Skip Navigation


Rheumatology Advance Access originally published online on September 27, 2005
Rheumatology 2006 45(1):72-75; doi:10.1093/rheumatology/kei101
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
45/1/72    most recent
kei101v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Ferri, C.
Right arrow Articles by Sebastiani, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ferri, C.
Right arrow Articles by Sebastiani, M.
Related Collections
Right arrow Systemic Sclerosis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Thymus alterations and systemic sclerosis

C. Ferri, M. Colaci, L. Battolla1, D. Giuggioli and M. Sebastiani

Rheumatology Unit, University of Modena & Reggio Emilia and Policlinico di Modena, Modena, and 1 Division of Radiodiagnostic II, Azienda Ospedaliera-Universitaria Pisana, Pisa, Italy.

Correspondence to: C. Ferri, Servizio di Reumatologia, Policlinico Università di Modena, Largo del Pozzo no 71, 41100 Modena, Italy. E-mail: clferri{at}unimo.it


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. The pathogenesis of systemic sclerosis (SSc) includes complex alterations to the immune system, possibly responsible for diffuse microvasculature and fibroblast dysfunction. Previous anecdotal observations suggest a possible role for thymus alterations in some autoimmune rheumatic diseases, including SSc. This study aimed to investigate the prevalence of radiological thymus alterations in SSc patients.

Methods. Thirthy-four unselected patients [28 female and 6 male, mean age (± S.D.) 49.7 ± 9.5 yr, range 33–67 yr] and 34 age- and sex-matched controls were included in the study. The presence of major radiological thymus alterations, i.e. an abnormally enlarged or nodular thymus, were blindly investigated by means of unenhanced multidetector computed tomography.

Results. Abnormally enlarged or nodular thymuses were detected in a statistically significant percentage of SSc patients compared with controls (21 vs 0%, P = 0.011). More interestingly, radiological thymus alterations were invariably observed in patients with shorter disease duration (≤5 yr, 41% vs >5 yr, 0%; P = 0.007), frequently associated with serum anti-Scl70 antibodies (P = 0.017). Among patients with thymus alterations one developed myasthenia gravis while two others showed thymus hyperplasia at histopathological evaluation after thymectomy.

Conclusions. The present study suggests a possible role of thymic disorders, mainly thymus hyperplasia, in a significant number of SSc patients. Due to the limitations of radiological evaluation, the actual relevance of such an association might be underestimated. The relationship of thymus alterations with shorter disease duration, as well as with serum anti-Scl70, suggests that thymic dysfunction could play a pathogenetic role mostly in the early phases of the disease, and possibly in specific SSc patient subsets.

KEY WORDS: Systemic sclerosis, Scleroderma, Thymus, Thymus hyperplasia, Computed tomography


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Systemic sclerosis (SSc) is a connective tissue disease characterized by involvement of the skin and visceral organs [1]. Although the aetiology of SSc remains obscure, complex pathogenetic mechanisms are responsible for the disease, including alterations to the immune system, microvasculature and fibroblasts [1]. Immunological abnormalities may represent the underlying disorder of SSc, as suggested by T-lymphocyte alterations and production of various autoantibodies [1, 2]. The thymus plays a crucial role in immune system homeostasis [3, 4]; several anecdotal reports suggest a possible pathogenic role for thymus alterations in some immune-mediated rheumatic diseases, including SSc [5–12]. In these patients the presence of pathological thymus alterations can be occasionally suspected on the basis of radiological investigations.

The present study preliminarily investigated the prevalence of radiological thymus alterations and their correlation with clinico-epidemiological features in an unselected series of SSc patients.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Thirty-four consecutive, unselected SSc patients were included in the study. All patients gave informed consent to enter the study, which was approved by the local ethical committee. Moreover, 34 age- and sex-matched control subjects without immunological or neoplastic disorders were randomly selected from the records of our Radiological Division.

