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Re-emergence of anti-topoisomerase I antibody with exacerbated development of skin sclerosis in a patient with systemic sclerosis
Re-emergence of anti-topoisomerase I antibody with exacerbated development of skin sclerosis in a patient with systemic sclerosis Yasuhito Hamaguchi, MD, PhD, Manabu Fujimoto, MD, Minoru Hasegawa, MD, PhD, Takashi Matsushita, MD, PhD, and Kazuhiko Takehara, MD, PhD Kanazawa, Japan A 41-year-old woman had noticed sclerodactyly for 9 months before consultation. She was diagnosed as having diffuse cutaneous systemic sclerosis based on the skin sclerosis of her extremities and trunk and assessed by the modified Rodnan skin score method. Her antietopoisomerase I antibody (antietopo I) level was 78.1 index (normal range, # 16 index). With oral prednisolone treatment, her skin sclerosis gradually improved and disappeared. In parallel, her serum antietopo I levels became undetectable. Prednisolone was eventually discontinued; however, 10 months after discontinuation, antietopo I reemerged and increased to 102.1 index, accompanied by newly developed skin sclerosis. Prednisolone was re-started, and the skin sclerosis improved, along with a reduction in antietopo I levels. Therefore, discontinuation of corticosteroids may have triggered the re-emergence of antietopo I and skin sclerosis. This case suggests a role for antietopo I in the pathogenesis of systemic sclerosis and an effect of corticosteroids on skin sclerosis and autoantibody production. ( J Am Acad Dermatol 2010;62:142-4.)
INTRODUCTION Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive fibrosis of the skin and internal organs. Although the pathogenesis of SSc remains unclear, the presence of antinuclear antibodies (ANA) is a representative feature.1 More than 90% of patients with SSc are positive for ANA, and anti-DNA topoisomerase I antibody (antietopo I) and anticentromere antibody are two representative ANA found in patients with SSc. The percentage of Japanese patients who have antietopo I or anticentromere antibodies is approximately 30% and 40%, respectively.2,3 Previous studies have revealed that patients with antietopo I generally display extensive skin thickening and frequently have severe internal organ involvement, such as
Abbreviations used: ANA: antinuclear antibodies antietopo I: anti-DNA topoisomerase I MRSS: modified Rodnan total skin score SSc: systemic sclerosis
pulmonary fibrosis.3,4 It is thought that the titers of SSc-specific ANA do not change during the disease course. Herein we describe a patient with SSc who had worsened skin sclerosis and re-emergence of antietopo I after discontinuation of corticosteroid treatment, and in whom skin sclerosis and serum antietopo I had previously disappeared.
CASE REPORT
From the Department of Dermatology, Kanazawa University Graduate School of Medical Science. Supported by a grant-in-aid from the Ministry of Health and Welfare of Japan (to M. F.). Conflicts of interest: None declared. Reprint requests: Yasuhito Hamaguchi, MD, PhD, Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan. E-mail: [email protected]. Published online September 7, 2009. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.01.032
142
A 41-year-old woman was admitted to our hospital with skin sclerosis. She had noticed sclerodactyly for 9 months and Raynaud’s phenomenon for 7 months before consultation, but she had not taken any drugs. Physical examination revealed sclerosis of the skin on her fingers, hands, toes, limbs, chest, neck, and face. Her modified Rodnan total skin score (MRSS) was 20 points. Punctuate hemorrhages of the nailfold capillaries, pitting scars on the fingertips, phalangeal contracture, and diffuse pigmentation involving her upper limbs were observed. Laboratory findings at admission were within normal limits, other than positive ANA. ANA had a
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and the patient’s skin sclerosis improved, along with a reduction in the antietopo I level.
DISCUSSION
Fig 1. Serial changes in serum antietopo I antibody levels in our patient who showed a decrease in antibody level in parallel with significant improvement in MRSS. Bold lines indicate MRSS; dashed lines indicate antietopo I antibody levels determined by enzyme-linked immunosorbent assay.
