Late Appearance of Acute Graft-vs-Host Disease After Suspending orTapering Immunosuppressive Drugs FREE

THE CONSTANT increase of transplantation procedures over the last fewyears has made the follow-up of patients receiving grafts a widespread practicefor many dermatologists. Graft-vs-host disease (GVHD) is the major cause ofmorbidity and mortality after bone marrow transplantation (BMT).

Prophylactic administration of cyclosporine in combination with methotrexateor corticosteroids has been shown to produce a clinically important reductionin acute GVHD without changing the incidence of chronic GVHD.^{1 - 4} The role of tapering or suspending immunosuppressive drugs in the developmentof GVHD has not been completely resolved. The success of cyclosporine therapyin preventing acute GVHD was related to the patient's cyclosporine level inone study,⁵ but was not confirmed in a follow-upstudy.⁶ However, the study by Nash et al⁶ did find a relationship between the onset of acuteGVHD and previous dose reductions of the combined therapy of cyclosporineand methotrexate.

Graft-vs-host disease has traditionally been divided into acute andchronic phases based on time course and clinical and histological features.The initial criterion of 100 days after transplantation for separating acutefrom chronic GVHD has been challenged because the lichenoid rash of chronicGVHD may be observed as early as day 31 after transplantation,⁷ and acute GVHD may persist after day 100 in some cases.⁸ In addition, a recent study indicates that specific histological featuresdo not consistently separate acute from chronic GVHD as defined by days afterBMT.⁹ However, the concept of acute cutaneousGVHD appearing after day 100 is not well established.

We describe 3 patients in whom a rash with clinical and histologicalfeatures of acute GVHD developed, between days 153 and 192 after allogeneicBMT or peripheral blood stem cell transplantation (PBSCT). In all patients,the late flare of acute GVHD occurred after tapering or suspending the immunosuppressiveregimen (a combination of cyclosporine or corticosteroids) and was accompaniedby the stigmata of chronic GVHD in other target organs.

A 27-year-old woman with chronic myelogenous leukemia underwent an allogeneicPBSCT from her sister after preparation with cyclophosphamide therapy andtotal body irradiation. She received GVHD prophylaxis of cyclosporine frompre-PBSCT day 1 on, and intravenous methotrexate infusion on post-PBSCT days1, 3, 6, and 11.

Between post-PBSCT days 17 and 21, she developed acute cutaneous GVHDgrade 2, and acute hepatic GVHD grade 3, which resolved after a short courseof methylprednisolone sodium succinate. On post-PBSCT day 34, prophylaxisfor Pneumocystis carinii with a combination of sulfamethoxazole-trimethoprimwas begun.

The daily dosage of cyclosporine was tapered gradually from post-PBSCTday 59 (6.8 mg/kg of body weight), and was reduced more drastically on day167 (1.4 to 0.7 mg/kg of body weight daily). The concentration of cyclosporinein the patient's serum dropped accordingly from 72 ng/mL on day 157 to 44ng/mL on day 168 and to 16 ng/mL on day 180. On post-PBSCT day 181, a pruriticerythematous macular eruption developed on the anterior thorax, back (Figure 1), arms, and thighs. The rash becamemore intense over the next few days and extended to the patient's forearms,calves, and the dorsal surface of both hands and feet, involving more than50% of the skin surface. Physical examination also revealed reticulate whitelesions on the right buccal mucosa. A skin biopsy specimen showed basal vacuolizationof the dermoepidermal junction, scattered necrotic keratinocytes, moderatespongiosis with occasional vesicle formation, and exocytosis of lymphocytes.The underlying papillary dermis showed a sparse perivascular predominantlylymphocytic infiltrate with occasional eosinophils. The findings were interpretedas a possible drug reaction vs acute GVHD grade 2. A biopsy specimen obtainedfrom the buccal mucosa was consistent with lichenoid GVHD grade 2.

