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Study |

Identification of Clonal T Cells in the Blood of Patients With Systemic Sclerosis:  Positive Correlation With Response to Photopheresis FREE

Lars E. French, MD; Stuart R. Lessin, MD; Kathakali Addya, PhD; Barbara Denardo, RN; David J. Margolis, MD, MSCE; Debra G. B. Leonard, MD, PhD; Alain H. Rook, MD
[+] Author Affiliations

From the Department of Dermatology (Drs French, Margolis, and Rook and Ms Denardo), and the Cancer Center Molecular Diagnostic Core, Department of Pathology and Laboratory of Medicine B (Drs Addya and Leonard), University of Pennsylvania, and Fox Chase Cancer Center (Dr Lessin), Philadelphia, Pa. Dr French is now with the Department of Dermatology, Geneva University Hospital, Geneva, Switzerland.


Arch Dermatol. 2001;137(10):1309-1313. doi:10.1001/archderm.137.10.1309.
Text Size: A A A
Published online

Objectives  To search for circulating clonal T-cell populations in patients with systemic sclerosis (SSc), and to determine whether T-cell clonality in the blood predicts therapeutic response to photopheresis.

Design  Analysis of clonal T-cell receptor γ gene rearrangements before photopheresis treatment and blinded clinical evaluation of cutaneous response to photopheresis in a case series.

Setting  University hospital setting.

Patients  Thirteen consecutive patients with SSc.

Interventions  Photopheresis in 11 patients.

Main Outcome Measures  Clonality of T cells in the blood before photopheresis and clinical response to photopheresis.

Results  Screening of blood samples from 13 SSc patients for clonal T-cell receptor γ gene rearrangements revealed a monoclonal T cell population in 6 (46%) of 13 SSc patients. Clinical response to photopheresis in 11 patients was evaluated in a blinded manner using skin severity scores. Clonality of T cells appeared to be associated with a higher chance of response to photopheresis therapy, as 4 (67%) of 6 patients in the clone-positive group vs 1 (20%) of 5 in the clone-negative group experienced a clinically significant response to treatment.

Conclusions  A high proportion of patients with SSc have detectable expanded clonal T-cell populations in the peripheral blood, and such patients appear more likely to respond to photopheresis.

Figures in this Article

SYSTEMIC SCLEROSIS (SSc) is a connective tissue disease characterized by humoral and cellular immune abnormalities that are associated with excessive deposition of collagen and obliterative vasculopathy primarily within the skin and frequently within visceral organs such as the kidneys, heart, lungs, and digestive tract.1 The development of SSc is influenced by age, race, genetic factors, and sex. The incidence in women is 3- to 8-fold higher than in men, with a peak incidence after the childbearing years. The prognosis of SSc has been shown to vary depending on the extent of skin thickening and its rate of progression. Patients in whom SSc is restricted to the hands have a 10-year survival of greater than 70%, whereas those with proximal involvement including the trunk have a 10-year survival of approximately 20%.2

Although the etiology and pathogenesis of SSc is at present unknown, evidence suggests that certain environmental agents (eg, organic solvents, specific tryptophan-containing products, adulterated oils), genetic backgrounds (specific HLA alleles such as DR5), and/or viruses (eg, retroviruses, cytomegalovirus) may be associated with the development of disease. Recently, in addition to the striking clinical and biological similarities between SSc and chronic graft-vs-host disease,3 it has been shown that fetal CD3+ T cells from prior pregnancies could be detected in the blood and lesional skin of a significant proportion (>50%) of females with SSc.4 Taken together, these data suggest that in certain cases, T-cell microchimerism may be directly involved in the pathogenesis of SSc by initiating a graft-vs-host–like response.

Photopheresis, a leukapheresis-based therapy that combines methoxsalen and UV-A irradiation, has been shown to be an effective treatment for advanced cutaneous T-cell lymphoma (CTCL) and in certain patients with SSc and chronic graft vs-host disease.57 In CTCL, clinical responsiveness to photopheresis has been shown to depend on the presence of detectable circulating clonal T cells in peripheral blood.5 Given the responsiveness of certain cases of SSc to photopheresis, we investigated whether circulating clonal T-cell populations are detectable in SSc patients and if their presence could predict clinical response to photopheresis, as is the case in CTCL.

