Adverse drug reactions and graft-versus-host reaction: unapproved treatments

Adverse Drug Reactions and Graft-Versus-Host Reaction: Unapproved Treatments VINCENZO RUOCCO, MD GUIDO SACERDOTI, MD PIETRO FARRO, MD ELEONORA RUOCCO, MD RONNI WOLF, MD

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utaneous reactions are among the most frequent side-effects of drug intake. They encompass a wide range of clinical patterns such as macular or maculopapular rashes, urticaria, eczematous or lichenoid lesions, fixed drug eruptions, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The strongest data to establish accurate estimates of rates of cutaneous reactions to drugs come from prospective collected data in population-based studies that monitor large number of patients and capture all adverse events that occur. Despite differences in the design of epidemiologic studies, there is remarkable agreement in the results. Because most drug-induced eruptions appear within the first week after the drug therapy is started, attributing an eruption to a specific drug is often straightforward but it becomes particularly difficult when the patient is taking multiple drugs.1 In this case epidemiologic studies can be extremely helpful in assessing the likelihood that a certain drug is responsive for that eruption. The most frequent (rashes, urticaria) and the most severe (Stevens-Johnson syndrome, toxic epidermal necrolysis) cutaneous drug reactions are considered here.

Rashes and Urticaria Macular rashes and urticaria account for more than 95% of skin reactions to drugs.2 Macular rashes usually have an acute, relatively short duration, and in the child a basic coexistent infection may play a role. On the conFrom the Department of Dermatology, Second University of Naples, School of Medicine and Surgery, Naples, Italy; the Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy; and the Dermatology Unit, Kaplan Medical Center, Rehovot, Israel. Address correspondence to Vincenzo Ruocco, MD, Department of Dermatology, Second University of Naples, Via S. Pansini, 5, 80131, Naples, Italy. E-mail address: [email protected] © 2002 by Elsevier Science Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010

trary, urticaria often follows a chronic course, which raises management problems when the patient cannot interrupt the use of the offending medication. This is the case of some NSAIDs, trimethoprim-sulfamethoxazole (TMP-SMX), ACE inhibitors, insulin, and allopurinol treatments. If several drugs can induce “ex novo” urticarial eruptions, an exceedingly large amount of common medications can provoke relapsing of a dormant chronic urticaria (even after many years of remission), especially in patients suffering from dermographism. Dermographism concerns 5% of the population and in about 3% of cases urticaria is caused by medication. Very little is known about the natural course of chronic urticaria. In a cohort study spontaneous remission occurred in approximately 47% of the patients within 1 year after referral.3 If reaching an etiological diagnosis is often difficult, treatment can be even more troublesome and frustrating. In addition to the conventional anti-H1 receptor antagonists and corticosteroids, some protocols include calcium-channel antagonists (eg, nifedipine), ␤2-adrenergic agonists (eg, terbutalin4), heparin,5 leukotriene modifiers,6 sulfasalazine,7 but their efficacy is far from being proved in drug-induced urticaria. There are only anecdotal data on the use of immunosuppressive agents such as methotrexate or cyclosporin in patients with chronic urticaria who are either unresponsive to steroids or require inordinate dosage. Plasmapheresis, IV gamma globulin, or other specific anti-inflammatory regimens can be considered but should be limited to properly controlled trials.8 A tentative list of non conventional therapies for urticaria, whether drug-induced or not, includes: acupuncture, homeopathy, hypnosis, phytotherapy, and psychotherapy.9 Controlled trials are still lacking and the question is whether many of these unconventional treatments can be reproducible.10 In selected patients, short-term psychotherapy can be the treatment of choice. Our experience suggests that in many cases of drug-induced urticaria, drug-fear is the main inducing 0738-081X/02/$–see front matter PII S0738-081X(02)00289-4

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factor. If this is the case, an empathic therapeutical partnership is the most effective strategy. In urticaria induced or elicited by aspirin and other NSAIDs, avoidance of the offending drug is mandatory. Alternative molecules, such as nimesulide or the selective anti-COX-2s, can be tested. They are usually well tolerated. When taking aspirin is absolutely necessary, antileukotrienes seem to have some efficacy in prevention of adverse events.

