0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Observation |

Systemic Toxicity Following Administration of Sirolimus (Formerly Rapamycin) for Psoriasis:  Association of Capillary Leak Syndrome With Apoptosis of Lesional Lymphocytes FREE

Mariana J. Kaplan, MD; Charles N. Ellis, MD; Zsuzsanna Bata-Csorgo, MD; Ross S. Kaplan, MD; Judith L. Endres, BS; David A. Fox, MD
[+] Author Affiliations

From the Departments of Internal Medicine (Drs M. J. Kaplan and Fox and Ms Endres) and Dermatology (Drs Ellis and Bata-Csorgo), University of Michigan Medical School, Ann Arbor; and the Department of Dermatology (Dr R. S. Kaplan), University of California-Irvine.


Arch Dermatol. 1999;135(5):553-557. doi:10.1001/archderm.135.5.553.
Text Size: A A A
Published online

ABSTRACT

Background  Sirolimus (formerly rapamycin) is an immunosuppressive agent that interferes with T-cell activation. After 2 individuals with psoriasis developed a capillary leak syndrome following treatment with oral sirolimus, lesional skin cells and activated peripheral blood cells were analyzed for induction of apoptosis.

Observations  A keratome skin specimen from 1 patient with sirolimus-induced capillary leak syndrome had a 2.3-fold increase in percentage of apoptotic cells (to 48%) compared with an unaffected sirolimus-treated patient with psoriasis (21%). Activated peripheral blood T cells from patients with psoriasis tended to exhibit greater spontaneous or dexamethasone-induced apoptosis than did normal T cells, particularly in the presence of sirolimus.

Conclusions  Severe adverse effects of sirolimus include fever, anemia, and capillary leak syndrome. These symptoms may be the result of drug-induced apoptosis of lesional leukocytes, especially activated T lymphocytes, and possibly release of inflammatory mediators. Because patients with severe psoriasis may develop capillary leak from various systemic therapies, clinical monitoring is advisable for patients with inflammatory diseases who are treated with immune modulators.

Figures in this Article

PSORIASIS MAY be caused by pathogenic blood-derived immunocytes inducing secondary activation and disordered growth of keratinocytes and vascular endothelium.1,2 Psoriatic lesions contain activated CD4+ T helper cells.3,4 T-lymphocyte clones from lesional skin release growth factors that induce keratinocyte proliferation.5 Adhesion molecules and other skin cell activation markers are up-regulated in the skin of patients with psoriasis.68 T cells in psoriasis exhibit a TH1-like cytokine secretion profile.9,10 Serum interleukin 2 (IL-2) and IL-2 receptor (IL-2R) levels are elevated in patients with chronic plaque psoriasis.11,12

Sirolimus (formerly rapamycin) is a macrolide immunosuppressant that interferes with T cells by impairing the activation response to lymphokines IL-2, IL-4, and IL-12.1315 Sirolimus prevents allograft rejection16 and shows suppressive activity in experimental models of autoimmune diseases.13,17

Although the immunosuppressive activity of sirolimus is commonly attributed to its antiproliferative effect on lymphoid cells, the drug affects a number of other cellular functions.18,19 Sirolimus inhibits proliferating cell nuclear antigen (PCNA) expression, thereby blocking the cell cycle in the G1 phase in human keratinocytes,20 and selectively blocks IL-2–induced PCNA gene expression in T lymphocytes.21 Sirolimus also blocks the activation of p70 S6 kinase, thus preventing a downstream cascade of events critical for cell growth.22

Inhibition of signal transduction may play an important role in the susceptibility of cells to apoptosis. Programmed cell death has been induced by sirolimus23,24 in many but not all malignant cell lines.25

We report 2 cases of systemic capillary leak syndrome characterized by clinical signs of vascular leakage with fever and anemia in patients with psoriasis after oral administration of sirolimus. We hypothesized that sirolimus might trigger this systemic toxic reaction by inducing programmed cell death in activated T cells in psoriatic skin lesions and blood. Lesional cells and activated peripheral blood T cells from patients with psoriasis and healthy controls were therefore studied for evidence of induction of apoptosis by sirolimus.

METHODS

As part of a phase I pharmacokinetic clinical trial at the University of Michigan, Ann Arbor, 6 patients with psoriasis (including patient 1 in the "Results" section) received 3, 5, or 8 mg/m2 body surface area per day of oral sirolimus. Keratome skin biopsy specimens from the hip or buttock area of these patients were taken before treatment (day 0), 2 days into treatment, and on the seventh day of treatment. Patients had used neither systemic immunosuppresives for at least 4 weeks nor systemic retinoids, corticosteroids, or phototherapy for at least 3 weeks before entry into the study. Patient 2 participated in a subsequent study at the University of California-Irvine (similar skin biopsy specimens were not obtained). All procedures were approved by each institution's internal review board, and informed consent was obtained from each subject.