PATIENTS AND THERAPY

Thirteen patients with progressive SSc of recent onset (<2 years) were selected to receive treatment with photopheresis. The clinical diagnosis of SSc was in all cases confirmed by histological examination of a skin biopsy specimen obtained from lesional skin. None of the 13 patients had the constellation of conditions (referred to as CREST syndrome [calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia]), localized forms of cutaneous sclerosis, chemically induced SSc, or other rheumatic disease. All patients were free of other underlying disease, notably lymphoma, as determined using results of detailed clinical examination, complete blood cell counts, chemical analysis, and a chest x-ray.

The treatment was performed on 2 consecutive days, once monthly, using a photopheresis system (UVAR; Therakos, West Chester, Pa) as described previously.6 Briefly, 2 hours after the ingestion of methoxsalen, 0.6 mg/kg, patients underwent a discontinuous leukapheresis procedure with exposure of removed leukocytes to UV-A radiation within the photopheresis system. During the procedure, approximately 240 mL of leukocyte-enriched blood was mixed with 300 mL of the patient's plasma and 200 mL of sterile isotonic sodium chloride solution plus approximately 10 000 U of heparin sodium. The final buffy coat preparation contains an estimated 25% to 50% of the total peripheral blood mononuclear cell (PBMC) compartment and a hematocrit content of 2.5% to 7.0%. The buffy coat is then passed as a 1-mm film through a sterile cassette, permitting an 180-minute exposure to UV-A light and yielding an average exposure per lymphocyte of 2 J/cm2. Following this procedure, the buffy coat is returned to the patient.

Clinical assessment of patient response to photopheresis was performed by the same physician without knowing the results of the molecular analysis of T-cell clonality on a monthly basis as described.6 Briefly, the severity of each patient's skin involvement was assessed using rating of the thickness of the skin on a 0 to 3+ scale in 15 areas of the body. A rating of 0 meant that the skin was normal; 1, minimal involvement; and 3, severe thickening or hide-bound skin. A rating of 2 was intermediate between 1 and 3.8 Addition of the values of all 15 areas thus yielded skin severity (thickness) scores ranging from 0 to 45. A change in the skin severity score during treatment was considered to be clinically relevant if it differed by at least 15% from the score at baseline.

MOLECULAR ANALYSIS

Blood was obtained from all patients before onset of photopheresis treatment, and PBMCs were immediately isolated from whole blood using the Ficoll-Hypaque (Amersham-Pharmacia, Uppsala, Sweden) technique. Samples were then frozen in liquid nitrogen until analysis for clonal T-cell receptor γ (TCRγ) rearrangements using polymerase chain reaction (PCR) and automated high-resolution capillary electrophoresis. Briefly, DNA was prepared from PBMC, and PCR was used to amplify a specific region of the TCRγ gene by using 2 primer mixes to cover all possible Vγ and Jγ combinations.9 The first mix contained consensus primers Vγ1 through Vγ8 and 3 fluoresceinated Jγ primers, and the second mix contained primers Vγ9 through Vγ12 and the 3 fluoresceinated Jγ primers. The PCR products were then denatured, and fluorescent fragments were separated by size using capillary electrophoresis (ABI PRISM 310 Genetic Analyzer; Perkin Elmer Instruments Inc, Foster City, Calif). Size determination (±1 base pair) and product quantitation were accomplished using commercially available software (ABI GeneScan 3.1; PE Applied Biosystems, Foster City). From the electrophoretic profiles, predominant clones in a background polyclonal population were identified by calculating the ratio of peak heights between a peak of concern and the average of 2 immediate flanking peaks (Rn value). An Rn value of greater than 3.0 was considered to be diagnostic of a monoclonal population based on analysis of 21 cases of T-cell lymphoma and 10 benign control specimens (S.R.L. and D.G.B.L., unpublished data, September 2000). Using this technique, the sensitivity of detecting a monoclonal population of T cells within a polyclonal background in blood ranges from 1% to 5%.

STATISTICAL ANALYSIS

The data presented herein are the result of a preliminary investigation. Consequently, descriptive statistics with their corresponding SDs are presented.