Patients with SSc were classified according to the American College of Rheumatology 1980 preliminary criteria [13]. According to the extent of skin sclerosis, patients were grouped into three cutaneous subset models [14]: limited cutaneous scleroderma (lcSSc: sclerosis of fingers with or without sclerosis of the neck and/or face), intermediate cutaneous scleroderma (icSSc: sclerosis of upper and lower limbs, neck and face, without truncal involvement) and diffuse cutaneous scleroderma (dcSSc: distal and truncal skin sclerosis) [14]. The disease duration was calculated on the basis of the age of presumed disease onset; i.e. the age at which the first signs and symptoms compatible with the disease appeared, namely Raynaud's with digital ischaemic lesions, puffy hands, sclerodactyly with or without proximal scleroderma, dyspnoea and/or dysphagia [14]. Standardized criteria were followed for the evaluation of clinical symptoms and involvement of the main visceral organs as previously described [14]. Moreover, the presence of serum autoantibodies was investigated by means of standard techniques [14], namely antinuclear (ANA) and antinucleolar antibodies (ANoA) by indirect immunofluorescence on rat liver and on Hep-2 cell lines: anticentromere antibodies (ACA); antiextractable nuclear antigen (ENA) antibodies, including anti-Scl70, anti-Sm, anti-RNP and anti-SSA/SSB.

The presence of interstitial lung involvement was investigated by standard chest X-ray, high-resolution computed tomography (HRCT) and spirometric evaluation.

The thymus alterations were evaluated in all patients and controls by unenhanced multidetector computed tomography (MDCT). Computed tomography exams were carried out at suspended end-inspiratory volume by means of a Somatom Volume Zoom 4 (Siemens, Germany). The technical parameters of MDCT examination, performed from apex to base without administration of contrast medium, were: 2.5 mm collimation, 5 mm thickness, 5 mm interval. Images of the thymus, reviewed at the mediastinal window, were then reconstructed using 3 mm thickness, 1 mm interval and a field of view small enough to include all the gland.

Radiological thymus alterations were evaluated according to the current methodology [15]: the most helpful value for thymus size was considered to be the ‘thickness’ measured perpendicular to the length, with 13 mm being the maximum normal value in adult subjects. A thymus thickness greater than 13 mm or a focal soft-tissue density of more than 7 mm can be considered specific for thymic hyperplasia or thymoma [15].

A trained radiologist evaluated, blindly and in random order, the MDCT scans of patients and controls. Radiological thymus features were classified as follows: 1, normal with complete or incomplete involution; 2, abnormally enlarged; 3, nodular thymus or mass-like or inhomogeneous in attenuation [15].

Group differences were tested for significance by Fisher's exact test and a P value of <0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
At the time of the study, the 34 SSc patients [28 female, six male, mean age (±S.D.) 49.7 ± 9.5 yr, range 33–67 yr] had a mean (±S.D.) disease duration of 8.4 ± 6.8 yr (range 1 to 33 yr). According to the skin involvement, they were classified as having limited (n = 16), intermediate (n = 11) or diffuse SSc (n = 7). The most frequent internal organ alterations were lung fibrosis (85%), and oesophageal (68%) and cardiac dysfunction (35%). Among serological markers, ANA were detected in 24/34 (71%) patients, ACA in 7/34 (21%), anti-Scl70 in 13/34 (38%) and ANoA in 1/34 (3%).

In SSc patients the MDCT revealed an abnormally enlarged thymus in 5/34 cases (15%), a nodular thymus in 2/34 (6%) and an incomplete organ involution in 9/34 (26%). This latter was detected in a comparable percentage of control subjects (29%), while neither abnormally enlarged nor nodular thymus was observed in the controls. Major radiological thymus alterations (abnormally enlarged or nodular thymus) were present in a statistically significant percentage of SSc patients compared with controls [7/34 (21%) vs 0/34 (0%), P = 0.011; Fig. 1a]. Interestingly, thymus alterations were invariably observed in patients with shorter disease duration [≤5 yr, 7/17 (41%) vs >5 yr, 0/17 (0%); P = 0.007; Fig. 1b]. Moreover, the seven patients with radiological thymus abnormalities showed the presence of serum anti-Scl70 in five and ANoA in one; while in the other patient serological markers were absent (Fig. 1c). The association between thymus abnormalities and anti-Scl70 was particularly relevant considering the subset of 15 patients with disease duration ≤5 yr: namely the prevalence of thymus alterations in anti-Scl70-positive patients was significantly higher compared with that found in anti-Scl70-negative subjects [5/6 (83%) vs 2/11 (18%); P = 0.017]. There were no significant correlations between thymus alterations and either cutaneous subsets or visceral organ involvement.