DNA STAINING OF DERMAL CELLS

Keratome specimens were placed into a neutral protease solution (Dispase; Collaborative Research Inc, Boston, Mass) for overnight incubation at 4°C. The dermis was separated from the epidermis and a single-cell suspension was prepared using collagenase, hyaluronidase, and deoxyribonuclease.26 Cells were fixed in 70% ethanol and stained with propidium iodide (PI), 50 µg/mL, plus RNAse, 100 U/mL for DNA content. Flow cytometry was performed using a flow cytometer (Epics Elite; Coulter Cytometry, Hialeah, Fla). Light scatter (forward and 90°) was used to gate out debris. Cell aggregates were eliminated from the DNA analysis based on the ratio of integrated to peak fluorescence of PI. Listmode data were analyzed using Elite software (Coulter Cytometry, version 2.4) and for cell-cycle analysis, Modfit (Verity Software House Inc, Topsham, Me, version 2.0).

CULTURE OF PERIPHERAL BLOOD LYMPHOCYTES AND DETECTION OF APOPTOSIS

Peripheral blood was obtained from 5 healthy volunteers (mean age, 32 years; age range, 19-50 years) and 4 patients with psoriasis (mean age, 52 years; age range, 40-57 years). Three of the patients had no adverse effects consistent with capillary leak syndrome, and the fourth was patient 1; the blood from patients was obtained 3 to 5 months after they had stopped sirolimus treatment. Peripheral blood mononuclear cells were isolated by centrifugation over Ficoll-Hypaque and washed 3 times. Peripheral blood mononuclear cells were cultured in medium (RPMI 1640 supplemented with 10% fetal bovine serum, 2% glutamine, 1% penicillin/streptomycin) and phytohemaglutinin (0.5 µg/mL), at a concentration of 1 × 106 cells per milliliter. At day 3 or 4 and every 3 to 4 days thereafter, cells were washed and resuspended in lectin-free medium (1 × 106 cells per milliliter) supplemented with IL-2 (10-20 U/mL). At day 14 to 18 of culture, cells were washed and subcultured for 18 hours in medium alone, IL-2 (20 U/mL), dexamethasone (10−5 mol/L), sirolimus (1, 10, 25, or 100 nmol/L), or combinations of these agents. The cells were fixed in 1% formaldehyde for 15 minutes at 4°C, washed with phosphate-buffered saline (PBS), and permeabilized with 70% ethanol.

DNA strand breaks associated with apoptosis were detected by flow cytometry.27 DNA was labeled with biotinylated deoxyuridine triphosphate using exogenous terminal deoxynucleotidyl transferase, and the incorporated biotinylated deoxyuridine triphosphate was detected by fluoresceinated avidin. Concurrent staining with PI was also done to allow determination of position in the cell cycle of apoptotic cells, and to detect cells with a subdiploid amount of DNA.27 For such experiments, 1 million cells were resuspended in 0.05 mL of cacodylate buffer (0.2 mol/L potassium cacodylate, 25 mmol/L tris-hydrochloride [pH 6.6], 2.5 mmol/L cobalt chloride, 0.25 mg/mL bovine serum albumin, 100 U/mL terminal deoxynucleotidyl transferase, 0.5 nmol/L biotin-16-deoxyuridine triphosphate) and incubated for 30 minutes at 37°C. Cells were rinsed in PBS, resuspended in 100 µL of saline citrate buffer (2.5 µg/mL fluoresceinated avidin, 0.1% Triton X-100, 5% wt/vol ratio nonfat dry milk, 0.6 mol/L sodium chloride, and 0.06 mol/L sodium citrate), and incubated for 30 minutes at room temperature in the dark. Cells were rinsed in PBS containing 0.1% Triton X-100 and resuspended in 1 mL of PI buffer (PBS, 5 µg/mL, PI, 0.1% RNAse A). For each condition, a control sample was stained in an identical manner, except that the terminal deoxynucleotidyl transferase was omitted. Staining was analyzed by flow cytometry using a Coulter Elite instrument (Coulter Cytometry). The results were adjusted after background was subtracted.

STATISTICAL ANALYSIS

Student t test corrected for repeated measures was used. A 2-tailed P≤.07 was considered significant.

RESULTS

CASE REPORTS
Patient 1

A 53-year-old woman with a 3-year history of severe psoriasis and no other notable medical problems had been treated in the past with cyclosporine, sulfasalazine, and topical corticosteroids without serious adverse effects. She received a single dose of sirolimus (8 mg/m2 per day) 1 week prior to beginning treatment with consecutive daily doses. After the third daily dose (also 8 mg/m2 per day), she developed fever (temperature 39.4°C), progressive severe lower extremity edema, orthopnea, weight gain of 5 kg, and hypotension. Sirolimus treatment was stopped. A complete blood cell count revealed normocytic anemia (hemoglobin, 90 g/L; hematocrit, 0.26; mean corpuscular volume, 83 pg) and leukocytosis with eosinophilia. Direct and indirect Coombs test results were negative, and no evidence of hemolysis was found; iron profile studies were consistent with anemia of chronic disease. A chest radiograph was consistent with pulmonary congestion and cardiomegaly. She was treated empirically with antibiotics without defervescence while an extensive evaluation was done, including blood and urine cultures, upper and lower gastrointestinal tract endoscopies, antinuclear antibody testing, rheumatoid factor testing, parvovirus B19 serologic testing, transesophageal echocardiogram, lower extremity Doppler studies, and ventilation-perfusion lung scan, all of which findings and results were negative or normal. The diagnosis of capillary leak syndrome due to sirolimus was made. Her clinical status began to improve 72 hours after the discontinuation of therapy with the drug; she had no sequelae. Figure 1 shows selected clinical features observed in this patient.