Is Desensitization Still an Unapproved Treatment? In case of drug allergy, it is a rule to recommend the exclusion of the suspected medicine and molecules of the same family or those having a similar structure.11 If alternative drugs are clearly less effective, or induce unacceptable side-effects, cautious administration of the “culprit” drug may be considered using a premedication regimen with antihistamines or steroids. An ultimate, not completely standardized alternative is drug desensitization, which should be employed in peculiar situations, such as need for penicillin in pregnant women with syphilis or need for TMP-SMX in HIV-infected patients at risk for Pneumocystis Carinii infection. Desensitization is supposed to prevent IgEmediated reactions only, but it is worth noting that some of the tested drugs (eg, aspirin) do not induce specific IgE. Desensitization is reversible, depending on the continuous presence of the drug. Despite desensitization has been proposed since the fifties,12 the putative immunologic mechanisms involved are not completely elucidated yet. A generic protocol for drug desensitization encompasses several steps: skin test, baseline monitoring of patient in intensive care setting, defining the starting dose, route of administration, dosing interval, dose escalation, and follow-up.13 Desensitization protocols employ an initial oral or parenteral administration at very low doses (1:10.000 of the conventional dose), which are usually doubled every 15–30 minutes. Full therapeutic doses are achieved within 4 – 8 hours. Longer intervals are frequently needed for aspirin desensitization. Acute desensitization protocols have been used in patients with reactions to penicillin, sulfonamides, aminoglycosides, clindamycin, cephalosporins, vancomycin, pentamidine, insulin, antitubercular agents, heterologous sera, deferoxamine, carbamazepine, heparin, corticotropin, D-penicillamine, chemotherapeutic agents, aspirin. A variety of desensitization protocols have been used for reintroducing TMP-SMX, dapsone, and other antimicrobials to reactive patients with AIDS. Hypersensitivity reactions to TMP-SMX are 10 to 50 times more frequent in HIV-infected patients than in other patients, prompting changes in therapy in up to 57% of individuals. Cutaneous eruptions show as generalized, maculopapular, often intensely pruritic rashes that de-

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velop 8 –12 days after initiating therapy, reach maximal intensity 1–2 days later, and sometimes disappear after 3–5 days despite continuing treatment. A rash is regarded as “severe” if involves mucous membranes, blisters, or causes intolerable itch. In this case discontinuation of TMP-SMX therapy is indicated. Anaphylaxis, cytopenia, transaminase elevations, Stevens-Johnson syndrome, and toxic epidermal necrolysis rarely occur. Given the advantages of TMP-SMX, protocols of graded challenge with this drug have been introduced, ranging in total duration from 4 hours to 26 days. Tolerance can often be induced safely, with an overall success rate varying from 33–100%.14 Anyway, these efforts have been directed at inducing tolerance in patients with history of late-onset morbilliform eruptions. That morbilliform eruptions can be desensitized by non-IgE-dependent mechanism is possible, but there is as yet no demonstration of this. Estimates of insulin allergy range from 5–10%. Local urticarial and papular reactions almost always disappear in 3– 4 weeks with continued insulin administration. Occasionally, they will persist and may precede a systemic reaction. Generalized urticaria, angioedema, bronchospasm, and hypotension are very rare. Several desensitization protocol schedules have been proposed to cope with insulin allergy.15 The list of drugs candidate for desensitization is increasing. Recently, the efficacy and safety of oral desensitization to NSAIDs16 and to allopurinol in the managenent of patients with hyperuricemia and allopurinol-induced maculopapular eruptions have been assessed.17

Severe Bullous Drug Reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe, often life-threatening, bullous adverse drug reactions of the skin and mucous membranes, which belong to a wide spectrum of disease with different degrees of severity. In fact, transitional forms of SJS/TEN, showing features of SJS or TEN simultaneously or subsequently in the same patient, are not exceedingly rare. The crucial point of management is supportive care (fluid and electrolyte replacement) and accurate prevention/treatment of infection. In other words, patients suffering from SJS/ TEN have to be treated symptomatically like extensively burned patients. The administration of systemic corticosteroids is disputed. The main arguments raised in favor of their use are the immunologically mediated pathogenesis of SJS/TEN and the numerous reports with positive outcomes attributed to the administration of steroids,18 in particular using dexamethasone pulse therapy.19 The use of glucocorticoids, however, may be detrimental. In fact, because of their very broad range of immunosuppression, high dose glucocorticoids in-

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crease the risk of catastrophic bacterial infection in patients who already have severely disrupted natural barriers to bacteria and impaired innate immune systems. Septicaemia is actually the main cause of deaths in TEN patients.20 This major concern has discouraged the use of corticosteroids and spurred a continued search for alternative treatments. They include cyclosporin, cyclophosphamide, pentoxifylline, IVIg, plasmapheresis, application of special biologic, synthetic, or medicamentous dressings, hyperbaric oxygen.

