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Positive Correlation With Response to Photopheresis

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

Arch Dermatol. 2001;137:1309-1313.

ABSTRACT
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 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 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.

INTRODUCTION

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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.^5-7 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 METHODS

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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 (TCR) 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 TCR gene by using 2 primer mixes to cover all possible V and J combinations.⁹ The first mix contained consensus primers V1 through V8 and 3 fluoresceinated J primers, and the second mix contained primers V9 through V12 and the 3 fluoresceinated J 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.

RESULTS

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T-CELL CLONALITY IN SCLERODERMA

Analysis of T-cell clonality using high-resolution fluorescent TCR 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 TCR PCR analysis of PBMC revealed the presence of a monoclonal population of T cells with a unique TCR 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.

View larger version (36K): [in this window] [in a new window] Figure 1. High-resolution capillary electrophoresis profiles of T-cell receptor (TCR) 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 TCR fragments, and the x-axis represents the size of the amplified TCR fragment as deduced by its migration distance in the high-resolution capillary electrophoresis gel.

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).

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%]).

View larger version (39K): [in this window] [in a new window] 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.

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.

COMMENT

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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 TCR. 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 TCR 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.^19-22 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.^23-25 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 .^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.

AUTHOR INFORMATION

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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{at}cmu.unige.ch).
Reprints: Alain H. Rook, MD, Department of Dermatology, University of Pennsylvania School of Medicine, 3600 Spruce St, Philadelphia, PA 19104.

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.

REFERENCES

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Treatment of systemic sclerosis with extracorporeal photochemotherapy: results of a multicenter trial. Arch Dermatol. 1992;128:337-346. FREE FULL TEXT 7. Greinix HT, Volc-Platzer B, Rabitsch W, et al. Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood. 1998;92:3098-3104. FREE FULL TEXT 8. Kahaleh MB, Sultany GL, Smith EA, Huffstutter JE, Loadholt CB, LeRoy EC. A modified scleroderma skin scoring method. Clin Exp Rheumatol. 1986;4:367-369. ISI | PUBMED 9. Kneba M, Bolz I, Linke B, Bertram J, Rothaupt D, Hiddemann 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;84:574-581. FREE FULL TEXT 10. Hingorani R, Choi IH, Akolkar P, et al. Clonal predominance of T cell receptors within the CD8⁺ CD45RO⁺ subset in normal human subjects. J Immunol. 1993;151:5762-5769. ABSTRACT 11. Posnett DN, Sinha R, Kabak S, Russo C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy". J Exp Med. 1994;179:609-618 [published erratum appears in J Exp Med. 1994;179:1077]. 12. Olive C. T-cell receptor usage in autoimmune disease. Immunol Cell Biol. 1995;73:297-307. PUBMED 13. Vandevyver C, Mertens N, van den Elsen P, Medaer R, Raus J, Zhang 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;25:958-968. ISI | PUBMED 14. DerSimonian H, Sugita M, Glass DN, et al. Clonal V12.1⁺ T-cell expansions in the peripheral blood of rheumatoid arthritis patients. J Exp Med. 1993;177:1623-1631. FREE FULL TEXT 15. Celis L, Vandevyver C, Geusens P, Dequeker J, Raus J, Zhang J. Clonal expansion of mycobacterial heat-shock protein-reactive T lymphocytes in the synovial fluid and blood of rheumatoid arthritis patients. Arthritis Rheum. 1997;40:510-519. ISI | PUBMED 16. Kraling BM, Maul GG, Jimenez SA. Mononuclear cellular infiltrates in clinically involved skin from patients with systemic sclerosis of recent onset predominantly consist of monocytes/macrophages. Pathobiology. 1995;63:48-56. FULL TEXT | ISI | PUBMED 17. Wilson C, Tiwana H, Ebringer A, Cunningham P, Ettelaie C. HLA-DR4 restriction, molecular mimicry and rheumatoid arthritis. Immunol Today. 1997;18:96-97. FULL TEXT | ISI | PUBMED 18. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy: preliminary results. N Engl J Med. 1987;316:297-303. ABSTRACT 19. Heald P, Rook A, Perez M, et al. Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy. J Am Acad Dermatol. 1992;27:427-433. ISI | PUBMED 20. Gottlieb SL, Wolfe JT, Fox 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;35:946-957. FULL TEXT | ISI | PUBMED 21. Zic JA, Stricklin GP, Greer JP, et al. Long-term follow-up of patients with cutaneous T-cell lymphoma treated with extracorporeal photochemotherapy. J Am Acad Dermatol. 1996;35:935-945. FULL TEXT | ISI | PUBMED 22. Duvic M, Hester JP, Lemak NA. Photopheresis therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol. 1996;35:573-579. FULL TEXT | ISI | PUBMED 23. Berger CL, Perez M, Laroche L, Edelson R. Inhibition of autoimmune disease in a murine model of systemic lupus erythematosus induced by exposure to syngeneic photoinactivated lymphocytes. J Invest Dermatol. 1990;94:52-57. FULL TEXT | ISI | PUBMED 24. Girardi M, Herreid P, Tigelaar RE. Specific suppression of lupus-like graft-versus-host disease using extracorporeal photochemical attenuation of effector lymphocytes. J Invest Dermatol. 1995;104:177-182. FULL TEXT | ISI | PUBMED 25. Perez MI, Edelson RL, John L, Laroche L, Berger CL. Inhibition of antiskin allograft immunity induced by infusions with photoinactivated effector T lymphocytes (PET cells). Yale J Biol Med. 1989;62:595-609. ISI | PUBMED 26. White B. Immunopathogenesis of systemic sclerosis. Rheum Dis Clin North Am. 1996;22:695-708. FULL TEXT | ISI | PUBMED 27. Kulozik M, Hogg A, Lankat-Buttgereit B, Krieg 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;86:917-922. 28. Smith EA, LeRoy EC. A possible role for transforming growth factor-beta in systemic sclerosis. J Invest Dermatol. 1990;95(suppl):125S-127S.

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