CED
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Fibroblastic rheumatism: the first case with infiltration of multinuclear giant cells and raised blood lead level X. W. Zou, J. Huo, J. M. Wang, J. Y. Yuan, Y. Y. Ma and Q. Y. Wang Department of Dermatology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China doi:10.1111/ced.12542
Summary
Fibroblastic rheumatism (FR) is a rare condition characterized by symmetrical polyarthritis and multiple cutaneous nodules. Approximately 30 cases have been reported worldwide to date. Laboratory tests are not particular useful to confirm the disease. Diagnosis is mainly dependent on the characteristic histopathological features: thickened collagen fibres with spindle-shaped cell proliferation in the skin lesion. We report a case of a 48-year-old Chinese man with typical clinical features of FR. In addition to the characteristic histopathological findings, multinuclear giant cell infiltration in skin lesions was detected, in this case. The evaluation of microelements revealed a raised blood lead level) of 129 lg/L (normal range 0–99 lg/L) These two features have never been described in the previous medical literature on FR. Thus, we propose that examining the infiltrated cells in detail in histopathological studies and inspecting the levels of lead and other microelements in the blood may increase our understanding of the pathogenesis of FR.
Fibroblastic rheumatism (FR) is a very rare dermatoarthropathy, originally described by Chaouat et al. in 1980.1 Only around 30 cases have been reported worldwide. This disease is characterized by symmetrical polyarthritis and multiple cutaneous nodules. Confirmative diagnosis is derived from the distinctive histopathological features of the skin nodules.2–6 We describe, for the first time to our knowledge, a case of FR with multinuclear giant cell infiltration and raised blood lead level (BLL).
Report A previously healthy 48-year-old man presented with a 1-year history of cutaneous nodules and a Correspondence: Dr Qiongyu Wang, Department of Dermatology, The Second Affiliated Hospital of Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an, Shaanxi Province 710004, China E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. The first two authors contributed equally to this work and should be considered joint first authors. Accepted for publication 20 June 2014
ª 2014 British Association of Dermatologists
6-month history of rapidly progressive articular contractures. Physical examination revealed numerous fleshcoloured to erythematous, firm, smooth, flat, freely mobile papules and nodules, 2–5 mm in diameter and nontender to touch, which were symmetrically distributed over the extensor surface of the patient’s metacarpophalangeal and interphalangeal joints, his palms, and over his abdomen and upper arms. There were obvious joint contractures without any redness or swelling involving all fingers, especially the little fingers, presenting a ‘main en griffe’ (claw hand) appearance (Fig. 1a). There was no sclerodactyly, Raynaud phenomenon, calcinosis or palmoplantar thickening. From the onset of the disease to presentation, there was no fever, weight loss or pruritus. Radiography showed periarticular osteopenia without joint destruction involving the interphalangeal, metacarpophalangeal, shoulder and hip joints (Fig. 1b). Magnetic resonance imaging suggested no soft-tissue damage. Thickened and disorganized collagenous fibres with marked proliferation of spindle cells were the most prominent histological feature of the skin nodules (Fig. 2a). Blood vessels and appendages with normal
Clinical and Experimental Dermatology (2015) 40, pp309–312
309
FR presenting with infiltration of multinuclear giant cells and raised blood lead level X. W. Zou et al.
(a)
(b)
Figure 1 (a) Flesh-coloured to erythematous papules and nodules
symmetrically distributed over the extensor surface of the fingers. The patient’s hands showed a ‘main en griffe’ appearance with obvious contracture. (b) Radiography of the hands revealed periarticular osteoporosis, but no erosion.