Place holder to copy figure label and caption
Figure 1.

Clinical features of patient 1 who developed a capillary leak syndrome after receiving daily sirolimus (formerly rapamycin) treatment. Arrowheads show when sirolimus treatment was started and discontinued.

Graphic Jump Location
Patient 2

A 58-year-old man with a history of severe psoriasis and psoriatic arthritis received sirolimus 1 mg/m2 per day (no preliminary dose was administered). Concurrent medications included ibuprofen, the combination drug trimethoprim-sulfamethoxazole, and acetaminophen. After 1 month of sirolimus treatment, he noticed low-grade fevers at night, progressive dizziness, and fatigue. He was found to have orthostatic hypotension, lower extremity edema, and a decreased hematocrit (hemoglobin, 74 g/L; hematocrit, 0.22; mean corpuscular volume, 84 pg). Direct and indirect Coombs test results were negative, and there was no evidence of hemolysis on the blood smear. Iron profile studies were consistent with anemia of chronic disease. Parvovirus-B19 serologic test results were negative. A bone marrow biopsy specimen showed trilineal hematopoiesis, 50% cellularity, normal megakaryocytes, a myeloid-erythroid ratio of 5:1, normal maturation of the myeloid series, and slight dyserythropoiesis with unusual vacuolation of the erythroblasts and normal maturation of the myeloid series. There was no evidence of an infiltrative process, and sideroblasts were not seen. Sirolimus treatment was discontinued. The patient was treated with intravenous furosemide and transfusion of packed red blood cells. His condition improved; follow-up revealed no sequelae.

LABORATORY FINDINGS

Skin biopsy specimens were taken from psoriasis lesions of patients while treated with daily sirolimus doses of 3 mg/m2 (2 patients), 5 mg/m2 (2 patients), or 8 mg/m2 (2 patients), and cell suspensions were analyzed by flow cytometry. The percentage of cells with sub-G1 DNA content, indicating apoptotic cells, was similar in all epidermal and dermal samples from days 0, 2, and 7 among the 6 patients (data not shown) with the exception of patient 1. Two days after initiation of sirolimus treatment, 48% of the dermal cells of patient 1 had sub-G1 DNA content, a 2.3-fold higher percentage than the other patient who also received 8 mg/m2 per day of sirolimus (21%) (Figure 2). The percentage of cells from patient 1 was 1.8-fold higher than in her day 0 sample, and coincided with the occurrence of clinical symptoms.

Place holder to copy figure label and caption
Figure 2.

Cell cycle analysis of lesional dermal cells for apoptosis based on propidium iodide staining from patient 1 (right) and from a patient without clinical adverse effects (left), each on the second day of sirolimus (formerly rapamycin) treatment. DNA content is shown as propidium iodide fluorescence. The solid lines represent the histogram of the experimental data, and shaded areas represent the best curve fits. Number of cells (y-axis) in sub-G0/G1 are shown in channels 0 through 80 (x-axis) and represent cells demonstrating apoptosis. Patient 1 has a greater percentage of total cells in the part of the curve between 0 and 80 (note differences in the Y scales). Cells in G0/G1, S, and G2/M phases of the cell cycle are shown to the right of channel 80.

Graphic Jump Location

Peripheral blood lymphocytes from patients with psoriasis and normal controls were cultured and induction of apoptosis was measured in the presence or absence of sirolimus. The results are shown as the percentage of cells with staining for DNA strand breaks above background levels (Figure 3).

Place holder to copy figure label and caption
Figure 3.

Apoptosis in cultured peripheral blood T cells from 4 patients with psoriasis and 5 control subjects shown as percentage of apoptotic cells (top) and mean channel fluorescence of cells (bottom) in each sample representing identification of DNA strand breaks. The dots show the results obtained using T cells from patient 1, who had experienced sirolimus toxic effects; patient 1 tends to have an increased response to apoptotic stimulators dexamethasone (Dex) and sirolimus (Sir). The apoptosis inhibitor interleukin 2 (IL-2) has a substantial protective effect in patient 1, but IL-2 activity may be reduced in vivo during sirolimus therapy. Results for sirolimus are for samples with 10 µg/mL of sirolimus added. Similar results were obtained at concentrations of 1, 25, and 100 µg/mL (data not shown).

Graphic Jump Location

Dexamethasone enhanced apoptosis in cultured activated T cells in both patients (P=.05) and controls (P=.04). Interleukin 2 tended to protect the cells of control subjects from apoptosis, but not the cells from patients with psoriasis (Figure 3). Sirolimus seemed to protect normal T cells from spontaneous or dexamethasone-induced apoptosis. Similar protection did not occur with psoriatic T cells, and sirolimus augmented dexamethasone-induced apoptosis in cultures from some patients (Figure 3). This effect was most evident when the mean channel fluorescence was measured (P=.06) (Figure 3, bottom). However, the variability of results in both controls and patients with psoriasis does not permit unequivocal distinction regarding susceptibility to apoptosis.