Cyclosporin Although the immunopathogenesis of TEN has not been fully explained, there is a large body of evidence suggesting a cell-mediated cytolytic process. An initial disturbance in drug metabolism or detoxification, causing antigenic alteration of keratinocytes, may trigger a cell-mediated immune response, influenced by a peculiar histocompatibility leukocyte antigen (HLA) haplotype. Antigen-specific cytotoxic lymphocyte proliferation occurs with CD8 lymphocytes targeting and destroying the antigenically altered keratinocytes. Theoretical advantages for the use of cyclosporin in this setting include its more selective actions blocking proliferation of activated and cytotoxic T-lymphocytes and reduction in intercellular adhesion molecule-1 (ICAM-1) expression on activated keratinocytes.20 The relatively selective immune modulatory actions of cyclosporin may only increase the risk of viral, fungal, and intracellular bacterial infections and temporarily reduce the cancer surveillance, but none of these drawbacks would usually be important in its short-term use for TEN. Therefore, cyclosporin appears to selectively target the immunologic changes seen in TEN without adversely increasing the risk of the main causes of morbility and mortality in TEN patients.20 Several cases of TEN were successfully treated with cyclosporin in conjunction with corticosteroids.20 –24 The dosages of cyclosporin ranged from 3–10 mg/kg/ die. In one case23 cyclosporin demonstrated to be effective as a monotherapy at the dose of 4 mg/kg/die. In another case22 the drug alone halted a relapse of the disease at the dose of 5 mg/kg/die. Taken together, these observations suggest that TEN can be beneficially affected by cyclosporin therapy. In particular, cyclosporin, while allowing to decrease detrimental dosages of corticosteroids, could be considered as treatment of choice in the early phase of TEN to arrest primary immunopathological processes.24

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treating SJS/TEN patients, cyclophosphamide may be effective as it prevents the proliferation of cytotoxic T cells responsible for epidermal necrosis.25,26 In fact, immunophenotyping studies demonstrated a marked decrease of CD8 lymphocytes infiltrating the epidermis following cyclophosphamide therapy.25 Management of SJS/TEN patients with cyclophosphamide, given IV at the daily dose of 100 –300 mg, in associations with glucocorticoids25 or alone,26 resulted in rapid cessation of blistering and in clinical improvement. Interestingly, these patients responded rapidly to cyclophosphamide doses that are lower than those necessary in other immune-mediated diseases such as lupus erythematosus or pemphigus.26

Pentoxifylline The hemorheologic drug pentoxifylline has been shown to have a marked effect on cellular mediators of inflammation and tissue injury. In particular, it inhibits both T-cell adherence to keratinocytes and cytokine production derived from macrophages and keratinocytes, such as tumor necrosis factor alpha (TNF-␣), interleukin-1 (IL-1), and interleukin-6 (IL-6).27 Indeed TNF-␣ has been found in the blister fluid of TEN and is believed to be partially responsible for the keratinocyte damage leading to the epidermal necrolysis.28 The use of IV pentoxifylline at the dosage of 12–15 mg/kg/day in SJS/TEN patients proved to be a satisfactory treatment.29,30 Pentoxifylline showed its beneficial effect repeatedly by curing relapses of TEN29 or SJS,30 previously stabilized with the same drug.

Human Intravenous Immunoglobulin (IVIG) An early morphologic feature of TEN is keratinocyte apoptosis, a type of cell death which precedes epidermal detachment. Apoptosis can be triggered by interaction between a cell-surface death receptor such as Fas and its respective ligand (FasL or CD95L).31 Keratinocytes from TEN patients express a lytically active FasL responsible for Fas-mediated apoptosis.31 Specific blockade of Fas with IVIG preparations containing specific anti-Fas antibodies has shown great promise in the treatment of TEN.31,32 In an open, uncontrolled pilot study, 10 patients with TEN were given IVIG at doses ranging from 200 –750 mg/kg/day for four consecutive days. The progression of skin disease was promptly halted in all 10 patients within 24 – 48 hours, with subsequent rapid re-epithelialization, a favorable vital outcome, and without significant side-effects.31

Cyclophosphamide Cyclophosphamide was originally developed to treat cancer but, because of the observation that it was cytotoxic to dividing lymphocytes, was subsequently regarded as an immunosuppressive agent as well. In

Plasmapheresis The usefulness of plasma exchange has been reported in several cases of TEN.33–35 The rationale of this treatment lies in removing a part of the offending drug or its

