Scleroderma is a condition in which chronic inflammation and immune effects in the tissue lead to fibrotic changes caused by excess collagen and potentially vascular damage in the skin.1,2 These immunologic changes lead to a hardening and thickening of various depths of the skin, which may have profound effects on a patient’s quality of life and requires complex medical management.1,2 Scleroderma is a potential presentation of chronic graft-versus-host disease (GVHD) of the skin seen in approximately 20% to 30% of patients who develop chronic GVHD.1-3
Several examples are available in the literature regarding how GVHD of the gut may affect the absorption of various oral medications, by increasing or decreasing absorption of the medication, depending on the specific pathologic process occurring during GVHD.4-7
No data are available in the literature on whether similar processes in cutaneous GVHD may alter the absorption of topically administered medications. Situations may arise, such as severe mucositis or bowel conditions, in which patients can no longer take oral medications and alternate routes of medication administration may be required.
Scleroderma could potentially alter the efficacy and/or increase the risk for toxicity of topically administered medications, including transdermal patches. Several articles have shown that the inflammatory processes in acute GVHD may increase the absorption of topical medications, such as tacrolimus or steroids, but no articles have addressed the effects of fibrotic changes.4-8
We discuss a case of a patient with GVHD-induced scleroderma who had rebound hypertension after conversion from oral to transdermal clonidine during presentation for a small bowel obstruction.
A 63-year-old Caucasian male was approximately 3 years post–matched-related donor allogeneic stem-cell transplant (ASCT) for acute myeloid leukemia, the use of a nonmyeloablative regimen of fludarabine with single-fraction total body irradiation. The initial GVHD prophylaxis was use of tacrolimus plus mycophenolate. The patient has been followed for continual management of mild chronic GVHD (score 1), including scleroderma of the lower leg, abdomen, and upper arms.
The patient did not have documented issues for acute GVHD, and approximately 9 months posttransplant he started to display signs or symptoms of chronic GVHD, including sclerotic changes of the hands, mouth, and feet. His condition initially improved with topical steroids, but eventually required restarting of systemic treatment with tacrolimus for approximately 1 year.
Five months after tapering off tacrolimus for the initial episode, the patient had worsening scleroderma in the lower extremities, as well as new sclerodermatous changes in the upper arms and abdomen. These lesions were managed with various interventions over the course of the subsequent year, including systemic corticosteroids, tacrolimus, sirolimus, extracorporeal photopheresis, methotrexate, and, most recently, ibrutinib. He also applied topical triamcinolone cream twice daily to the affected areas. Because of his status, ibrutinib was discontinued at admission, as discussed below.
The patient presented to the emergency department with symptoms suspicious of a small bowel obstruction and was admitted to the hospital; he was given a nothing-by-mouth (NPO) status in context of the complete bowel obstruction. At the time of admission to the hospital, the patient was receiving a hypertensive regimen that included amlodipine 10 mg daily and clonidine 0.1 mg twice daily. He had been receiving oral clonidine for several years for his concomitant hypertension, which was the only medication that adequately controlled his hypertension.
At the time of his admission, the patient was only receiving 1 medication (ie, prednisone) that could contribute to his hypertension; no other medications contributed to blood pressure issues at the time of his admission. At admission, he was transitioned to a 0.2-mg daily clonidine patch so that he could be placed on an NPO status. The patient’s last dose of oral clonidine was taken the morning of admission; however, because of his NPO status, he was unable to have the recommended cross-titration from oral to patch.9 It is unknown whether his bowel obstruction had any effect on the absorption of his previous oral medication dosing.
Within 48 hours of the change to the patch, the patient had rebound hypertension, with blood pressures elevated to 160-180 mmHg systolic and 90-100 mmHg diastolic, including heart rate elevations as high as 150 beats per minute, but typically residing at the 90 beats per minute range. In addition, he began having frontal headaches without focal neurologic findings. He started a trial of intravenous (IV) hydralazine, initially at 10 mg every 8 hours, increased to 20 mg every 8 hours after 3 days, which resulted in modest response (range, 130-140 mmHg systolic, 80-99 mmHg diastolic), but he had no change in the headaches. The pharmacist then noticed that his clonidine patch was placed on his outer left upper arm, which was one of the locations of his scleroderma.
Despite the relatively mild grade (ie, grading score 1) of scleroderma, concern arose about potential absorption issues of the patch. However, moving the patch to the inner arm from the outer arm, increasing the dosing to 0.3 mg daily, and continuing treatment for 3 weeks did not lead to improvements in his symptoms. With continued hypertension, elevated heart rate, and headaches while receiving intermittent hydralazine, a trial of IV metoprolol was initiated, first at 2.5 mg every 6 hours, which was increased to 5 mg every 6 hours because of lack of response after 2 days, in an effort to control his blood pressure and headaches. After 1 week of therapy, it was determined that his symptoms were not responsive to metoprolol.
His blood pressure showed a modest response, similar to the initiation of hydralazine therapy, but no improvement was seen in his headaches. The patient required approximately 4 mg to 5 mg of IV hydromorphone and IV acetaminophen, because his headaches were unresponsive to other interventions.
One week after his initial admission, the patient was taken to surgery for correction of the unresolving small bowel obstruction. After successful postsurgery removal of the nasogastric tube, the patient was transitioned back to his oral medications, including clonidine. Within 48 hours of restarting oral clonidine, the majority of his blood pressure measurements were reduced to the 120-140 mmHg systolic and 70-80 mmHg diastolic range, and his headaches resolved. The use of an opiate was reduced slowly, as the patient was able to tolerate his postsurgical pain.