View larger version (21K):
[in this window]
[in a new window]
  		FIG. 1. Prevalence of radiological thymus alterations in (a) SSc patients and controls, (b) SSc patients with disease duration ≤5 yr and >5 yr and (c) SSc patients with different serological markers (for abbreviations see text). Considering the subset of 15 patients with disease duration ≤5 yr, the prevalence of thymus alterations in anti-Scl70-positive patients was significantly higher than that found in anti-Scl70-negative subjects (5/6 = 83% vs 2/11 = 18%; P = 0.017).

 
At the time of the study, 15 patients had been treated with immunosuppressive agents (cyclophosphamide, ciclosporin A and/or methotrexate); however, the prevalence of thymus alterations between two groups of treated and non-treated subjects was not statistical significant (26 vs 16%, respectively). In no cases had high doses of steroids been administered.

Case reports
Case 1
Since 1997 a 33-yr-old female (Fig. 2) had developed Raynaud's phenomenon, arthralgias, melanodermia, diffuse cutaneous sclerosis, skin ulcers, oesophageal and pulmonary involvement, scleroderma capillaroscopic changes and serum anti-Scl70 antibodies. The MDCT demonstrated the presence of a nodular thymus. Given the severity and the progression of the disease a therapeutic attempt with thymectomy was decided upon. Histological evaluation revealed thymic hyperplasia. However, the patient's clinical status did not change during the following 6-month period, while an improvement of the cutaneous sclerosis and stabilization of lung involvement were observed with a combined treatment with steroids, iloprost and oral cyclophosphamide.



View larger version (123K):
[in this window]
[in a new window]
  		FIG. 2. An MDCT evaluation in cases 1, 2 and 3 and in a control subject: 1, presence of nodular thymus; 2, 3, abnormally enlarged thymus; 4, complete involution of the thymus.

 
Case 2
A 33-yr-old female (Fig. 2) who had been suffering from Raynaud's phenomenon since 1994 was referred to our rheumatology unit where a diagnosis of SSc, limited cutaneous variant, was made (Raynaud's, sclerodactyly, scleroderma capillaroscopic alterations, lung fibrosis and high-titre ANoA). An MDCT study demonstrated an abnormal enlargement of the thymus. Considering the presence of active disease (recurrent skin ulcers and interstitial lung involvement) and the possible pathogenetic role of the thymus, the patient underwent a thymectomy. Thymic hyperplasia was diagnosed by histological evaluation. Consequently, the patient showed clinical improvement of both cutaneous and lung involvement, which remained stable during the following 2-yr follow-up period.

Case 3
A 67-yr-old man, (Fig. 2) suffering since 1998 from Raynaud's phenomenon, sclerodactyly, and melanodermia, was diagnosed with SSc (sclerodactyly, Raynaud's, telangiectasias, typical capillaroscopic changes, oesophageal dysmotility, lung interstitial involvement). In 2000 he developed mild bilateral ptosis and progressive limb and neck fatigue. These latter symptoms suggested the diagnosis of myasthenia gravis, confirmed by the presence of antiacetyl-choline receptor antibodies, electromyographic alterations and positive prostigmine test. An MDCT examination revealed an abnormally enlarged thymus. The patient was treated with prostigmine, steroids (prednisolone 40 mg/day) and long-term selective plasmapheresis (protein A immunoadsorption, Immunosorba, Excorim, Fresenius Hemocare GmbH, StWendel, Germany). The patient's clinical status, particularly the myasthenic symptoms showed a clear improvement. One year later the patient died due to myocardial infarction.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
The results of the present study suggest a possible role for thymic disorders in a significant number of unselected SSc patients compared with control subjects; obviously, our preliminary data need to be confirmed in other patient series. Thymic hyperplasia seems to be the main pathological alteration, as suggested by radiological features and confirmed in two cases by hystopathological evaluation. Moreover, we can hypothesize that the actual relevance of such an association might be underestimated due to the following considerations. Although the current methodology, based on the measurement of gland thickness and focal soft-tissue density, is considered as the best non-invasive diagnostic approach [15], we cannot exclude possible false-negative results. Previous studies on large series of patients with myasthenia gravis, comparing radiological findings with histopathological diagnosis after thymectomy, support this hypothesis [16]. Besides, incomplete thymus involution, as well as residual ectopic thymus, can hide small areas of functional tissue. On the other hand, the striking correlation between thymus alterations and shorter disease duration suggests that thymic dysfunction could play a pathogenetic role mostly in the early phases of the disease. In addition, thymic dysfunction might be particularly involved in specific SSc subsets, as indirectly suggested by the frequent anti-Scl70 seropositivity in patients with thymus alterations and, vice versa, the constant absence of ACA. These autoantibodies are regarded as hallmarks of different clinico-prognostic SSc subsets, possibly related to specific aetiopathogenetic factors [1, 2, 14]. Thus, future studies should evaluate larger SSc series by stratifying patients according to disease duration and other clinico-epidemiological and serological features.