On post-PBSCT day 187, the daily dose of cyclosporine was increasedto 2 mg/kg of body weight. During the next few days the rash became more intenseand extended to the patient's neck and cheeks, and new lesions appeared onthe dorsal surface of both hands and feet, involving 80% of the skin surface.On post-PBSCT day 192, treatment was started with prednisone at a daily doseof 1.7 mg/kg of body weight. A second biopsy specimen showed intense basalvacuolization of the dermoepidermal junction, numerous necrotic keratinocytes,and a perivascular lymphocytic infiltrate in the papillary dermis (Figure 2). The findings were consistent withacute GVHD grade 2.

The treatment with systemic corticosteroids stopped the spread of thecutaneous lesions, which had become confluent (Figure 3), and a gradual diminution of the erythema with subsequentappearance of postinflammatory hyperpigmentation was seen over the next fewdays. Lichenoid lesions on the skin have not been observed at any moment duringthe course of treatment. She also did not develop signs or symptoms consistentwith intestinal or hepatic GVHD. On post-PBSCT day 226, additional erythematousmacular lesions appeared on the patient's face, which extended during thenext 48 hours. On post-PBSCT day 228, treatment with sulfamethoxazole-trimethoprimwas discontinued. The lesions resolved without additional treatment or changein the dosage of the systemic corticosteroids. However, sulfamethoxazole-trimethoprimtherapy was reintroduced on post-PBSCT day 243 without complications.

A 34-year-old woman who had refractory anemia with an excess of blastsunderwent allogeneic BMT from an unrelated donor after preparation with cyclophosphamidetherapy and total body irradiation. She received GVHD prophylaxis with cyclosporinefrom pre-BMT day 1 until post-BMT day 160, and intravenous methotrexate therapyon post-BMT days 1, 3, 6, and 11.

Between post-BMT days 17 and 19, she developed acute cutaneous GVHDgrade 3, intestinal GVHD grade 3, and hepatic GVHD grade 2, all of which resolvedafter treatment with methylprednisolone. The systemic corticosteroid doseswere gradually tapered and suspended on post-BMT day 63. Prophylaxis for P carinii with a combination of sulfamethoxazole-trimethoprimwas started on post-BMT day 56. The daily dosage of cyclosporine was graduallytapered from 5.6 mg/kg of body weight on day 78 to 4 mg/kg of body weighton day 155, was reduced rapidly over the next week, and was discontinued onday 160.

On post-BMT day 192, an erythematous macular eruption developed on thepatient's face, neck, trunk, and arms with involvement of the palms. The rashbecame more intense and confluent over the next few days involving more than50% of the skin surface. Physical examination also revealed several reticulatewhite lesions on the buccal mucosae. A skin biopsy specimen obtained on post-BMTday 197 showed intense basal vacuolization of the dermoepidermal junction,numerous necrotic keratinocytes, and a discrete perivascular predominantlylymphocytic infiltrate with occasional eosinophils in the papillary dermis.These findings were interpreted as acute cutaneous GVHD grade 2.

On post-BMT day 197, treatment was started with prednisone at a dailydose of 1.7 mg/kg of body weight, which resolved the rash. Lichenoid GVHDlesions on the skin have not been observed at any time during the course oftreatment. However, the lesions on the buccal mucosae were recalcitrant; shehas never been free of lesions. A biopsy specimen obtained from the buccalmucosa (on post-BMT day 216) was consistent with GVHD grade 2. On post-BMTday 209, she developed a bilateral keratoconjunctivitis with positive Schirmertest. She did not develop signs or symptoms consistent with gastrointestinalor hepatic GVHD.

A 21-year-old woman with acute lymphoblastic leukemia underwent an HLA-identicalallogeneic BMT from her sister following a preparation with a regimen of cyclophosphamidetherapy and total body irradiation. She received GVHD prophylaxis with cyclosporinefrom pre-BMT day 1 until post-BMT day 60, when the drug treatment was discontinuatedbecause of renal failure.

Between post-BMT days 17 and 21, she developed acute cutaneous GVDHgrade 3 and intestinal GVHD grade 4, which resolved with methylprednisolonetherapy. The treatment with systemic corticosteroids was discontinued on post-BMTday 38 but was reintroduced on day 39 because of a new flare of intestinalGVHD that ceased in 24 hours. Between post-BMT days 39 and 54, she also developedhepatic GVHD grade 1. Although the levels of bilirubin normalized on post-BMTday 59, other liver values remained abnormal.