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metabolites, along with cytotoxic factors or inflammatory mediators leading to epidermal necrolysis. One to three 3-L plasma exchanges were effective in producing rapid improvement in TEN patients at the early advancing stages of epidermal sloughing.33,35 Membrane-based plasma exchange proves to be particularly effective in removing strongly protein-bound drugs with a long half-life and a small volume of distribution; however, if the offending drug is also strongly bound to tissue receptors (eg, phenytoin), its plasma concentration may rebound to pretreatment levels soon after the exchange is completed.34 Plasmapheresis has not negligible complications. Moreover, obtaining vascular access in the presence of large areas of denuded skin may be difficult, and the access site is a potential source of infection as well.34

Dressings Wound care is a vital aspect of TEN treatment, but controversy exists on how best to manage the vast cutaneous lesions. For example, silver sulfadiazine cream has traditionally been considered the topical treatment of choice, but it has fallen out of favor because of reports of associate leukopenia and the frequent implication of sulfonamides as etiologic agents of TEN.34 Once the extension of the necrolytic process has ceased, accurate debridement of necrotic tissue, which can harbor bacteria, and application of biologic or synthetic dressings, which decrease pain, inhibit fluid loss, improve thermal regulation, reduce the risk of sepsis, and possibly enhance re-epithelialization, are recommended by the majority of specialized intensive care units or burn centers, which usually face the great problems raised by denuded dermis.18,34 Lately, however, a new silver-nitrate impregnated dressings, originally designed for burn victims, has proved to be very effective in treating SJS/TEN patients.36 This dressing can repeatedly be impreganted with 0.5% silver nitrate solution and allows for a moist wound-healing environment. Partially fitted, it can be left in place for 2–3 days, which prevents further damage to the skin and decreases the labor required.

Hyperbaric Oxygen In our experience, a therapeutical procedure particularly apt to cope with the crucial problem of denuded dermis, which is the chief pathogenic factor leading to fatal complications in TEN (hypovolemic shock, severe electrolyte imbalance, sepsis), is hyperbaric oxygen (HBO) treatment.18,37,38 In fact, HBO is known to promote necrotic tissue sloughing, enhance dermal vascularization, reduce re-epithelialization time, and have an antiseptic effect.18,34 Taken together, these actions exactly meet the main therapeutic needs for TEN patients. Although limited to few patients and uncontrolled,

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our clinical experience with HBO in TEN confirmed the theoretical expectations. The treatment was performed in a pressure chamber with pure oxygen at 2 atm (203 kPa) for 60 –120 minutes daily. Re-epithelialization occurred quickly in all patients and was complete after 8 –12 treatments. No side effects or adverse reactions were noted during any treatment and follow-up periods.37,38 Confirmation of the efficacy of HBO in the management of TEN will of course require a controlled multicentric clinical trial.

Graft-versus-Host Reaction (GVHR) Graft-versus-host disease (GVHD) is a clinical syndrome where immunocompetent cells from a donor (graft) attack the tissues of an immunosuppressed histoincompatible recipient (host). The most common setting for GVHD is bone marrow transplantation for leukemia, aplastic anemia, or immune defects. Graftversus-host reaction (GVHR) refers to the expression of GVHD in a specific organ such as the skin (cutaneous GVHR). There are two forms of cutaneous GVHR: the acute form, occurring between 1 week and 3 months after transplantation, and the chronic form, which occurs after 3 months. The acute form shares clinical, histologic and immunologic features with TEN.39 The chronic form is traditionally divided into lichenoid and sclerodermoid forms.

Acute GVHR The incidence of acute GVHR has been reduced by the prophylactic use of cyclosporin, methotrexate and prednisolone, and in particular by combination of these drugs. Another approach to the prophylaxis of this condition has been the donor’s T cell depletion by using anti-T cell receptor antibodies40,41 or administration of monoclonal antibodies directed against host released cytokines, such as tumor necrosis factor ␣42,43 or interleukin-2.44 Intravenous IgG (500 mg/kg weekly to day 90, then monthly to day 360 after transplantation) has also been claimed to decrease the risk of acute GVHD,45 but the value of this treatment awaits confirmation. In any case, the antimicrobial effect of this unapproved therapy may help the management of frequently associated infections. Lately, a promising therapeutic option for acute GVHD refractory to steroids and cyclosporin has been offered by combination treatment with tacrolimus (0.025 to 0.1 mg/kg/d) and antithymocyte globulin (ATGAM: 15 mg/kg for 5 days).46 Extracorporeal exposure of peripheral blood mononuclear cells to the photo-sensitizing compound 8-methoxypsoralen (8-MOP) and ultraviolet A radiation (extracorporeal photochemotherapy or photopheresis) has been shown to be effective and safe in the treatment of both