Thymus morphology varies considerably with age; gland involution proceeds from puberty to the age of about 25 yr [17]. Previous radiological investigations clearly demonstrated the absence of significant thymus abnormalities in normal subjects over the age of 30 yr [17]. If so, the possible relevance of false-positive results due to age-related residual thymus can be excluded in our patients series. Similarly, the possible effects of immunosuppressive treatments on the MDCT findings can be reasonably ruled out.

The presence of thymic hyperplasia in SSc has been suggested on the basis of anecdotal observations, but not sufficiently investigated in large patients series [15, 17]. This is the first attempt to evaluate the possible involvement of the thymus in the SSc. The disease is characterized by a wide spectrum of clinical variants, suggesting a multifactorial and multistep pathogenetic mechanism, including complex alterations to the immune system. Different causative factors, i.e. infectious and/or toxic agents, have been proposed in the pathogenesis of SSc, although their exact role still remains to be definitely established [1, 2]. Moreover, the thymus exerts a key role in the balance between tolerance and immunity [3, 4]. The recognition of self and foreign peptides is fundamental in physiological conditions, while its failure may be crucial in the pathogenesis of various autoimmune disorders [3, 4]. The thymic stromal cells and hormones play a key role in modulating the immune reactions through their effects on T-lymphocyte differentiation of both helper and suppressor/cytotoxic cells. The role of thymic dysfunction has been investigated in both murine models [18] and autoimmune diseases of humans [19]. In SSc, different defects of T lymphocytes have been reported, even if their exact pathogenetic role remains largely obscure, probably due to the small number and the inhomogeneity of patient series investigated [2]. On the other hand, the lack of suitable animal models of scleroderma represents a further limitation. In rare conditions simulating the clinical features of SSc, such as in UCD L200 chickens, the presence of abnormalities of the thymic microenvironment might induce altered T-cell differentiation that may predispose to autoimmune disease [18]. Thymic dysfunction might be crucial in the inducing phase of the disease when the correct recognition of potentially triggering factor(s) is determinant, with the possible contribution of a genetically driven immune reactivity [2]. Successively, we can hypothesize the presence of a self-perpetuating, thymus-independent mechanism of disease. Moreover, in patients with advanced SSc we can observe the natural involution of the thymus, probably accelerated by diffuse scleroderma organ fibrosis. The timing of thymus dysfunction during the natural history of SSc might be crucial; it can be indirectly suggested by the variability of radiological findings observed in our SSc patients, characterized by a wide range of disease durations. Finally variable polarization of thymus activity [5, 20] could explain the contrasting effects of thymectomy observed in our two patients.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Black CM, Denton CP. Scleroderma and related disorders in adults and children. In: Isenberg DA, Maddison PJ, Woo P, Glass D, Breedveld FC (eds). Oxford Textbook of Rheumatology, Vol. 2. Oxford: Oxford University Press, 2004:872–95.
  2. White B. Immunopathogenesis of systemic sclerosis. Rheum Dis Clin North Am 1996;22:695–708.[CrossRef][ISI][Medline]