COMMENT

We describe 2 patients with psoriasis who developed capillary leak syndrome,28 fever, and anemia after being exposed to sirolimus, with resolution after stopping treatment with the drug. In both patients, no other etiologies for the fluid retention, peripheral edema, progressive drop of hematocrit, and fever were found. The clinical findings were similar to the cases of capillary leak syndrome induced by endogenous cytokine release or exogenous administration of cytokines (eg, cancer chemotherapy with interleukin 2).2931 Furthermore, sirolimus promotes prostacyclin release,32 which could play a role in the vasodilation observed in our patients who developed capillary leak.

No clear etiology for the anemia in our patients was found. Sirolimus blocks the proliferative response of cell lines to a variety of hematopoietic growth factors.33 In addition, IL-1 and tumor necrosis factor α inhibit bone marrow hematopoiesis and erythropoietin formation; therefore, the triggering of a cytokine release syndrome by sirolimus could have contributed to the drop in the hematocrit.3335

The incidence of this form of sirolimus toxicity is not known. However, besides patient 1, 3 other individuals of the 34 patients with psoriasis who received treatment with sirolimus at the University of Michigan developed adverse effects that included lower extremity edema and a drop in hematocrit. Two of them discontinued sirolimus treatment and later restarted it without recurrence of the symptoms (C.N.E., unpublished data, October 2, 1998). These findings may represent milder forms of the syndrome. We are unable to identify factors that predispose individuals to this reaction.

Dermis from patient 1 showed a significant increase in the percentage of apoptotic cells compared with other sirolimus-treated subjects with psoriasis, including one who received an identical dose. This supports the hypothesis that sirolimus can trigger programmed cell death and probably cytokine release from cells in psoriatic lesions in certain individuals. Sirolimus was associated with greater apoptosis of cultured T cells in patients with psoriasis (including patient 1) than in control subjects when dexamethasone was added.

Sirolimus may induce apoptosis by altering signal transduction pathways or inhibiting cell survival signals. Blocking the activation of p70 S6 kinase with the administration of sirolimus may be important because a downstream target of p70 S6 kinase is p34cdc2 kinase, which regulates apoptosis of cells exposed to cytotoxic agents.24

Capillary leak syndromes have been reported previously among patients with severe psoriasis.3640 In 5 of 7 patients, a systemic therapy (etretinate in 4 and methotrexate in 1) was begun shortly before the syndrome developed; in the other 2 cases, the timing of the syndrome in relation to the patients' etretinate and cyclosporine therapies is not clear. All of these therapeutic agents induce cell apoptosis in certain situations,4145 and retinoids and cyclosporine have been associated with capillary leak syndrome in subjects without psoriasis.46,47 Our findings suggest a new explanation for capillary leak syndrome in patients with psoriasis not recognized by previous authors; namely, it is possible that in some patients the administration of systemic therapy triggers apoptosis that results in substantive cytokine release. The capillary leak syndrome could be an adverse effect of current and future systemic therapies for psoriasis.

ARTICLE INFORMATION

Accepted for publication February 4, 1999.

This study was supported in part by the University of Michigan Multipurpose Arthritis and Musculoskeletal Diseases Center, the Dermatology Alumni Fund of the University of Michigan Medical School, and the General Clinical Research Center at the University of Michigan, Ann Arbor; by grants M01RR00042 from the National Center for Research Resources and AR38477, National Institutes of Health, Bethesda, Md; and by Wyeth-Ayerst Research, Philadelphia, Pa.

We thank Toni Shull, RN, and Patricia A. Bayhan for assistance.

Reprints: Mariana J. Kaplan, MD, 3918 Taubman Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0358 (e-mail: makaplan@umich.edu).