construction were surrounded by dense collagen fibres (Fig. 2b). Mild perivascular dermal inflammatory infiltrates composed of mononuclear histiocytes and multi(a)
nucleated giant cells without a ‘ground-glass’ appearance were observed (Fig. 2b). Immunohistochemistry showed that the spindle cells were positive for vimentin, and negative for smooth muscle actin (SMA), desmin and CD68. Mononuclear histocytes and multinucleated giant cells were positive for CD68, but not for CD1a, CD4 or CD8. Weigert– Unna–Taenzer staining showed absence of elastic fibres (Fig. 3). Laboratory investigations of microelements (including zinc, iron, calcium, magnesium, lead and copper) was initially made to assess blood calcium level to explore the cause of the osteopenia. Unexpectedly, the results revealed only an increased BLL of 129 lg/L (normal range 0–99 lg/L). All the other routine and immunological tests were negative or within normal ranges, including anti-streptolysin O antibodies, rheumatoid factor, C-reactive protein, erythrocyte sedimentation rate (ESR), antinuclear antibodies, anti-doublestranded DNA antibody, and anti-CCP, anti-Jo-1, antiSSA and anti-SSB antibodies. The diagnosis of FR was based on the unique histopathological features, skin nodules, joint symptoms and nondiagnostic serology test. Other conditions such as rheumatoid arthritis or multicentric reticulohistiocytosis could not explain all these characteristics. The patient was prescribed oral thalidomide 100 mg/day, along with calcium supplementation and lead-excreting treatment. After 3 months, the skin lesions and articular symptoms remained clinically unchanged without obvious recession or progress. BLL was within the normal range. The patient is undergoing regular follow-up. FR remains unfamiliar to most clinicians. Without sufficient consideration of skin features, the arthritic (b)
Figure 2 (a) Skin biopsy from the finger showed dense collagen fibres with marked proliferation of spindle cells (arrow). (b) Blood ves-
sels with normal construction were surrounded by dense collagen fibres. Mild infiltration of mononuclear histiocytes and multinucleated giant cells (arrow) without ‘ground-glass’ appearance were visible. Haematoxylin and eosin, original magnification (a) 9 40; (b,c) 9 200.
310
Clinical and Experimental Dermatology (2015) 40, pp309–312
ª 2014 British Association of Dermatologists
FR presenting with infiltration of multinuclear giant cells and raised blood lead level X. W. Zou et al.
(a)
(b)
(c)
(d)
Figure 3 Immunohistochemical examination: (a) Spindle cells were positive for vimentin (original magnification 9 100). (b) Absence of elastic fibres (Weigert–Unna–Taenzer stain, original magnification 9 100). (c) Spindle cells were negative for smooth muscle actin (original magnification 9 100). (d) Histiocytes and multinucleated giant cells, but not spindle cells, were positive for CD68 (original magnification 9 100).
complaints may be easily confused with other rheumatic disorders. Multiple cutaneous nodules (mainly involving the periarticular sites of the hands) and symmetrical polyarthritis are the typical clinical presentations. The course of the disease is variable, and joint deformities with severe destruction on radiography may be present. Severe functional disability of the hands is common due to flexion contracture of the fingers, with a ‘main en griffe’ appearance. Simultaneous phenomena such as slerodactyly,1–3 Raynaud phenomenon1,3,4 and fever1 have also been reported previously, but were absent in our patient. The cutaneous histopathological features, characterized by thickened collagenous fibres occasionally arranged in a ‘whorling’ pattern and marked proliferation of spindle cells, are pivotal for the diagnosis.1–8 Recent immunohistochemical studies have shown that most of the spindle cells are positive for SMA or vimentin, but negative for most histiocytic/dendrocytic markers (CD68, S100 and CD1a), indicating myofibroblastic differentiation.5 Of note, CD68 is not a selective macrophage marker, and is also found in nonhaematopoietic cells such as fibroblasts and endothelial cells.9 There-
ª 2014 British Association of Dermatologists
fore, it is difficult to conclude that the origin is histiocytic, although Lee et al.4 observed a few CD68+ spindle cells. Inflammatory infiltrate has been described in previous literature, and is composed of macrophages and lymphocytes.3–5 To our knowledge, the case of FR presented in this paper is the first with multinuclear giant cell infiltration in the skin lesions. Recent studies have highlighted the important role of inflammatory cells in FR. For example, two phases of the inflammatory response (initial inflammatory phase and chronic phase) have been recognized by the cell density of the lesions.6 In addition, some studies have indicated that fibrogenic cytokines (such as transforming growth factor-b), secreted by the macrophages and lymphocytes in the initial inflammatory phase, may be important stimuli in mediating fibroblastic proliferation and myofibroblastic differentiation. Romas et al.7 suggested that factors responsible for transdifferentiation of fibroblasts also stimulate the secretion of matrix metalloproteinases and/or promote collagen phagocytosis by myofibroblasts, leading to joint destruction. The multinuclear giant cell infiltration reported in this case adds to the features that
Clinical and Experimental Dermatology (2015) 40, pp309–312
311
FR presenting with infiltration of multinuclear giant cells and raised blood lead level X. W. Zou et al.