  3. Gorozny JJ, Weyand CM. Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis. Trends Immunol 2001;22:251–5.[CrossRef][ISI][Medline]
  4. Seddon B, Mason D. The third function of the thymus. Immunol Today 2000;21:94–9.
  5. Boonen A, Rennenberg R, van der Linden S. Thymoma-associated systemic lupus erythematosus, exacerbating after thymectomy. A case report and review of the literature. Rheumatology 2000;39:1044–6.[Free Full Text]
  6. Levy Y, Afek A, Sherer Y et al. Malignant thymoma associated with autoimmune diseases: a retrospective study and review of the literature. Semin Arthritis Rheum 1998;28:73–9.[CrossRef][Medline]
  7. Biggart JD, Nevin NC. Hyperplasia of the thymus in progressive systemic sclerosis. J Pathol Bacteriol 1967;93:334–7.[Medline]
  8. Carter J, Ewen SW, Gray E, Beck JS. The thymus in systemic sclerosis. J Pathol 1973;110:97–100.[Medline]
  9. Sundstrom C. Thymoma in a case of scleroderma. Acta Path Microbiol Scand A 1976;84:317–21.
  10. Ben-Shahar M, Rosenblatt R, Green J, Cohen I. Case report: malignant thymoma associated with progressive systemic sclerosis. Am J Med Sci 1987;294:262–7.[Medline]
  11. Hausmanowa-Petrusewicz I, Blaszczyk M, Jablonska S. Coexistence of scleromyositis associated with PM-Scl antibody and myasthenia. Neuromuscular Disord 1995;5:145–7.[Medline]
  12. Sakuragi T, Furukawa T, Yonemura T, Yoshida T, Irie K. Thymoma associated with progressive systemic sclerosis-a case report. Nippon Kyobu Geka Gakkai Zassh 1995;43:135–8.
  13. Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581–90.[ISI][Medline]
  14. Ferri C, Valentini G, Cozzi F et al. Systemic sclerosis—demographic, clinical and serologic features and survival in 1012 Italian patients. Medicine 2002;81:139–53.[CrossRef][Medline]
  15. Naidich DP. Computed tomography and magnetic resonance of the thorax. Philadelphia: Lippincott-Raven, 1999:57–73.
  16. Nicolaou S, Muller NL, Li DK, Oger JJ. Thymus in myasthenia gravis: comparison of CT and pathologic findings and clinical outcome after thymectomy. Radiology 1996;201:4771–4.
  17. Francis IR, Glazer GM, Bookstein FL, Gross BH. The thymus: reexamination of age-related changes in size and shape. Am J Roentgenol 1985;145:249–54.[Abstract/Free Full Text]
  18. Boyd RL, Wilson TJ, Van De Water J, Haapanen LA, Gershwin ME. Selective abnormalities in the thymic microenvironment associated with avian Scleroderma, an inherited fibrotic disease of L200 chickens. J Autoimm 1991;4:369–80.
  19. Hoffacker V, Schultz A, Tiesinga JJ et al. Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease. Blood 2000;96:3872–9.[Abstract/Free Full Text]
  20. Shoenfeld Y, Lorber M, Yucel T, Yazici H. Primary antiphospholipid syndrome emerging following thymectomy for myasthenia gravis: additional evidence for the kaleidoscope of autoimmunity. Lupus 1997;6:474–6.[Abstract/Free Full Text]
Submitted 24 February 2005; revised version accepted 5 August 2005.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Rheumatology (Oxford)Home page
A. Antonelli, C. Ferri, P. Fallahi, S. M. Ferrari, D. Giuggioli, M. Colaci, A. Manfredi, S. Frascerra, F. Franzoni, F. Galetta, et al.
CXCL10 ({alpha}) and CCL2 ( ) chemokines in systemic sclerosis a longitudinal study
Rheumatology, January 1, 2008; 47(1): 45 - 49.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
45/1/72    most recent
kei101v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Ferri, C.
Right arrow Articles by Sebastiani, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ferri, C.
Right arrow Articles by Sebastiani, M.
Related Collections
Right arrow Systemic Sclerosis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?