REFERENCES

Valdimarsson  HBaker  BSJonsdottir  IFry  L Psoriasis: a disease of abnormal keratinocyte proliferation induced by T lymphocytes. Immunol Today. 1986;7259- 262
Link to Article
Bata-Csorgo  ZHammerberg  CVoorhees  JJCooper  KD Intralesional T-lymphocyte activation as a mediator of psoriatic epidermal hyperplasia. J Invest Dermatol. 1995;105 (suppl 1) 89S- 94S
Link to Article
Bos  JDHulsebosch  HJKrieg  SRBakker  PMCormane  RH Immunocompetent cells in psoriasis: in situ immunophenotyping by monoclonal antibodies. Arch Dermatol Res. 1983;275181- 189
Link to Article
Gupta  AKBaadsgaard  OEllis  CNVoorhees  JJCooper  KD Lymphocytes and macrophages of the epidermis and dermis in lesional psoriatic skin, but not epidermal Langerhans cells, are depleted by treatment with cyclosporin A. Arch Dermatol Res. 1989;281219- 226
Link to Article
Strange  PCooper  KDHansen  ER  et al.  T lymphocyte clones initiated from lesional psoriatic skin release growth factors that induce keratinocyte proliferation. J Invest Dermatol. 1993;101695- 700
Link to Article
Griffiths  CEMVoorhees  JJNickoloff  BJ Characterization of intercellular adhesion molecule-1 and HLA-DR expression in normal and inflamed skin: modulation by recombinant gamma interferon and tumor necrosis factor. J Am Acad Dermatol. 1989;20617- 629
Link to Article
Morhenn  VBAbel  EAMahrle  G Expression of HLA-DR antigen in skin from patients with psoriasis. J Invest Dermatol. 1982;78165- 168
Link to Article
Gottlieb  ABLuster  ADPosnett  DNCarter  DM Detection of a gamma interferon-induced protein IP-10 in psoriatic plaques. J Exp Med. 1988;168941- 948
Link to Article
Uyemura  KYamamura  MFivenson  DFModlin  RLNickolloff  BJ The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol. 1993;101701- 705
Link to Article
Schlaak  JFBuslau  MJochum  W  et al.  T cells involved in psoriasis vulgaris belong to the TH1 subset. J Invest Dermatol. 1994;102145- 149
Link to Article
Kapp  ANeuner  PKrutmann  JLuger  TASchopf  E Production of IL-2 by mononuclear cells in vitro in patients with atopic dermatitis and psoriasis: comparison with serum IL-2 receptor levels. Acta Derm Venereol. 1991;71403- 406
Kennet  DSymens  JAColvar  GBDuff  GW Serum-soluble interleukin 2 receptor in psoriasis: failure to reflect clinical improvement. Acta Derm Venereol. 1990;70 (3) 264- 266
Sehgal  SNMolnar-Kimber  KOcain  TDWeichman  BM Rapamycin: a novel immunosuppressive macrolide. Med Res Rev. 1994;141- 22
Link to Article
Henderson  DJNaya  IBundick  RVSmith  GMSchmidt  JA Comparison of the effects of FK-506, cyclosporin A and rapamycin on IL-2 production. Immunology. 1991;73316- 321
Luo  HChen  HDaloze  PWu  J Effects of rapamycin on human HLA-unrestricted cell killing. Clin Immunol Immunopathol. 1992;6560- 64
Link to Article
Schmidbauer  GHancock  WWWasowska  BBadger  AMKupiec-Weglinski  JW Abrogation by rapamycin of accelerated rejection in sensitized rats by inhibition of alloantibody responses and selective suppression of intragraft mononuclear and endothelial cell activation, cytokine production, and cell adhesion. Transplantation. 1994;57933- 941
Link to Article
Carlson  RPHartman  DATomchek  LA  et al.  Rapamycin, a potential disease-modifying antiarthritic drug. J Pharmacol Exp Ther. 1993;2661125- 1138
Chen  HLuo  HDaloze  P  et al.  Long-term in vivo effects of rapamycin on humoral and cellular immune responses in the rat. Immunobiology. 1993;188303- 315
Link to Article
Askelband  YHarding  MWNelson  PA Rapamycin inhibits spontaneous and fibroblast growth factor beta-stimulated proliferation of endothelial cells and fibroblasts. Transplant Proc. 1991;232833- 2836
Javier  AFBata-Csorgo  ZEllis  CNKang  SVoorhees  JJCooper  KD Rapamycin (sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells. J Clin Invest. 1997;992094- 2099
Link to Article
Feuerstein  NHuang  DPrystowsky  MB Rapamycin selectively blocks interleukin 2–induced proliferating cell nuclear antigen gene expression in T lymphocytes: evidence for inhibition of CREB/ATF binding activities. J Biol Chem. 1995;2709454- 9458
Link to Article
Price  DJGrove  JRCalvo  VAvruch  JBierer  BE Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science. 1992;257973- 977
Link to Article
Muthukkumar  SRamesh  TMBondada  S Rapamycin, a potent immunosuppressive drug causes programmed cell death in B lymphoma cells. Transplantation. 1995;60264- 270
Link to Article
Shi  YFrankel  ARadvanyi  LGPenn  LZMiller  RGMills  GB Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res. 1995;551982- 1988
Staruch  MJSigal  NHDumont  FJ Differential effects of the immunosuppressive macrolide FK-506 and rapamycin on activation-induced T cell apoptosis. Int J Immunopharmacol. 1991;13677- 685
Link to Article
Meunier  LGonzales-Ramos  ACooper  KD Heterogeneous populations of class II MHC positive cells in human dermal cell suspensions: identification of a small subset responsible for potent dermal antigen-presenting cell activity with features analogous to Langerhans cells. J Immunol. 1993;1514067- 4080
Nicoletti  IMigliorati  GPagliacci  MCGrignani  FRiccardi  C A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 1991;139271- 279
Link to Article