must be considered in the aetiology and pathogenesis of FR. but its definite role needs further investigation. Except for raised ESR, observed occasionally in the acute stage,8 laboratory tests are usually nondiagnostic for FR. However, the laboratory analysis for microelements revealed a raised BLL in this case. Upon further questioning of the patient, he reported that he had worked for 3 years in a foundry 10 years previously, which involved extensive exposure to lead. Lead and other microelements (such as Ca, Cu, Zn and Fe) can affect the metabolism of the whole body, including the bones and skin. For example, lead exposure results in bone dysplasia and osteonecrosis.10 FR involves both skin and joints, and osteoporosis and bone destruction were seen on our patient’s radiographs. Given these findings, it is important to further determine whether changes in lead or other microelement levels are contributing factors in the aetiology and pathogenesis of FR. Microelement levels have not been studied in previous reports. Our findings suggest that clinicians should examine microelement levels regularly when evaluating patients with FR. Overall, our study suggests that detailed examination of the infiltrated cells during histopathological examination along with evaluation of blood microelement levels may promote further understanding of the pathogenesis of FR.
Learning points • FR is a very rare dermatoarthropathy. • The diagnosis is confirmed by histopathological
features showing thickened collagen fibres with proliferation of spindle-shaped cells in skin lesions. • Joint deformities with severe destruction on radiography may develop, thus early detection and treatment of FR are required. • Recent studies have tended to highlight the important roles of these inflammatory cells in FR. • Fibrogenic cytokines secreted by these cells may be important stimuli in mediating fibroblastic proliferation and myofibroblastic differentiation. • Microelement inspection should be given adequate attention in laboratory investigations, as it may be another clue to the pathogenesis of FR.
312
Clinical and Experimental Dermatology (2015) 40, pp309–312
Acknowledgements We thank Dr S. Doty for her valuable assistance in editing the manuscript.
References 1 Chaouat Y, Aron-Brnetiere R, Faures B et al. Une nouvelle entite: le rheumatisme fibloblastique. Rev Rhum Mal Osteoartic 1980; 47: 345–51. 2 Taccari E, Teodori S, Zoppini A. Fibroblastic rheumatism of the elderly. Histopathological, ultrastructural data and problems of differential diagnosis. Rev Rhum Mal Osteoartic 1987; 54: 463. 3 Marconi IML, Rivitti-Machado MC, Sotto MN et al. Fibroblastic rheumatism. Clin Exp Dermatol 2008; 34: 29–32. 4 Lee JM, Sundel RP, Liang MG. Fibroblastic rheumatism: case report and review of the literature. Pediatr Dermatol 2002; 19: 532–5. 5 Fam AG, Hanna W, Mak V et al. Fibroblastic rheumatism: clinical and histologic evolution of cutaneous manifestations. J Rheumatol 1998; 25: 2261– 6. 6 du Toit R, Schneider JW, Whitelaw DA. Fibroblastic rheumatism. J Clin Rheumatol 2006; 12: 201–3. 7 Romas E, Finlay M, Woodruff T. The arthropathy of fibroblastic rheumatism. Arthritis Rheum 1997; 40: 183– 7. 8 Paupitz JA, de Carvalho JF. Good clinical response to methotrexate treatment in a patient with fibroblastic rheumatism. Rheumatol Int 2012; 32: 1789– 91. 9 Gottfried E, Kunz-Schughart LA, Weber A et al. Expression of CD68 in non myeloid cell types. Scand J Immunol 2008; 67: 453–63. 10 Ferm VH, Carpenter SJ. Developmental malformations resulting from the administration of lead salts. Exp Mol Pathol 1967; 7: 208–13.
ª 2014 British Association of Dermatologists
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Fibroblastic rheumatism: the first case with infiltration of multinuclear giant cells and raised blood lead level X. W. Zou, J. Huo, J. M. Wang, J. Y. Yuan, Y. Y. Ma and Q. Y. Wang Department of Dermatology, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China doi:10.1111/ced.12542
Summary
Fibroblastic rheumatism (FR) is a rare condition characterized by symmetrical polyarthritis and multiple cutaneous nodules. Approximately 30 cases have been reported worldwide to date. Laboratory tests are not particular useful to confirm the disease. Diagnosis is mainly dependent on the characteristic histopathological features: thickened collagen fibres with spindle-shaped cell proliferation in the skin lesion. We report a case of a 48-year-old Chinese man with typical clinical features of FR. In addition to the characteristic histopathological findings, multinuclear giant cell infiltration in skin lesions was detected, in this case. The evaluation of microelements revealed a raised blood lead level) of 129 lg/L (normal range 0–99 lg/L) These two features have never been described in the previous medical literature on FR. Thus, we propose that examining the infiltrated cells in detail in histopathological studies and inspecting the levels of lead and other microelements in the blood may increase our understanding of the pathogenesis of FR.