T-CELL CLONALITY IN SCLERODERMA

Analysis of T-cell clonality using high-resolution fluorescent TCRγ PCR analysis of PBMCs was performed in 13 patients with SSc (mean age, 41.2 years; range, 21-73 years). All patients (2 men and 11 women) had severe SSc of recent onset; the mean skin severity score of the group was 27 ± 10 (range, 16-40), for a theoretical maximum of 45. Duration of disease from onset to analysis of T-cell clonality in each patient is given in the following tabulation:

As shown in Figure 1, high-resolution fluorescent TCRγ PCR analysis of PBMC revealed the presence of a monoclonal population of T cells with a unique TCRγ gene rearrangement in 6 (46%) of 13 patients with SSc. In all cases, the presence of a clonal T-cell population was confirmed using a separately frozen sample of PBMC, and lymphoproliferative disease was not present or did not develop in any of these patients during the 12-month study. The study of T-cell clonality in lesional skin biopsy specimens could not be performed owing to the lack of adequate skin biopsy material at the time of active disease in the concerned patient group.

In the cohort of patients undergoing analysis, those with a circulating clonal population of T cells (patients 1-6) were on average slightly older (51.8 ± 14.0 vs 32.1 ± 9.0 years) than were those without evidence of T-cell clonality (patients 7-13). The group of patients with a circulating clonal population of T cells also had disease for a longer time than patients without evidence of T-cell clonality (26.1 ± 6.1 vs 14.3 ± 5.5 months). However, no significant difference in antibody status, organ involvement, or previous therapy was found between groups (not shown). Also, SSc patients with a T-cell clone had on average a similar severity of skin involvement at the onset of photopheresis (mean skin severity score, 28.3 ± 12.3 vs 27.4 ± 10.0).

Place holder to copy figure label and caption
Figure 1.

High-resolution capillary electrophoresis profiles of T-cell receptor γ (TCRγ) in a healthy control subject (A) and patients with systemic sclerosis in whom a T-cell clone (arrow) was detected (B). The y-axis represents the relative abundance of the amplified fluorescent TCRγ fragments, and the x-axis represents the size of the amplified TCRγ fragment as deduced by its migration distance in the high-resolution capillary electrophoresis gel.

Graphic Jump Location
T-CELL CLONALITY AND RESPONSIVENESS TO PHOTOPHERESIS

Because the presence of a clonal population of T cells in the blood has been shown to indicate responsiveness to photopheresis in patients with CTCL, we analyzed the clinical response of SSc patients to photopheresis with respect to the presence or absence of a circulating T-cell clone, to determine if the same could be true for SSc. Clinical data concerning responsiveness of skin lesions to photopheresis was available for 11 of our 13 patients. When these data were analyzed for this cohort independently of T-cell clonality status, significant improvement in skin severity scores (≥15%) was observed after treatment in 5 (45%) of 11 patients. As shown in Figure 2, when clone-positive and clone-negative groups were analyzed separately, although the groups were small, the response rate between each group clearly differed. In the clone-positive group, 4 (67%) of 6 patients showed a significant improvement in their skin severity scores, compared with 1 (20%) of 5 patients in the clone-negative group. Similarly, although significant (≥15%) progression of skin disease was observed in 4 (36%) of 11 patients, this was clearly more frequent in the clone-negative group (3/5 [60%]) than in the clone-positive group (1/6 [17%]).

Place holder to copy figure label and caption
Figure 2.

Evolution of skin severity scores during photopheresis in the clone-positive (A) and clone-negative (B) groups of systemic sclerosis. The dotted line indicates the baseline skin severity score. A, Four of 6 patients in the clone-positive group had significant improvement of their skin severity scores during photopheresis. B, Only 1 of 5 patients in the clone-negative group improved with the same treatment.

Graphic Jump Location

To determine if responsiveness to photopheresis in patients with SSc is associated with disappearance of the clone, T-cell clonality was analyzed in patients 1, 2, 3, 4, and 6 (5 of the 6 patients in the clone-positive group) after completion of photopheresis and occurrence of a clinical response. This analysis did not reveal any modifications in the T-cell receptor profile (not shown), suggesting that response to photopheresis in SSc does not correlate with disappearance of the clonally amplified T-cell populations.

