD kept on escalating steroids instead of escalating to ruxolitinib (REACH-2).^[13]

Outcomes and prognosis

Severity at grade and steroid responsiveness set survival. Grade I acute GVHD barely dents it; higher grades carry substantial non-relapse mortality, and high stool volume predicts poor prognosis independently. Steroid-refractory acute GVHD historically carried a dismal outlook; in REACH-2, adding ruxolitinib lifted overall response at day 28 to 62 percent versus 39 percent with best available therapy and lengthened median failure-free survival from 1.0 to 5.0 months.^[3][13]

Severity by the NIH scoring system tracks long-term outcome: mild disease carries an excellent prognosis, while severe disease — particularly with bronchiolitis obliterans or steroid-refractory activity — drives late mortality; thrombocytopenia at chronic GVHD onset is an established poor prognostic marker.^[1][9]

Special situations — the ones outside the standard timeline

Hyperacute GVHD (onset before day 14) is fulminant and treatment-refractory with a grim prognosis; consider anti-thymocyte globulin. Engraftment syndrome — fever, rash, weight gain, pulmonary oedema at neutrophil recovery (day 7–14) — mimics acute GVHD but responds to brief corticosteroids. Overlap syndrome carries simultaneous acute and chronic features per NIH criteria.^[1]

Transfusion-associated GVHD (TA-GVHD) is the one to fear outside transplant: viable donor T-lymphocytes engraft in a host who cannot destroy them — classically an immunocompetent recipient of blood from an HLA-homozygous first-degree relative — and attack marrow, skin, gut, and liver; mortality exceeds 90 percent and treatment is largely ineffective. The prevention is absolute: irradiation of cellular blood products for every immunocompromised patient and for all directed family donations (leukoreduction alone does not prevent it). Maternal-fetal GVHD occurs in SCID/Omenn syndrome from engrafted maternal T-cells.^[17]

The mantra, and the memory device

^[1]

The mantra: steroids first, the refractory pathway ready — ruxolitinib for acute, ruxolitinib-belumosudil-ibrutinib for chronic — and never leave the sicca, the mouth, or the lungs untreated.^[1][3]

Ward-round test — three stems, thirty seconds each

Stem 1 — the day-28 transplant rash (answer)ShowHide

A man on day 28 after a matched-unrelated-donor transplant has a rash that began on his palms and earlobes, now on his trunk, with diarrhoea and a bilirubin of 60. What is it, and what is the first step? Model: This is acute GVHD, Stage II–III — the acral onset plus diarrhoea and cholestasis after transplant is the classic triad; acral onset distinguishes it from a drug eruption. Confirm with skin biopsy (basal vacuolar change, apoptotic keratinocytes, lymphocytic satellitosis) if there is doubt, exclude CMV and C. difficile in the stool, and start methylprednisolone 2 mg/kg/day IV. Grade overall severity across skin, liver, and gut. Have ruxolitinib (REACH-2) ready, because about half are steroid-refractory.^[3][4][13]

Stem 2 — the changing oral ulcer (answer)ShowHide

A patient with five years of chronic lichenoid GVHD has an oral leukoplakic plaque that has ulcerated and will not heal over two months. Next step? Model: Urgent biopsy to exclude squamous cell carcinoma — chronic GVHD skin and mucosa carry an increased SCC risk, often multiple and aggressive. Do not keep dressing it or attributing it to a flare. Stage with imaging, involve head-and-neck surgery and oncology, and tighten photoprotection and surveillance. Lifelong full-skin and oral surveillance is mandatory for every chronic GVHD survivor.^[6]

Stem 3 — sclerodermoid chronic GVHD failing steroids (answer)ShowHide

A patient with sclerodermoid chronic GVHD and progressive joint contractures is still worsening on prednisone 1 mg/kg/day plus tacrolimus after eight weeks. What now, and why this drug? Model: Declare steroid-refractory chronic GVHD (progression on prednisone 1 mg/kg/day beyond a week, or no response on 0.5 mg/kg/day after 4 weeks) and escalate. For sclerodermoid disease where fibrosis dominates, belumosudil 200 mg once daily is a logical targeted choice — ROCK2 inhibition rebalances Th17/Treg via STAT3/STAT5 (ROCKstar: best ORR 74 percent after 2–5 prior lines). Ruxolitinib 10 mg BD and ECP are alternatives; add urgent physiotherapy to prevent permanent contracture. Never leave the fasciitis untreated while you escalate only the systemic drug.^[12][20]

References20ShowHide

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