homogeneous pattern with nucleolar staining, and the ANA titer was 1:320. The antietopo I level was evaluated with a specific enzyme-linked immunosorbent assay, carried out according to the manufacturer’s instructions (MBL Corp, Nagoya, Japan). The assay was calibrated in relative arbitrary units and more than 16 index was considered positive. The antietopo I level was elevated to 78.1 index. The patient’s serum was negative for other ANA. A forearm skin biopsy specimen showed thickened homogeneous collagen bundles in all layers of the dermis. She had slight bibasilar pulmonary interstitial shadows, but pulmonary fibrosis was considered to be inactive by a pulmonary function test. Therefore the diagnosis was diffuse cutaneous SSc. Treatment with oral prednisolone (0.5 mg/kg body weight) was started (Fig 1). Her skin sclerotic changes improved slowly, and the prednisolone dosage was decreased gradually. Skin sclerosis disappeared completely by 8 years after her first admission, and prednisolone was stopped. The patient’s antietopo I level was below detectable limits when the prednisolone was stopped. Nine years after her first admission, antietopo I reemerged, and the index was 22.9. Ten months after the re-emergence of antietopo I, the patient again showed sclerodactyly. Raynaud’s phenomenon continued after the discontinuation of prednisolone, but it became more severe after the appearance of sclerodactyly. Thereafter, the patient developed sclerosis of the skin on her fingers and hands, with an MRSS of 4 points at 8 months after the reemergence of antietopo I. The antietopo I index increased to 102.1. Pulmonary fibrosis was not advanced. Oral prednisolone (0.4 mg/kg body weight) was re-started,
SSc-related ANA are closely associated with disease subset and organ involvement. It is well described that clinical features are not identical among different ethnic groups.2,3,5 Corticosteroids are commonly avoided for Caucasian or black patients, as steroids could induce scleroderma renal crisis.6 In contrast, corticosteroids are used occasionally to treat skin sclerosis in Japanese patients, as renal involvement rarely occurs in Japanese individuals, especially those without anti-RNA polymerase antibodies.2,3 Careful observation is recommended in some cases, as skin sclerosis generally regresses spontaneously several years after the onset of the disease.7 We treated our patient with an oral corticosteroid that resulted in improvement of the skin sclerosis without renal crisis. Therefore, corticosteroid treatment might be useful in certain individuals. However, the possibility could not be ruled out that the improvement in skin sclerosis reflected only spontaneous regression. The presence of ANA is one hallmark of immunological abnormality in SSc.8 Generally, ANA levels are almost constant and do not reflect disease activity, in contrast with the double-stranded DNA antibody that is detected in systemic lupus erythematosus. Changes in antietopo I levels have not been associated with any particular clinical manifestations.9 However, a correlation of serum antietopo I levels with disease severity and activity has been described in SSc.10 We also reported that decreased levels of antietopo I were accompanied mainly by atrophic skin changes during the follow-up period, whereas increasing levels were associated with new onset or worsening of organ involvement.11 Additionally, 6 SSc patients in whom antietopo I disappeared had less extensive skin and lung involvement than patients in whom antietopo I persisted.12 Corticosteroids may reduce the number of autoreactive B cells that produce antietopo I and result in the reduction of antietopo I levels. Thus it is likely that antietopo I levels have a potential significance in evaluating the severity and prognosis of SSc. In conclusion, our case suggests that oral corticosteroid administration might be effective for skin sclerosis by suppression of autoantibody production in SSc. Moreover, it appeared that discontinuation of the corticosteroid became a trigger for the re-emergence of antietopo I and a new onset of skin sclerosis. However, the exact mechanisms involved in the reduction of autoantibody levels are unknown. It has been reported that the autoantigen topo I itself bound specifically to fibroblasts, where it was recognized by antietopo I from SSc patients.
144 Case reports
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The binding of antietopo I subsequently stimulated adhesion and activation of monocytes, resulting in amplification of the fibrogenic cascade by a topo I/antietopo I complex. Therefore antietopo I might have a pathogenic role in SSc.13 Further study will be needed to reveal the biological significance of antietopo I in the development of SSc and the influence of corticosteroids on the modification of immunological abnormalities. REFERENCES 1. Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol 1989;44:93-151. 2. Kuwana M, Kaburaki J, Okano Y, Tojo T, Homma M. Clinical and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis. Arthritis Rheum 1994;37:75-83. 3. Hamaguchi Y, Hasegawa M, Fujimoto M, Matsushita T, Komura K, Kaji K, et al. The clinical relevance of serum antinuclear antibodies in Japanese patients with systemic sclerosis. Br J Dermatol 2008;158:487-95. 4. Shero JH, Bordwell B, Rothfield NF, Earnshaw WC. High titers of autoantibodies to topoisomerase I (Scl-70) in sera from scleroderma patients. Science 1986;231:737-40. 5. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005;35:35-42.
6. Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 1998; 41:1613-9. 7. Steen VD, Medsger TA Jr. Epidemiology and natural history of systemic sclerosis. Rheum Dis Clin North Am 1990;16:1-10. 8. Reveille JD, Solomon DH. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum 2003;49:399-412. 9. Va´zquez-Abad D, Russell CA, Cusick SM, Earnshaw WC, Rothfield NF. Longitudinal study of anticentromere and antitopoisomerase-I isotypes. Clin Immunol Immunopathol 1995;74:257-70. 10. Hu PQ, Fertig N, Medsger TA Jr, Wright TM. Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Arthritis Rheum 2003;48:1363-73. 11. Sato S, Hamaguchi Y, Hasegawa M, Takehara K. Clinical significance of anti-topoisomerase I antibody levels determined by ELISA in systemic sclerosis. Rheumatology 2001;40: 1135-40. 12. Kuwana M, Kaburaki J, Mimori T, Kawakami Y, Tojo T. Longitudinal analysis of autoantibody response to topoisomerase I in systemic sclerosis. Arthritis Rheum 2000;43:1074-84. 13. He´nault J, Robitaille G, Sene´cal JL, Raymond Y. DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti-topoisomerase I autoantibodies from systemic sclerosis patients. Arthritis Rheum 2006;54:963-73.
INTRODUCTION Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive fibrosis of the skin and internal organs. Although the pathogenesis of SSc remains unclear, the presence of antinuclear antibodies (ANA) is a representative feature.1 More than 90% of patients with SSc are positive for ANA, and anti-DNA topoisomerase I antibody (antietopo I) and anticentromere antibody are two representative ANA found in patients with SSc. The percentage of Japanese patients who have antietopo I or anticentromere antibodies is approximately 30% and 40%, respectively.2,3 Previous studies have revealed that patients with antietopo I generally display extensive skin thickening and frequently have severe internal organ involvement, such as
Abbreviations used: ANA: antinuclear antibodies antietopo I: anti-DNA topoisomerase I MRSS: modified Rodnan total skin score SSc: systemic sclerosis
pulmonary fibrosis.3,4 It is thought that the titers of SSc-specific ANA do not change during the disease course. Herein we describe a patient with SSc who had worsened skin sclerosis and re-emergence of antietopo I after discontinuation of corticosteroid treatment, and in whom skin sclerosis and serum antietopo I had previously disappeared.
CASE REPORT
From the Department of Dermatology, Kanazawa University Graduate School of Medical Science. Supported by a grant-in-aid from the Ministry of Health and Welfare of Japan (to M. F.). Conflicts of interest: None declared. Reprint requests: Yasuhito Hamaguchi, MD, PhD, Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan. E-mail: [email protected]. Published online September 7, 2009. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.01.032
142
A 41-year-old woman was admitted to our hospital with skin sclerosis. She had noticed sclerodactyly for 9 months and Raynaud’s phenomenon for 7 months before consultation, but she had not taken any drugs. Physical examination revealed sclerosis of the skin on her fingers, hands, toes, limbs, chest, neck, and face. Her modified Rodnan total skin score (MRSS) was 20 points. Punctuate hemorrhages of the nailfold capillaries, pitting scars on the fingertips, phalangeal contracture, and diffuse pigmentation involving her upper limbs were observed. Laboratory findings at admission were within normal limits, other than positive ANA. ANA had a
Case reports 143
J AM ACAD DERMATOL VOLUME 62, NUMBER 1
and the patient’s skin sclerosis improved, along with a reduction in the antietopo I level.
DISCUSSION
Fig 1. Serial changes in serum antietopo I antibody levels in our patient who showed a decrease in antibody level in parallel with significant improvement in MRSS. Bold lines indicate MRSS; dashed lines indicate antietopo I antibody levels determined by enzyme-linked immunosorbent assay.
homogeneous pattern with nucleolar staining, and the ANA titer was 1:320. The antietopo I level was evaluated with a specific enzyme-linked immunosorbent assay, carried out according to the manufacturer’s instructions (MBL Corp, Nagoya, Japan). The assay was calibrated in relative arbitrary units and more than 16 index was considered positive. The antietopo I level was elevated to 78.1 index. The patient’s serum was negative for other ANA. A forearm skin biopsy specimen showed thickened homogeneous collagen bundles in all layers of the dermis. She had slight bibasilar pulmonary interstitial shadows, but pulmonary fibrosis was considered to be inactive by a pulmonary function test. Therefore the diagnosis was diffuse cutaneous SSc. Treatment with oral prednisolone (0.5 mg/kg body weight) was started (Fig 1). Her skin sclerotic changes improved slowly, and the prednisolone dosage was decreased gradually. Skin sclerosis disappeared completely by 8 years after her first admission, and prednisolone was stopped. The patient’s antietopo I level was below detectable limits when the prednisolone was stopped. Nine years after her first admission, antietopo I reemerged, and the index was 22.9. Ten months after the re-emergence of antietopo I, the patient again showed sclerodactyly. Raynaud’s phenomenon continued after the discontinuation of prednisolone, but it became more severe after the appearance of sclerodactyly. Thereafter, the patient developed sclerosis of the skin on her fingers and hands, with an MRSS of 4 points at 8 months after the reemergence of antietopo I. The antietopo I index increased to 102.1. Pulmonary fibrosis was not advanced. Oral prednisolone (0.4 mg/kg body weight) was re-started,
SSc-related ANA are closely associated with disease subset and organ involvement. It is well described that clinical features are not identical among different ethnic groups.2,3,5 Corticosteroids are commonly avoided for Caucasian or black patients, as steroids could induce scleroderma renal crisis.6 In contrast, corticosteroids are used occasionally to treat skin sclerosis in Japanese patients, as renal involvement rarely occurs in Japanese individuals, especially those without anti-RNA polymerase antibodies.2,3 Careful observation is recommended in some cases, as skin sclerosis generally regresses spontaneously several years after the onset of the disease.7 We treated our patient with an oral corticosteroid that resulted in improvement of the skin sclerosis without renal crisis. Therefore, corticosteroid treatment might be useful in certain individuals. However, the possibility could not be ruled out that the improvement in skin sclerosis reflected only spontaneous regression. The presence of ANA is one hallmark of immunological abnormality in SSc.8 Generally, ANA levels are almost constant and do not reflect disease activity, in contrast with the double-stranded DNA antibody that is detected in systemic lupus erythematosus. Changes in antietopo I levels have not been associated with any particular clinical manifestations.9 However, a correlation of serum antietopo I levels with disease severity and activity has been described in SSc.10 We also reported that decreased levels of antietopo I were accompanied mainly by atrophic skin changes during the follow-up period, whereas increasing levels were associated with new onset or worsening of organ involvement.11 Additionally, 6 SSc patients in whom antietopo I disappeared had less extensive skin and lung involvement than patients in whom antietopo I persisted.12 Corticosteroids may reduce the number of autoreactive B cells that produce antietopo I and result in the reduction of antietopo I levels. Thus it is likely that antietopo I levels have a potential significance in evaluating the severity and prognosis of SSc. In conclusion, our case suggests that oral corticosteroid administration might be effective for skin sclerosis by suppression of autoantibody production in SSc. Moreover, it appeared that discontinuation of the corticosteroid became a trigger for the re-emergence of antietopo I and a new onset of skin sclerosis. However, the exact mechanisms involved in the reduction of autoantibody levels are unknown. It has been reported that the autoantigen topo I itself bound specifically to fibroblasts, where it was recognized by antietopo I from SSc patients.
144 Case reports
J AM ACAD DERMATOL JANUARY 2010
The binding of antietopo I subsequently stimulated adhesion and activation of monocytes, resulting in amplification of the fibrogenic cascade by a topo I/antietopo I complex. Therefore antietopo I might have a pathogenic role in SSc.13 Further study will be needed to reveal the biological significance of antietopo I in the development of SSc and the influence of corticosteroids on the modification of immunological abnormalities. REFERENCES 1. Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol 1989;44:93-151. 2. Kuwana M, Kaburaki J, Okano Y, Tojo T, Homma M. Clinical and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis. Arthritis Rheum 1994;37:75-83. 3. Hamaguchi Y, Hasegawa M, Fujimoto M, Matsushita T, Komura K, Kaji K, et al. The clinical relevance of serum antinuclear antibodies in Japanese patients with systemic sclerosis. Br J Dermatol 2008;158:487-95. 4. Shero JH, Bordwell B, Rothfield NF, Earnshaw WC. High titers of autoantibodies to topoisomerase I (Scl-70) in sera from scleroderma patients. Science 1986;231:737-40. 5. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005;35:35-42.
6. Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 1998; 41:1613-9. 7. Steen VD, Medsger TA Jr. Epidemiology and natural history of systemic sclerosis. Rheum Dis Clin North Am 1990;16:1-10. 8. Reveille JD, Solomon DH. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum 2003;49:399-412. 9. Va´zquez-Abad D, Russell CA, Cusick SM, Earnshaw WC, Rothfield NF. Longitudinal study of anticentromere and antitopoisomerase-I isotypes. Clin Immunol Immunopathol 1995;74:257-70. 10. Hu PQ, Fertig N, Medsger TA Jr, Wright TM. Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Arthritis Rheum 2003;48:1363-73. 11. Sato S, Hamaguchi Y, Hasegawa M, Takehara K. Clinical significance of anti-topoisomerase I antibody levels determined by ELISA in systemic sclerosis. Rheumatology 2001;40: 1135-40. 12. Kuwana M, Kaburaki J, Mimori T, Kawakami Y, Tojo T. Longitudinal analysis of autoantibody response to topoisomerase I in systemic sclerosis. Arthritis Rheum 2000;43:1074-84. 13. He´nault J, Robitaille G, Sene´cal JL, Raymond Y. DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti-topoisomerase I autoantibodies from systemic sclerosis patients. Arthritis Rheum 2006;54:963-73.