This case presented an interesting question about the effect of scleroderma-type cutaneous GVHD on topical medication absorption. Our thorough literature search in PubMed, which included the search terms “clonidine,” “transdermal,” “absorption,” “scleroderma,” and “rebound,” revealed no information on the impact of the thickening effects of scleroderma on transdermal medication absorption.
Olson and colleagues discussed GVHD increasing absorption of tacrolimus cream, as assessed by therapeutic drug monitoring; however, the authors did not describe the type of cutaneous GVHD, noting that inflammatory changes leading to changes in skin permeability were likely the associated cause.8 This indicates a potentially alternate inflammatory rather than fibrotic cutaneous process, which may be different from the process seen in our patient.
Clonidine is well-known to cause rebound effects, including hypertension, headache, and increased heart rate, as a result of adrenergic overactivity with abrupt withdrawal.9-11 This phenomenon has been known for many decades, without much recent research on the topic of management. One study examined the management of this effect by using a combination of oral alpha and beta blockers,10 and another article examined the use of IV labetalol to manage the hyperadrenergic state of adrenergic blocker withdrawal.11 However, neither of these studies addressed the ability to manage the rebound headache, which may be mediated by the alpha-2 activity of clonidine.10,11
Given that we were only able to control our patient’s blood pressure with clonidine, it is logical that, in combination with the different mechanisms of action, IV metoprolol and hydralazine would not adequately control his blood pressure. It is also known that alpha-2 activity has pain management–related effects, because of the presence of alpha-2 receptors in the brain that clonidine may positively modulate.12
This raises the question whether the use of labetalol in this patient would have had any benefit for his headaches. It is also known that clonidine oral-to-patch conversion is complicated, because of the lack of equivalent dosing between the routes of administration, and because the patch takes 2 to 3 days to achieve therapeutic levels.9
Our patient used the clonidine transdermal patch for more than 2 weeks, with no demonstrated change in headaches and only modest blood pressure control, despite an increase in the dose. According to the pharmacologic properties of the patch, the patient should have reached steady state within 3 days of patch application.9
Based on this information, his medical team believed that he received the adequate duration of therapy to assess the benefit if the patch were being absorbed properly. In addition, because the patient’s symptoms resolved within a few days of restarting oral clonidine, the potential effect of scleroderma on patch absorption was further scrutinized by the medical team.
This case raises important concerns about the potential for inadequate absorption of transdermal medications in patients with fibrotic skin changes related to GVHD post-ASCT. Further studies are needed to confirm the pharmacokinetic and pharmacodynamic effects of fibrotic skin changes, such as scleroderma, but caution should be used in relying on transdermal absorption for medications with narrow therapeutic indices in this patient population.
Author Disclosure Statement
Dr Mancini, Ms Hooker, and Dr Kreisle have no conflicts of interest to report.
- Shreberk-Hassidim R, Neumark M, Greenberger S, et al. Cutaneous chronic graft versus host disease following allogeneic haematopoietic stem cell transplantation in children: a retrospective study. Acta Derm Venereol. 2018;98:206-211.
- Prieto-Torres L, Boggio F, Gruber-Wackernagel A, Cerroni L. Nodular sclerodermatous chronic cutaneous graft-versus-host disease (GvHD): a new clinicopathological variant of cutaneous sclerodermatous GvHD resembling nodular/keloidal scleroderma. Am J Dermatopathol. 2017;39:910-913.
- Inamoto Y, Storer BE, Petersdorf EW, et al. Incidence, risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease. Blood. 2013;121:5098-5103.
- Pogue JM, DePestel DD, Kaul DR, et al. Systemic absorption of oral vancomycin in a peripheral blood stem cell transplant patient with severe graft-versus-host disease of the gastrointestinal tract. Transpl Infect Dis. 2009;11:467-470.
- Grigg AP, Brown M, Roberts AW, et al. A pilot study of targeted itraconazole prophylaxis in patients with graft-versus-host disease at high risk of invasive mould infections following allogeneic stem cell transplantation. Bone Marrow Transplant. 2004;34:447-453.
- Chin A, Pergam SA, Fredricks DN, et al. Evaluation of posaconazole serum concentrations from delayed-release tablets in patients at high risk for fungal infections. Antimicrob Agents Chemother. 2017;61:pii:e00569-17.
- Tonini J, Thiébaut A, Jourdil JF, et al. Therapeutic drug monitoring of posaconazole in allogeneic hematopoietic stem cell transplantation patients who develop gastrointestinal graft-versus-host disease. Antimicrob Agents Chemother. 2012;56:5247-5252.
- Olson KA, West K, McCarthy PL. Toxic tacrolimus levels after application of topical tacrolimus and use of occlusive dressings in two bone marrow transplant recipients with cutaneous graft-versus-host disease. Pharmacotherapy. 2014;34:e60-e64.
- Sica DA, Grubbs R. Transdermal clonidine: therapeutic considerations. J Clin Hypertens (Greenwich). 2005;7:558-562.ica DA, Grubbs R. Transdermal clonidine: therapeutic considerations. J Clin Hypertens (Greenwich). 2005;7:558-562.
- Reid JL, Campbell BC, Hamilton CA. Withdrawal reactions following cessation of central alpha-adrenergic receptor agonists. Hypertension. 1984;6(5 Pt 2):II71-II75.
- Mehta JL, Lopez L. Rebound hypertension following abrupt cessation of clonidine and metoprolol: treatment with labetalol. Arch Intern Med. 1987;147:389-390.
- Giovannitti JA Jr, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. 2015;62:31-38.