Fibroblastic rheumatism (FR) is a very rare dermatoarthropathy, originally described by Chaouat et al. in 1980.1 Only around 30 cases have been reported worldwide. This disease is characterized by symmetrical polyarthritis and multiple cutaneous nodules. Confirmative diagnosis is derived from the distinctive histopathological features of the skin nodules.2–6 We describe, for the first time to our knowledge, a case of FR with multinuclear giant cell infiltration and raised blood lead level (BLL).
Report A previously healthy 48-year-old man presented with a 1-year history of cutaneous nodules and a Correspondence: Dr Qiongyu Wang, Department of Dermatology, The Second Affiliated Hospital of Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an, Shaanxi Province 710004, China E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. The first two authors contributed equally to this work and should be considered joint first authors. Accepted for publication 20 June 2014
ª 2014 British Association of Dermatologists
6-month history of rapidly progressive articular contractures. Physical examination revealed numerous fleshcoloured to erythematous, firm, smooth, flat, freely mobile papules and nodules, 2–5 mm in diameter and nontender to touch, which were symmetrically distributed over the extensor surface of the patient’s metacarpophalangeal and interphalangeal joints, his palms, and over his abdomen and upper arms. There were obvious joint contractures without any redness or swelling involving all fingers, especially the little fingers, presenting a ‘main en griffe’ (claw hand) appearance (Fig. 1a). There was no sclerodactyly, Raynaud phenomenon, calcinosis or palmoplantar thickening. From the onset of the disease to presentation, there was no fever, weight loss or pruritus. Radiography showed periarticular osteopenia without joint destruction involving the interphalangeal, metacarpophalangeal, shoulder and hip joints (Fig. 1b). Magnetic resonance imaging suggested no soft-tissue damage. Thickened and disorganized collagenous fibres with marked proliferation of spindle cells were the most prominent histological feature of the skin nodules (Fig. 2a). Blood vessels and appendages with normal
Clinical and Experimental Dermatology (2015) 40, pp309–312
309
FR presenting with infiltration of multinuclear giant cells and raised blood lead level X. W. Zou et al.
(a)
(b)
Figure 1 (a) Flesh-coloured to erythematous papules and nodules
symmetrically distributed over the extensor surface of the fingers. The patient’s hands showed a ‘main en griffe’ appearance with obvious contracture. (b) Radiography of the hands revealed periarticular osteoporosis, but no erosion.
construction were surrounded by dense collagen fibres (Fig. 2b). Mild perivascular dermal inflammatory infiltrates composed of mononuclear histiocytes and multi(a)
nucleated giant cells without a ‘ground-glass’ appearance were observed (Fig. 2b). Immunohistochemistry showed that the spindle cells were positive for vimentin, and negative for smooth muscle actin (SMA), desmin and CD68. Mononuclear histocytes and multinucleated giant cells were positive for CD68, but not for CD1a, CD4 or CD8. Weigert– Unna–Taenzer staining showed absence of elastic fibres (Fig. 3). Laboratory investigations of microelements (including zinc, iron, calcium, magnesium, lead and copper) was initially made to assess blood calcium level to explore the cause of the osteopenia. Unexpectedly, the results revealed only an increased BLL of 129 lg/L (normal range 0–99 lg/L). All the other routine and immunological tests were negative or within normal ranges, including anti-streptolysin O antibodies, rheumatoid factor, C-reactive protein, erythrocyte sedimentation rate (ESR), antinuclear antibodies, anti-doublestranded DNA antibody, and anti-CCP, anti-Jo-1, antiSSA and anti-SSB antibodies. The diagnosis of FR was based on the unique histopathological features, skin nodules, joint symptoms and nondiagnostic serology test. Other conditions such as rheumatoid arthritis or multicentric reticulohistiocytosis could not explain all these characteristics. The patient was prescribed oral thalidomide 100 mg/day, along with calcium supplementation and lead-excreting treatment. After 3 months, the skin lesions and articular symptoms remained clinically unchanged without obvious recession or progress. BLL was within the normal range. The patient is undergoing regular follow-up. FR remains unfamiliar to most clinicians. Without sufficient consideration of skin features, the arthritic (b)
Figure 2 (a) Skin biopsy from the finger showed dense collagen fibres with marked proliferation of spindle cells (arrow). (b) Blood ves-
sels with normal construction were surrounded by dense collagen fibres. Mild infiltration of mononuclear histiocytes and multinucleated giant cells (arrow) without ‘ground-glass’ appearance were visible. Haematoxylin and eosin, original magnification (a) 9 40; (b,c) 9 200.
310
Clinical and Experimental Dermatology (2015) 40, pp309–312
ª 2014 British Association of Dermatologists
FR presenting with infiltration of multinuclear giant cells and raised blood lead level X. W. Zou et al.