Amoura  ZPapo  TNinet  J  et al.  Systemic capillary leak syndrome: report on 13 patients with special focus on course and treatment. Am J Med. 1997;103514- 519
Link to Article
Lissoni  PBarni  SCataneo  G  et al.  Activation of the complement system during immunotherapy of cancer with interleukin-2: a possible explanation of the capillary leak syndrome. Int J Biol Markers. 1990;5195- 197
Martin  SMaruta  KBurkart  VGillis  SKolb  H Interleukin-1 and interferon-gamma increase vascular permeability. Immunology. 1988;64301- 305
Vial  TDescotes  J Clinical toxicity of interleukin-2. Drug Saf. 1992;7417- 433
Link to Article
Yatscoff  RWFryer  JThliveris  TA Comparison of the effect of rapamycin and FK506 on release of prostacyclin and endothelin in vitro. Clin Biochem. 1993;26409- 414
Link to Article
Quesniaux  VFJWehrli  SSteiner  C  et al.  The immunosuppressant rapamycin blocks in vitro responses to hematopoietic cytokines and inhibits recovering but not steady-state hematopoiesis in vivo. Blood. 1994;841543- 1552
Jelkmann  WEFandrey  JFrede  SPagel  H Inhibition of erythropoietin production by cytokines: implication for the anemia involved in inflammatory states. Ann N Y Acad Sci. 1994;718300- 309
Link to Article
Fuchs  DHausen  AReibnegger  G  et al.  Immune activation and the anaemia associated with chronic inflammatory disorders. Eur J Haematol. 1991;4665- 70
Link to Article
McGregor  JMBarker  JNMacDonald  DM Pulmonary capillary leak syndrome complicating generalized pustular psoriasis: possible role of cytokines. Br J Dermatol. 1991;125472- 474
Link to Article
Handfield-Jones  SEGarvey  MMcGibbon  DHBlack  MM Capillary leak syndrome in generalized pustular psoriasis. Br J Dermatol. 1992;12764
Link to Article
O'Donnell  PGHughes  JRHiggins  EMGroves  RWPembroke  AC A fatal case of capillary leak syndrome in erythrodermic psoriasis. Br J Dermatol. 1995;132160- 161
Link to Article
Sadeh  JSRudikoff  DGordon  MLBowden  JGoldman  BDLebwohl  M Pustular and erythrodermic psoriasis complicated by acute respiratory distress syndrome. Arch Dermatol. 1997;133747- 750
Link to Article
Doval  IGPeteiro  CToribio  J Acute respiratory distress syndrome and generalized pustular psoriasis: another case report. Arch Dermatol. 1998;134103
Link to Article
Horigome  AHirano  TOka  K  et al.  Glucocorticoids and cyclosporine induce apoptosis in mitogen-activated human peripheral mononuclear cells. Immunopharmacology. 1997;3787- 94
Link to Article
Andjelic  SKhanna  ASuthanthiran  MNicolic-Zugic  J Intracellular Ca2+ elevation and cyclosporin A synergistically induce TGF-beta 1-mediated apoptosis in lymphocytes. J Immunol. 1997;1582527- 2534
Heenen  MLaporte  MNoel  JCde Graef  C Methotrexate induces apoptotic cell death in human keratinocytes. Arch Dermatol Res. 1998;290240- 245
Link to Article
Genestier  LPaillot  RFournel  SFerraro  CMiossec  PRevillard  JP Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest. 1998;102322- 328
Link to Article
Smith  MRXie  TJoshi  ISchilder  RJ Dexamethasone plus retinoids decrease IL-6/IL-6 receptor and induce apoptosis in myeloma cells. Br J Haematol. 1998;1021090- 1097
Link to Article
Ponzinibbio  C Retinoic acid syndrome. Medicina. 1997;57473- 485
Harper  JIKendra  JRDesai  SStaughton  RCBarrett  AJHobbs  JR Dermatological aspects of the use of cyclosporin A for prophylaxis of graft-versus-host disease. Br J Dermatol. 1984;110469- 474
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Clinical features of patient 1 who developed a capillary leak syndrome after receiving daily sirolimus (formerly rapamycin) treatment. Arrowheads show when sirolimus treatment was started and discontinued.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Cell cycle analysis of lesional dermal cells for apoptosis based on propidium iodide staining from patient 1 (right) and from a patient without clinical adverse effects (left), each on the second day of sirolimus (formerly rapamycin) treatment. DNA content is shown as propidium iodide fluorescence. The solid lines represent the histogram of the experimental data, and shaded areas represent the best curve fits. Number of cells (y-axis) in sub-G0/G1 are shown in channels 0 through 80 (x-axis) and represent cells demonstrating apoptosis. Patient 1 has a greater percentage of total cells in the part of the curve between 0 and 80 (note differences in the Y scales). Cells in G0/G1, S, and G2/M phases of the cell cycle are shown to the right of channel 80.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Apoptosis in cultured peripheral blood T cells from 4 patients with psoriasis and 5 control subjects shown as percentage of apoptotic cells (top) and mean channel fluorescence of cells (bottom) in each sample representing identification of DNA strand breaks. The dots show the results obtained using T cells from patient 1, who had experienced sirolimus toxic effects; patient 1 tends to have an increased response to apoptotic stimulators dexamethasone (Dex) and sirolimus (Sir). The apoptosis inhibitor interleukin 2 (IL-2) has a substantial protective effect in patient 1, but IL-2 activity may be reduced in vivo during sirolimus therapy. Results for sirolimus are for samples with 10 µg/mL of sirolimus added. Similar results were obtained at concentrations of 1, 25, and 100 µg/mL (data not shown).