She received prophylaxis for P carinii withsulfamethoxazole-trimethoprim from post-BMT day 62 on. On day 89, she developedbilateral keratoconjunctivitis with a positive Schirmer test. The daily doseof methylprednisolone sodium succinate was gradually tapered from 1 mg/kgof body weight on day 88 to 0.5 mg/kg of body weight on day 144. On day 151,the daily dosage was rapidly reduced to 0.3 mg/kg of body weight every otherday.

On post-BMT day 153, a pruritic erythematous tenuous macular eruptiondeveloped on the patient's forearms, wrists, and thighs. The rash became moreintense over the next few days and became generalized with involvement ofthe patient's cheeks, pinnae, retroauricular areas, neck, trunk, arms, thighs,and the dorsal surface of both hands with involvement of the palms. The rashaffected 50% to 80% of the skin surface. No lesions were observed on the oralmucosa. A biopsy specimen obtained from the abdomen on post-BMT day 164 wasconsistent with GVHD grade 2.

On post-BMT day 167, the daily dosage of methylprednisolone sodium succinatewas increased to 1 mg/kg of body weight every other day, which resolved therash. Lichenoid lesions have not been observed on the skin, but a physicalexamination on post-BMT day 218 revealed lichenoid lesions in oral mucosae.She did not develop signs or symptoms consistent with gastrointestinal GVHD.However, she developed hepatic GVHD grade 4 and on post-BMT day 240, she diedof hepatic failure. An autopsy liver sample confirmed the diagnosis of chronichepatic GVHD. On post-BMT day 153, treatment with sulfamethoxazole-trimethoprimhad been discontinued because of the rash but was reintroduced on day 181without any cutaneous complications.

Graft-vs-host disease is still divided into acute and chronic formsdefined as number of days after transplantation. Acute cutaneous GVHD usuallypresents as a pruritic erythematous, macular rash around the time of marrowengraftment, generally between post-BMT days 10 and 40.^{10 - 11} Chronic cutaneous GVHD presents as lichenoid skin and/or oral mucous membranelesions, and/or as sclerodermoid skin lesions with poikiloderma and sclerosis,all of which appear usually more than 100 days after BMT.^{10 ,12 - 13} The histological features of acute and chronic GVHD both include a vacuolarinterface dermatitis with a dermal infiltrate of lymphocytes, basal vacuolaralteration, and necrosis of epidermal cells.^{11 ,14} Whereas the added findings of acanthosis, hypergranulosis, hyperkeratosis,and saw-toothed rete ridges are considered diagnostic characteristics of chroniclichenoid GVHD^{9 ,15} the sclerodermoidform is characterized by sclerosis of the dermis with progressive entrapmentand destruction of adnexal structures and less prominent interface dermatitis.^{12 ,16}

Despite the apparent simplicity of the traditional classification ofGVHD into acute and chronic phases defined as number of days after transplantation,this separation is not that precise. The initial criterion of 100 days aftertransplantation for separation into acute and chronic GVHD has been challengedbecause the lichenoid rash of chronic GVHD may be observed as early as day31 after transplantation⁷ and acute GVHD maypersist after day 100 in some cases.⁸ Moreover,a recent study showed that fully evolved histological features of chroniclichenoid GVHD and acute GVHD do not consistently reflect the clinical phaseas defined by number of days after BMT.⁹ Inaddition, atypical variants of cutaneous GVHD have been described that donot fit into this diagnostic classification either. Hyperacute or explosivepresentations of GVHD may be observed after allogeneic transplantations withoutor with insufficient GVHD prophylaxis, which are characterized by severe systemicinvolvement, high mortality, and an erythroderma that evolves from acute tolichenoid within several days of onset with histological features of bothacute and chronic lichenoid GVHD.^{11 ,17 - 18}