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acute and chronic GVHD.47 The procedure, consisting of infusion of UVA irradiated autologus peripheral blood mononuclear cells collected by apheresis and incubated with 8-MOP, was carried out on two consecutive days every 2 weeks for the first 3 months and thereafter every 4 weeks until resolution of GVHD. Complete remission of skin lesions was achieved in 4-6 patients with acute GVHD. The remainder had partial remission. The only side effect was a reversible decrease in peripheral blood neutrophil counts during the first cycles of treatment. The mechanism whereby extracorporeal photopheresis works benefit in GVHD may depend on its inducing apoptosis in lymphocytes.48 It has been hypothesized that the procedure enhances the apoptotic process leading to deletion of graft reactive cells after tolerance induction by donor bone marrow.47

Chronic GVHR Chronic GVHD mainly involves the skin and the liver, but oral immunosuppressive therapy (corticosteroids, cyclosporin and azathioprine in various combinations) is routinely used because the disease is considered to be systemic. The use of thalidomide, as an immunomodulating agent, has been documented in several case reports and small series showing a favorable response.49,50 The drug was started at a dose of 100 mg po four times a day and, if no side effects were encountered, was escalated to 200 and 300 four times a day. Complete or partial remission was obtained in about 20% of patients, however a high incidence of reversible side effects (sedation, constipation, neuritis, and neutropenia) limited dose intensity and possibly reduced the number of patients who could benefit from treatment.50 Pentoxifylline, a xantine derivative capable of downregulating tumor necrosis factor ␣ production, may help to prevent GVHD. Patients enrolled at increasing dosages (1200 to 2000 mg/d) from day ⫺10 through day ⫹100 post-transplant experienced less mucositis than controls.51,52 Theoretically, this hemorheologic drug may also be beneficial in the treatment of the sclerodermoid form of cutaneous GVHR, when cutaneous ischemia due to severe sclerotic change results in erosion and ulceration.53 Etretinate is also receiving attention as a possible treatment of this form.53 Photochemotherapy (PUVA) has been reported as successful to some extent in controlling skin lesions of the lichenoid form of cutaneous GVHR.54,55 Interestingly, in the older trial,54 oral lesions never exposed to PUVA healed in one patient and improved in another. In the more recent report,55 intra-oral GVHR was treated with PUVA by means of a glass fiber extension. Like in the acute form, extracorporeal photochemotherapy (or photopheresis) is a safe and effective adjunct therapy also in the chronic form of GVHD. Complete remission of skin lesions was

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obtained in 12 of 15 patients, while oral lesions regressed in 11 patients of the same series.47 Besides inducing apoptosis in lymphocytes,48 PUVA disrupts the mechanism by which keratinocytes receive the signal to synthesize class II antigens, a process most likely mediated by the lymphokine gamma interferon (IFN␥). IFN-␥ may be inactivated by UV-induced cytokines, or its release by activated T cell may be blocked after UV-induced numeric reduction of putative IFN-␥-synthesizing cells.54 Taken togheter, these data can explain the beneficial effects of both PUVA and photopheresis in the management of chronic cutaneous GVHR. Unapproved topical treatments of cutaneous GVHR include cyclosporin in solution as a mouthwash or a potent corticosteroid as an inhaler (Becotide威) for oral erosive lichenoid lesions;56 a potent topical steroid ointment (Eumovate威) for phimosis or localized chronic GVHR elsewhere;56 halofuginone, an inhibitor of collagen alpha 1 (I) gene expression, in ointment for the sclerodermoid form;57 and 0.1% tacrolimus ointment for treating erythematous and itching lesions of steroid-refractory, chronic cutaneous GVHR.58

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48. Enomoto DN, Schellekens PT, Yong SL, et al. Extracorporeal photochemotherapy (photopheresis) induces apoptosis in lymphocytes: a possible mechanism of action of PUVA therapy. Photochem Photobiol 1997;65:177–80. 49. Vogelsang GB, Farmer ER, Hess AD, et al. Thalidomide for the treatment of chronic graft-versus-host disease. N Engl J Med 1992;326:1055–8. 50. Parker PM, Chao N, Nademanee A, et al. Thalidomide as salvage therapy for chronic graft-versus-host disease. Blood 1995;86:3604 –9. 51. Bianco JA, Appelbaum FR, Nemunaitis J, et al. Phase I-II trial of pentoxifylline for the prevention of transplantrelated toxicities following bone marrow transplantation. Blood 1991;78:1205–11. 52. Ferra C, de Sanjose S, Lastra CF, et al. Pentoxifylline, ciprofloxacin and prednisone failed to prevent transplantrelated toxicities in bone marrow transplant recipients and were associated with an increased incidence of infectious complications. Bone Marrow Transplant 1997;20: 1075–80.

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