Graphic Jump Location

Tables

References

Valdimarsson  HBaker  BSJonsdottir  IFry  L Psoriasis: a disease of abnormal keratinocyte proliferation induced by T lymphocytes. Immunol Today. 1986;7259- 262
Link to Article
Bata-Csorgo  ZHammerberg  CVoorhees  JJCooper  KD Intralesional T-lymphocyte activation as a mediator of psoriatic epidermal hyperplasia. J Invest Dermatol. 1995;105 (suppl 1) 89S- 94S
Link to Article
Bos  JDHulsebosch  HJKrieg  SRBakker  PMCormane  RH Immunocompetent cells in psoriasis: in situ immunophenotyping by monoclonal antibodies. Arch Dermatol Res. 1983;275181- 189
Link to Article
Gupta  AKBaadsgaard  OEllis  CNVoorhees  JJCooper  KD Lymphocytes and macrophages of the epidermis and dermis in lesional psoriatic skin, but not epidermal Langerhans cells, are depleted by treatment with cyclosporin A. Arch Dermatol Res. 1989;281219- 226
Link to Article
Strange  PCooper  KDHansen  ER  et al.  T lymphocyte clones initiated from lesional psoriatic skin release growth factors that induce keratinocyte proliferation. J Invest Dermatol. 1993;101695- 700
Link to Article
Griffiths  CEMVoorhees  JJNickoloff  BJ Characterization of intercellular adhesion molecule-1 and HLA-DR expression in normal and inflamed skin: modulation by recombinant gamma interferon and tumor necrosis factor. J Am Acad Dermatol. 1989;20617- 629
Link to Article
Morhenn  VBAbel  EAMahrle  G Expression of HLA-DR antigen in skin from patients with psoriasis. J Invest Dermatol. 1982;78165- 168
Link to Article
Gottlieb  ABLuster  ADPosnett  DNCarter  DM Detection of a gamma interferon-induced protein IP-10 in psoriatic plaques. J Exp Med. 1988;168941- 948
Link to Article
Uyemura  KYamamura  MFivenson  DFModlin  RLNickolloff  BJ The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol. 1993;101701- 705
Link to Article
Schlaak  JFBuslau  MJochum  W  et al.  T cells involved in psoriasis vulgaris belong to the TH1 subset. J Invest Dermatol. 1994;102145- 149
Link to Article
Kapp  ANeuner  PKrutmann  JLuger  TASchopf  E Production of IL-2 by mononuclear cells in vitro in patients with atopic dermatitis and psoriasis: comparison with serum IL-2 receptor levels. Acta Derm Venereol. 1991;71403- 406
Kennet  DSymens  JAColvar  GBDuff  GW Serum-soluble interleukin 2 receptor in psoriasis: failure to reflect clinical improvement. Acta Derm Venereol. 1990;70 (3) 264- 266
Sehgal  SNMolnar-Kimber  KOcain  TDWeichman  BM Rapamycin: a novel immunosuppressive macrolide. Med Res Rev. 1994;141- 22
Link to Article
Henderson  DJNaya  IBundick  RVSmith  GMSchmidt  JA Comparison of the effects of FK-506, cyclosporin A and rapamycin on IL-2 production. Immunology. 1991;73316- 321
Luo  HChen  HDaloze  PWu  J Effects of rapamycin on human HLA-unrestricted cell killing. Clin Immunol Immunopathol. 1992;6560- 64
Link to Article
Schmidbauer  GHancock  WWWasowska  BBadger  AMKupiec-Weglinski  JW Abrogation by rapamycin of accelerated rejection in sensitized rats by inhibition of alloantibody responses and selective suppression of intragraft mononuclear and endothelial cell activation, cytokine production, and cell adhesion. Transplantation. 1994;57933- 941
Link to Article
Carlson  RPHartman  DATomchek  LA  et al.  Rapamycin, a potential disease-modifying antiarthritic drug. J Pharmacol Exp Ther. 1993;2661125- 1138
Chen  HLuo  HDaloze  P  et al.  Long-term in vivo effects of rapamycin on humoral and cellular immune responses in the rat. Immunobiology. 1993;188303- 315
Link to Article
Askelband  YHarding  MWNelson  PA Rapamycin inhibits spontaneous and fibroblast growth factor beta-stimulated proliferation of endothelial cells and fibroblasts. Transplant Proc. 1991;232833- 2836
Javier  AFBata-Csorgo  ZEllis  CNKang  SVoorhees  JJCooper  KD Rapamycin (sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells. J Clin Invest. 1997;992094- 2099
Link to Article
Feuerstein  NHuang  DPrystowsky  MB Rapamycin selectively blocks interleukin 2–induced proliferating cell nuclear antigen gene expression in T lymphocytes: evidence for inhibition of CREB/ATF binding activities. J Biol Chem. 1995;2709454- 9458
Link to Article
Price  DJGrove  JRCalvo  VAvruch  JBierer  BE Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science. 1992;257973- 977
Link to Article
Muthukkumar  SRamesh  TMBondada  S Rapamycin, a potent immunosuppressive drug causes programmed cell death in B lymphoma cells. Transplantation. 1995;60264- 270
Link to Article