Although the criterion of 100 days for separating acute from chronicGVHD has been challenged, the concept of acute cutaneous GVHD appearing afterday 100 (without progression to lichenoid or sclerodermoid GVHD) is not wellestablished. To our surprise, we found only 2 references in the hematologicliterature dealing with this form. One reference mentions the appearance ofacute GVHD several months after BMT on withdrawal of cyclosporine therapyin some patients, but it does not describe the clinical and histological featuresof these patients.¹⁹ A case report describeda patient in whom a clinical syndrome suggestive of acute GVHD developed 236days after BMT and several weeks after remission induction with high-doseintravenous cytarabine.²⁰

We describe 3 patients in whom a rash with clinical and histologicalfeatures of acute GVHD developed between days 153 and 192 after allogeneicBMT or allogeneic PBSCT. In all patients, the rash constituted a recurrenceof acute GVHD, which was accompanied by stigmata of chronic GVHD in othertarget organs and occurred after tapering or suspending the immunosuppressiveregimen of the combination of cyclosporine and corticosteroids. The rashesresolved with treatment with cyclosporine and/or corticosteroids without progressionto lichenoid or sclerodermatous GVHD. The existence of late acute cutaneousGVHD complicates the differential diagnosis of late erythematous eruptionsafter transplantation, which includes chronic lichenoid GVHD, drug hypersensitivityeruptions, sepsis, and viral exanthems as principal alternative options. However,none of these options were likely in our patients.

Our patients had stigmata of chronic GVHD in other target organs, butthe clinical and histological features of the rash were inconsistent withlichenoid or sclerodermoid GVHD at any time. All 3 patients were receivingprophylactic treatment with a combination of sulfamethoxazole-trimethoprimand folic acid at the onset of rash. However, these drugs did not cause theeruption as the rash resolved despite the maintenance of treatment or theirlater reintroduction without producing a rash.

The histological findings of a viral exanthem may be rather nonspecific.There was no serologic or culture evidence of sepsis or infection with herpesvirusor cytomegalovirus in any of the patients at the onset of the rash, and noneof the biopsy specimens showed the typical cytopathic changes of these 2 viruses.

There seemed to be a relationship between the appearance of the rashand previous dose reductions of the GVHD immunosuppressive regimen in patients1 and 3. The rash appeared 14 days after a 50% dose reduction in cyclosporinein patient 1, and during this period the serum levels of cyclosporine haddropped 67%. In patient 3, the rash developed 9 days after a 67% dose reductionin methylprednisolone. However, the relationship was less clear in patient2, as the rash appeared 32 days after suspending cyclosporine therapy. Therole of the tapering or suspending of the immunosuppressive drugs in the developmentof GVHD has not been completely resolved. One study found a significant correlationbetween the serum cyclosporine concentration for a given week and the riskthat acute GVHD would develop during the next week.⁵ However, a follow-up study could not confirm this correlation but did finda relationship between the appearance of acute GVHD and previous dose reductionsof methotrexate and cyclosporine therapy.⁶

Although the prophylactic administration of cyclosporine combined withmethotrexate or corticosteroids has been shown to be beneficial in the preventionof acute GVHD, it has not changed the incidence of chronic GVHD.^{1 - 4 ,21} In our patients, the acute rash appeared after tapering or withdrawal of theimmunosuppressive regimen with cyclosporine or corticosteroids. Reticulatewhite lesions of the buccal mucosae also developed when cyclosporine therapywas tapered or withdrawn in patients 1 and 2. However, bilateral keratoconjunctivitiswith a positive Schirmer test and chronic hepatic GVHD developed despite thetreatment with methylprednisolone in patient 3. In conclusion, the rash ofacute GVHD may be observed as late as 192 days after transplantation, especiallyafter tapering or suspending immunosuppressive drugs, and should be consideredin the differential diagnosis of late erythematous eruptions after transplantation.The time of occurrence is no reliable parameter for the clinical picture ofGVHD, and there may exist overlap cases between acute and chronic lichenoidGVHD.

Accepted for publication July 6, 2000.

Corresponding author: Ruud Valks, MD, PhD, Department of Dermatology,Hospital Universitario de la Princesa, Diego de León 62, 28006 Madrid,Spain (e-mail: agarciad@meditex.es).