The results described herein demonstrate for the first time the presence of an expanded monoclonal T-cell population in the circulation of patients with progressive SSc. Of the patients described herein, 46% were shown to have a circulating population of monoclonal T cells as detected by means of fluorescent-based PCR and automated high-resolution capillary electrophoresis of the TCRγ. In addition, analysis of clinical response to photopheresis in these patients shows that patients with circulating clonal T cells may be more likely to respond to treatment than patients without a T-cell clone.

Clonality of T cells is a feature most frequently observed in malignant neoplasms involving the T-cell lineage such as CTCL, T-cell leukemias, and certain non-Hodgkin lymphomas. However, T-cell clonality can also be detected in certain nonmalignant conditions, and recently it has become apparent that clonal expansion of T cells can occur in certain autoimmune and infectious diseases, and even occasionally in apparently healthy humans.10,11 The technique we used herein for the detection of TCRγ gene rearrangements did not reveal the presence of circulating clonal T cells in 10 healthy control subjects. Likewise, none of the patients with clonal T-cell expansions in this study had clinical or laboratory variables suggestive of T-cell lymphoma or leukemia at initial presentation or during follow-up. The significant amplification of clonal T-cell populations observed in our patients was therefore considered to be specific to their SSc.

Evidence has begun to emerge showing that in several human autoimmune diseases, autoreactive T cells undergo clonal activation and expansion.12 For example, in patients with multiple sclerosis, in vivo clonal expansion of myelin basic protein–specific T cells is detectable in a subset of patients.13 Likewise, in rheumatoid arthritis, clonal expansion of T cells has been observed in peripheral blood and synovial fluid.14,15 Systemic sclerosis bears certain similarities to multiple sclerosis and rheumatoid arthritis that may be relevant to the pathogenesis of this group of diseases. In all 3 diseases, T cells are central to the development of tissue damage and dominate the inflammatory infiltrates observed in affected tissues.16 Also, development of these diseases is known to be influenced by genetic factors such as HLA restriction.4,17 These similarities suggest that T cell–mediated autoimmune mechanisms may play an important role in the inflammatory tissue destructive process. In multiple sclerosis and rheumatoid arthritis, current evidence exists to support the hypothesis that the clonal expansion of T cells is antigen driven, possibly by mycobacterial heat shock protein 65 in rheumatoid arthritis15 and by myelin basic protein in multiple sclerosis.13 It is therefore possible that the T-cell clones observed in our patients with SSc represent an in vivo– activated clonal expansion of T cells that are responsive to an antigen or autoantigen implicated in the pathogenesis of SSc. Alternatively, such an event could be associated with exposure to superantigens during past microbial infections. Whether the clonal T cells identified in our patients are critical to the pathogenesis of SSc remains to be determined. However, if this were the case, these clonal T-cell populations together with associated major histocompatibility complex molecules could offer new tools to examine specific T-cell antigens in this autoimmune disorder of unknown etiology.

The mechanism by which photophoresis is of therapeutic benefit in scleroderma is at present unclear. Photopheresis and its mechanism of action have been best studied in patients with Sézary syndrome, the leukemic form of CTCL.5,18 In this disease, photopheresis induces long-term clinical responses and possibly enhanced survival rates.1922 Accumulating evidence suggests that the therapeutic effect of photopheresis in CTCL is due to the induction of an immune response against defined lymphocyte populations that are central to its pathogenesis. Indeed, in patients with Sézary syndrome, complete clinical responses have been shown to correlate with the complete disappearance of the malignant T-cell clone as judged by means of morphologic, immunocytochemical, and molecular analyses.5 In addition, experimental data acquired from animal autoimmune and transplantation studies suggest that photopheresed cells induce an antigen-specific immune response directed to pathogenic T-cell populations without affecting general immunocompetence.2325 In the case of scleroderma, quite strong evidence of ongoing abnormal immune activation detectable by the presence of activated T cells within the peripheral blood and the sites of abnormal collagen production now exists.26 These cells may be indirectly involved in enhancing collagen synthesis and deposition via the secretion of cytokines such as transforming growth factor β.27,28 Photopheresis might induce an immune response that targets such autoreactive disease–mediating cells. The clinical data reported herein, although preliminary, suggest that SSc patients with circulating clonal T cells have a greater chance of responding to photopheresis. These findings support previous reports that photopheresis may be most effective in diseases with circulating clonal cells, and suggest that the clonal T cells observed in SSc may be involved in the pathogenesis of the disease.

Accepted for publication February 16, 2001.

This work was supported in part by grant CA 10815 from the National Institutes of Health, Bethesda, Md.

We thank P. Bromley, RN, and W. H. Macey, RN, for help in collecting clinical samples.

Corresponding author: Lars E. French, MD, Department of Dermatology, Geneva University Hospital, 24, rue Micheli-du-Crest, CH-1211 Genève 14 Switzerland (e-mail: french@cmu.unige.ch).

Reprints: Alain H. Rook, MD, Department of Dermatology, University of Pennsylvania School of Medicine, 3600 Spruce St, Philadelphia, PA 19104.

Perez  MIKohn  SR Systemic sclerosis. J Am Acad Dermatol. 1993;28525- 547
Link to Article
Barnett  AJMiller  MHLittlejohn  GO A survival study of patients with scleroderma diagnosed over 30 years (1953-1983): the value of a simple cutaneous classification in the early stages of the disease. J Rheumatol. 1988;15276- 283
Furst  DEClements  PJGraze  PGale  RRoberts  N A syndrome resembling progressive systemic sclerosis after bone marrow transplantation: a model for scleroderma? Arthritis Rheum. 1979;22904- 910
Link to Article
Artlett  CMSmith  JBJimenez  SA New perspectives on the etiology of systemic sclerosis. Mol Med Today. 1999;574- 78
Link to Article
Rook  AHSuchin  KRKao  DM  et al.  Photopheresis: clinical applications and mechanism of action. J Investig Dermatol Symp Proc. 1999;485- 90
Link to Article
Rook  AHFreundlich  BJegasothy  BV  et al.  Treatment of systemic sclerosis with extracorporeal photochemotherapy: results of a multicenter trial. Arch Dermatol. 1992;128337- 346
Link to Article
Greinix  HTVolc-Platzer  BRabitsch  W  et al.  Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood. 1998;923098- 3104
Kahaleh  MBSultany  GLSmith  EAHuffstutter  JELoadholt  CBLeRoy  EC A modified scleroderma skin scoring method. Clin Exp Rheumatol. 1986;4367- 369
Kneba  MBolz  ILinke  BBertram  JRothaupt  DHiddemann  W Characterization of clone-specific rearrangement T-cell receptor gamma-chain genes in lymphomas and leukemias by the polymerase chain reaction and DNA sequencing. Blood. 1994;84574- 581
Hingorani  RChoi  IHAkolkar  P  et al.  Clonal predominance of T cell receptors within the CD8+ CD45RO+ subset in normal human subjects. J Immunol. 1993;1515762- 5769
Posnett  DNSinha  RKabak  SRusso  C Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy". J Exp Med. 1994;179609- 618[published erratum appears in J Exp Med. 1994;179:1077]
Link to Article
Olive  C T-cell receptor usage in autoimmune disease. Immunol Cell Biol. 1995;73297- 307
Link to Article
Vandevyver  CMertens  Nvan den Elsen  PMedaer  RRaus  JZhang  J Clonal expansion of myelin basic protein-reactive T cells in patients with multiple sclerosis: restricted T cell receptor V gene rearrangements and CDR3 sequence. Eur J Immunol. 1995;25958- 968
Link to Article
DerSimonian  HSugita  MGlass  DN  et al.  Clonal Vα12.1+ T-cell expansions in the peripheral blood of rheumatoid arthritis patients. J Exp Med. 1993;1771623- 1631
Link to Article
Celis  LVandevyver  CGeusens  PDequeker  JRaus  JZhang  J Clonal expansion of mycobacterial heat-shock protein-reactive T lymphocytes in the synovial fluid and blood of rheumatoid arthritis patients. Arthritis Rheum. 1997;40510- 519
Link to Article
Kraling  BMMaul  GGJimenez  SA Mononuclear cellular infiltrates in clinically involved skin from patients with systemic sclerosis of recent onset predominantly consist of monocytes/macrophages. Pathobiology. 1995;6348- 56
Link to Article
Wilson  CTiwana  HEbringer  ACunningham  PEttelaie  C HLA-DR4 restriction, molecular mimicry and rheumatoid arthritis. Immunol Today. 1997;1896- 97
Link to Article
Edelson  RBerger  CGasparro  F  et al.  Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy: preliminary results. N Engl J Med. 1987;316297- 303
Link to Article
Heald  PRook  APerez  M  et al.  Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy. J Am Acad Dermatol. 1992;27427- 433
Link to Article
Gottlieb  SLWolfe  JTFox  FE  et al.  Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis monotherapy and in combination with recombinant interferon alfa: a 10-year experience at a single institution. J Am Acad Dermatol. 1996;35946- 957
Link to Article
Zic  JAStricklin  GPGreer  JP  et al.  Long-term follow-up of patients with cutaneous T-cell lymphoma treated with extracorporeal photochemotherapy. J Am Acad Dermatol. 1996;35935- 945
Link to Article
Duvic  MHester  JPLemak  NA Photopheresis therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol. 1996;35573- 579
Link to Article
Berger  CLPerez  MLaroche  LEdelson  R Inhibition of autoimmune disease in a murine model of systemic lupus erythematosus induced by exposure to syngeneic photoinactivated lymphocytes. J Invest Dermatol. 1990;9452- 57
Link to Article
Girardi  MHerreid  PTigelaar  RE Specific suppression of lupus-like graft-versus-host disease using extracorporeal photochemical attenuation of effector lymphocytes. J Invest Dermatol. 1995;104177- 182
Link to Article
Perez  MIEdelson  RLJohn  LLaroche  LBerger  CL Inhibition of antiskin allograft immunity induced by infusions with photoinactivated effector T lymphocytes (PET cells). Yale J Biol Med. 1989;62595- 609
White  B Immunopathogenesis of systemic sclerosis. Rheum Dis Clin North Am. 1996;22695- 708
Link to Article
Kulozik  MHogg  ALankat-Buttgereit  BKrieg  T Co-localization of transforming growth factor beta 2 with alpha 1(I) procollagen mRNA in tissue sections of patients with systemic sclerosis. J Clin Invest. 1990;86917- 922
Link to Article
Smith  EALeRoy  EC A possible role for transforming growth factor-beta in systemic sclerosis. J Invest Dermatol. 1990;95(suppl)125S- 127S
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