Shi  YFrankel  ARadvanyi  LGPenn  LZMiller  RGMills  GB Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res. 1995;551982- 1988
Staruch  MJSigal  NHDumont  FJ Differential effects of the immunosuppressive macrolide FK-506 and rapamycin on activation-induced T cell apoptosis. Int J Immunopharmacol. 1991;13677- 685
Link to Article
Meunier  LGonzales-Ramos  ACooper  KD Heterogeneous populations of class II MHC positive cells in human dermal cell suspensions: identification of a small subset responsible for potent dermal antigen-presenting cell activity with features analogous to Langerhans cells. J Immunol. 1993;1514067- 4080
Nicoletti  IMigliorati  GPagliacci  MCGrignani  FRiccardi  C A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 1991;139271- 279
Link to Article
Amoura  ZPapo  TNinet  J  et al.  Systemic capillary leak syndrome: report on 13 patients with special focus on course and treatment. Am J Med. 1997;103514- 519
Link to Article
Lissoni  PBarni  SCataneo  G  et al.  Activation of the complement system during immunotherapy of cancer with interleukin-2: a possible explanation of the capillary leak syndrome. Int J Biol Markers. 1990;5195- 197
Martin  SMaruta  KBurkart  VGillis  SKolb  H Interleukin-1 and interferon-gamma increase vascular permeability. Immunology. 1988;64301- 305
Vial  TDescotes  J Clinical toxicity of interleukin-2. Drug Saf. 1992;7417- 433
Link to Article
Yatscoff  RWFryer  JThliveris  TA Comparison of the effect of rapamycin and FK506 on release of prostacyclin and endothelin in vitro. Clin Biochem. 1993;26409- 414
Link to Article
Quesniaux  VFJWehrli  SSteiner  C  et al.  The immunosuppressant rapamycin blocks in vitro responses to hematopoietic cytokines and inhibits recovering but not steady-state hematopoiesis in vivo. Blood. 1994;841543- 1552
Jelkmann  WEFandrey  JFrede  SPagel  H Inhibition of erythropoietin production by cytokines: implication for the anemia involved in inflammatory states. Ann N Y Acad Sci. 1994;718300- 309
Link to Article
Fuchs  DHausen  AReibnegger  G  et al.  Immune activation and the anaemia associated with chronic inflammatory disorders. Eur J Haematol. 1991;4665- 70
Link to Article
McGregor  JMBarker  JNMacDonald  DM Pulmonary capillary leak syndrome complicating generalized pustular psoriasis: possible role of cytokines. Br J Dermatol. 1991;125472- 474
Link to Article
Handfield-Jones  SEGarvey  MMcGibbon  DHBlack  MM Capillary leak syndrome in generalized pustular psoriasis. Br J Dermatol. 1992;12764
Link to Article
O'Donnell  PGHughes  JRHiggins  EMGroves  RWPembroke  AC A fatal case of capillary leak syndrome in erythrodermic psoriasis. Br J Dermatol. 1995;132160- 161
Link to Article
Sadeh  JSRudikoff  DGordon  MLBowden  JGoldman  BDLebwohl  M Pustular and erythrodermic psoriasis complicated by acute respiratory distress syndrome. Arch Dermatol. 1997;133747- 750
Link to Article
Doval  IGPeteiro  CToribio  J Acute respiratory distress syndrome and generalized pustular psoriasis: another case report. Arch Dermatol. 1998;134103
Link to Article
Horigome  AHirano  TOka  K  et al.  Glucocorticoids and cyclosporine induce apoptosis in mitogen-activated human peripheral mononuclear cells. Immunopharmacology. 1997;3787- 94
Link to Article
Andjelic  SKhanna  ASuthanthiran  MNicolic-Zugic  J Intracellular Ca2+ elevation and cyclosporin A synergistically induce TGF-beta 1-mediated apoptosis in lymphocytes. J Immunol. 1997;1582527- 2534
Heenen  MLaporte  MNoel  JCde Graef  C Methotrexate induces apoptotic cell death in human keratinocytes. Arch Dermatol Res. 1998;290240- 245
Link to Article
Genestier  LPaillot  RFournel  SFerraro  CMiossec  PRevillard  JP Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest. 1998;102322- 328
Link to Article
Smith  MRXie  TJoshi  ISchilder  RJ Dexamethasone plus retinoids decrease IL-6/IL-6 receptor and induce apoptosis in myeloma cells. Br J Haematol. 1998;1021090- 1097
Link to Article
Ponzinibbio  C Retinoic acid syndrome. Medicina. 1997;57473- 485
Harper  JIKendra  JRDesai  SStaughton  RCBarrett  AJHobbs  JR Dermatological aspects of the use of cyclosporin A for prophylaxis of graft-versus-host disease. Br J Dermatol. 1984;110469- 474
Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

* * SCHEDULED MAINTENANCE * *

Our websites may be periodically unavailable between midnight and 04:00 ET Thursday, July 10th, for regularly scheduled maintenance.

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 32

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles