Journal of the American Academy of Dermatology
Volume 62, Issue 1 , Pages 142-144, January 2010

Re-emergence of anti-topoisomerase I antibody with exacerbated development of skin sclerosis in a patient with systemic sclerosis

published online 07 September 2009.

Article Outline

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 anti–topoisomerase I antibody (anti–topo 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 anti–topo I levels became undetectable. Prednisolone was eventually discontinued; however, 10 months after discontinuation, anti–topo 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 anti–topo I levels. Therefore, discontinuation of corticosteroids may have triggered the re-emergence of anti–topo I and skin sclerosis. This case suggests a role for anti–topo I in the pathogenesis of systemic sclerosis and an effect of corticosteroids on skin sclerosis and autoantibody production.

Abbreviations used: ANA, antinuclear antibodies, anti–topo I, anti-DNA topoisomerase I, MRSS, modified Rodnan total skin score, SSc, systemic sclerosis

 

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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 (anti–topo I) and anticentromere antibody are two representative ANA found in patients with SSc. The percentage of Japanese patients who have anti–topo I or anticentromere antibodies is approximately 30% and 40%, respectively.2, 3 Previous studies have revealed that patients with anti–topo I generally display extensive skin thickening and frequently have severe internal organ involvement, such as 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 anti–topo I after discontinuation of corticosteroid treatment, and in whom skin sclerosis and serum anti–topo I had previously disappeared.

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Case report 

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 homogeneous pattern with nucleolar staining, and the ANA titer was 1:320. The anti–topo 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 anti–topo 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 anti–topo I level was below detectable limits when the prednisolone was stopped.

  • View full-size image.
  • Fig 1. 

    Serial changes in serum anti–topo 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 anti–topo I antibody levels determined by enzyme-linked immunosorbent assay.

Nine years after her first admission, anti–topo I reemerged, and the index was 22.9. Ten months after the re-emergence of anti–topo 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 anti–topo I. The anti–topo I index increased to 102.1. Pulmonary fibrosis was not advanced. Oral prednisolone (0.4 mg/kg body weight) was re-started, and the patient's skin sclerosis improved, along with a reduction in the anti–topo I level.

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Discussion 

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 anti–topo I levels have not been associated with any particular clinical manifestations.9 However, a correlation of serum anti–topo I levels with disease severity and activity has been described in SSc.10 We also reported that decreased levels of anti–topo 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 anti–topo I disappeared had less extensive skin and lung involvement than patients in whom anti–topo I persisted.12 Corticosteroids may reduce the number of autoreactive B cells that produce anti–topo I and result in the reduction of anti–topo I levels. Thus it is likely that anti–topo 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 anti–topo 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 anti–topo I from SSc patients. The binding of anti–topo I subsequently stimulated adhesion and activation of monocytes, resulting in amplification of the fibrogenic cascade by a topo I/anti–topo I complex. Therefore anti–topo I might have a pathogenic role in SSc.13 Further study will be needed to reveal the biological significance of anti–topo I in the development of SSc and the influence of corticosteroids on the modification of immunological abnormalities.

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References 

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  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
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  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;43:1074–1084
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 Supported by a grant-in-aid from the Ministry of Health and Welfare of Japan (to M. F.).

 Conflicts of interest: None declared.

PII: S0190-9622(09)00129-7

doi:10.1016/j.jaad.2009.01.032

Journal of the American Academy of Dermatology
Volume 62, Issue 1 , Pages 142-144, January 2010