High-resolution capillary electrophoresis profiles of T-cell receptor γ (TCRγ) in a healthy control subject (A) and patients with systemic sclerosis in whom a T-cell clone (arrow) was detected (B). The y-axis represents the relative abundance of the amplified fluorescent TCRγ fragments, and the x-axis represents the size of the amplified TCRγ fragment as deduced by its migration distance in the high-resolution capillary electrophoresis gel.

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

Evolution of skin severity scores during photopheresis in the clone-positive (A) and clone-negative (B) groups of systemic sclerosis. The dotted line indicates the baseline skin severity score. A, Four of 6 patients in the clone-positive group had significant improvement of their skin severity scores during photopheresis. B, Only 1 of 5 patients in the clone-negative group improved with the same treatment.

Graphic Jump Location

References

Perez  MIKohn  SR Systemic sclerosis. J Am Acad Dermatol. 1993;28525- 547
Link to Article
Barnett  AJMiller  MHLittlejohn  GO A survival study of patients with scleroderma diagnosed over 30 years (1953-1983): the value of a simple cutaneous classification in the early stages of the disease. J Rheumatol. 1988;15276- 283
Furst  DEClements  PJGraze  PGale  RRoberts  N A syndrome resembling progressive systemic sclerosis after bone marrow transplantation: a model for scleroderma? Arthritis Rheum. 1979;22904- 910
Link to Article
Artlett  CMSmith  JBJimenez  SA New perspectives on the etiology of systemic sclerosis. Mol Med Today. 1999;574- 78
Link to Article
Rook  AHSuchin  KRKao  DM  et al.  Photopheresis: clinical applications and mechanism of action. J Investig Dermatol Symp Proc. 1999;485- 90
Link to Article
Rook  AHFreundlich  BJegasothy  BV  et al.  Treatment of systemic sclerosis with extracorporeal photochemotherapy: results of a multicenter trial. Arch Dermatol. 1992;128337- 346
Link to Article
Greinix  HTVolc-Platzer  BRabitsch  W  et al.  Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood. 1998;923098- 3104
Kahaleh  MBSultany  GLSmith  EAHuffstutter  JELoadholt  CBLeRoy  EC A modified scleroderma skin scoring method. Clin Exp Rheumatol. 1986;4367- 369
Kneba  MBolz  ILinke  BBertram  JRothaupt  DHiddemann  W Characterization of clone-specific rearrangement T-cell receptor gamma-chain genes in lymphomas and leukemias by the polymerase chain reaction and DNA sequencing. Blood. 1994;84574- 581
Hingorani  RChoi  IHAkolkar  P  et al.  Clonal predominance of T cell receptors within the CD8+ CD45RO+ subset in normal human subjects. J Immunol. 1993;1515762- 5769
Posnett  DNSinha  RKabak  SRusso  C Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy". J Exp Med. 1994;179609- 618[published erratum appears in J Exp Med. 1994;179:1077]
Link to Article
Olive  C T-cell receptor usage in autoimmune disease. Immunol Cell Biol. 1995;73297- 307
Link to Article
Vandevyver  CMertens  Nvan den Elsen  PMedaer  RRaus  JZhang  J Clonal expansion of myelin basic protein-reactive T cells in patients with multiple sclerosis: restricted T cell receptor V gene rearrangements and CDR3 sequence. Eur J Immunol. 1995;25958- 968
Link to Article
DerSimonian  HSugita  MGlass  DN  et al.  Clonal Vα12.1+ T-cell expansions in the peripheral blood of rheumatoid arthritis patients. J Exp Med. 1993;1771623- 1631
Link to Article
Celis  LVandevyver  CGeusens  PDequeker  JRaus  JZhang  J Clonal expansion of mycobacterial heat-shock protein-reactive T lymphocytes in the synovial fluid and blood of rheumatoid arthritis patients. Arthritis Rheum. 1997;40510- 519
Link to Article
Kraling  BMMaul  GGJimenez  SA Mononuclear cellular infiltrates in clinically involved skin from patients with systemic sclerosis of recent onset predominantly consist of monocytes/macrophages. Pathobiology. 1995;6348- 56
Link to Article
Wilson  CTiwana  HEbringer  ACunningham  PEttelaie  C HLA-DR4 restriction, molecular mimicry and rheumatoid arthritis. Immunol Today. 1997;1896- 97
Link to Article
Edelson  RBerger  CGasparro  F  et al.  Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy: preliminary results. N Engl J Med. 1987;316297- 303
Link to Article
Heald  PRook  APerez  M  et al.  Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy. J Am Acad Dermatol. 1992;27427- 433
Link to Article
Gottlieb  SLWolfe  JTFox  FE  et al.  Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis monotherapy and in combination with recombinant interferon alfa: a 10-year experience at a single institution. J Am Acad Dermatol. 1996;35946- 957
Link to Article
Zic  JAStricklin  GPGreer  JP  et al.  Long-term follow-up of patients with cutaneous T-cell lymphoma treated with extracorporeal photochemotherapy. J Am Acad Dermatol. 1996;35935- 945
Link to Article
Duvic  MHester  JPLemak  NA Photopheresis therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol. 1996;35573- 579
Link to Article
Berger  CLPerez  MLaroche  LEdelson  R Inhibition of autoimmune disease in a murine model of systemic lupus erythematosus induced by exposure to syngeneic photoinactivated lymphocytes. J Invest Dermatol. 1990;9452- 57
Link to Article
Girardi  MHerreid  PTigelaar  RE Specific suppression of lupus-like graft-versus-host disease using extracorporeal photochemical attenuation of effector lymphocytes. J Invest Dermatol. 1995;104177- 182
Link to Article
Perez  MIEdelson  RLJohn  LLaroche  LBerger  CL Inhibition of antiskin allograft immunity induced by infusions with photoinactivated effector T lymphocytes (PET cells). Yale J Biol Med. 1989;62595- 609
White  B Immunopathogenesis of systemic sclerosis. Rheum Dis Clin North Am. 1996;22695- 708
Link to Article
Kulozik  MHogg  ALankat-Buttgereit  BKrieg  T Co-localization of transforming growth factor beta 2 with alpha 1(I) procollagen mRNA in tissue sections of patients with systemic sclerosis. J Clin Invest. 1990;86917- 922
Link to Article
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