(a)
(b)
(c)
(d)
Figure 3 Immunohistochemical examination: (a) Spindle cells were positive for vimentin (original magnification 9 100). (b) Absence of elastic fibres (Weigert–Unna–Taenzer stain, original magnification 9 100). (c) Spindle cells were negative for smooth muscle actin (original magnification 9 100). (d) Histiocytes and multinucleated giant cells, but not spindle cells, were positive for CD68 (original magnification 9 100).
complaints may be easily confused with other rheumatic disorders. Multiple cutaneous nodules (mainly involving the periarticular sites of the hands) and symmetrical polyarthritis are the typical clinical presentations. The course of the disease is variable, and joint deformities with severe destruction on radiography may be present. Severe functional disability of the hands is common due to flexion contracture of the fingers, with a ‘main en griffe’ appearance. Simultaneous phenomena such as slerodactyly,1–3 Raynaud phenomenon1,3,4 and fever1 have also been reported previously, but were absent in our patient. The cutaneous histopathological features, characterized by thickened collagenous fibres occasionally arranged in a ‘whorling’ pattern and marked proliferation of spindle cells, are pivotal for the diagnosis.1–8 Recent immunohistochemical studies have shown that most of the spindle cells are positive for SMA or vimentin, but negative for most histiocytic/dendrocytic markers (CD68, S100 and CD1a), indicating myofibroblastic differentiation.5 Of note, CD68 is not a selective macrophage marker, and is also found in nonhaematopoietic cells such as fibroblasts and endothelial cells.9 There-
ª 2014 British Association of Dermatologists
fore, it is difficult to conclude that the origin is histiocytic, although Lee et al.4 observed a few CD68+ spindle cells. Inflammatory infiltrate has been described in previous literature, and is composed of macrophages and lymphocytes.3–5 To our knowledge, the case of FR presented in this paper is the first with multinuclear giant cell infiltration in the skin lesions. Recent studies have highlighted the important role of inflammatory cells in FR. For example, two phases of the inflammatory response (initial inflammatory phase and chronic phase) have been recognized by the cell density of the lesions.6 In addition, some studies have indicated that fibrogenic cytokines (such as transforming growth factor-b), secreted by the macrophages and lymphocytes in the initial inflammatory phase, may be important stimuli in mediating fibroblastic proliferation and myofibroblastic differentiation. Romas et al.7 suggested that factors responsible for transdifferentiation of fibroblasts also stimulate the secretion of matrix metalloproteinases and/or promote collagen phagocytosis by myofibroblasts, leading to joint destruction. The multinuclear giant cell infiltration reported in this case adds to the features that
Clinical and Experimental Dermatology (2015) 40, pp309–312
311
FR presenting with infiltration of multinuclear giant cells and raised blood lead level X. W. Zou et al.
must be considered in the aetiology and pathogenesis of FR. but its definite role needs further investigation. Except for raised ESR, observed occasionally in the acute stage,8 laboratory tests are usually nondiagnostic for FR. However, the laboratory analysis for microelements revealed a raised BLL in this case. Upon further questioning of the patient, he reported that he had worked for 3 years in a foundry 10 years previously, which involved extensive exposure to lead. Lead and other microelements (such as Ca, Cu, Zn and Fe) can affect the metabolism of the whole body, including the bones and skin. For example, lead exposure results in bone dysplasia and osteonecrosis.10 FR involves both skin and joints, and osteoporosis and bone destruction were seen on our patient’s radiographs. Given these findings, it is important to further determine whether changes in lead or other microelement levels are contributing factors in the aetiology and pathogenesis of FR. Microelement levels have not been studied in previous reports. Our findings suggest that clinicians should examine microelement levels regularly when evaluating patients with FR. Overall, our study suggests that detailed examination of the infiltrated cells during histopathological examination along with evaluation of blood microelement levels may promote further understanding of the pathogenesis of FR.
Learning points • FR is a very rare dermatoarthropathy. • The diagnosis is confirmed by histopathological
features showing thickened collagen fibres with proliferation of spindle-shaped cells in skin lesions. • Joint deformities with severe destruction on radiography may develop, thus early detection and treatment of FR are required. • Recent studies have tended to highlight the important roles of these inflammatory cells in FR. • Fibrogenic cytokines secreted by these cells may be important stimuli in mediating fibroblastic proliferation and myofibroblastic differentiation. • Microelement inspection should be given adequate attention in laboratory investigations, as it may be another clue to the pathogenesis of FR.
312
Clinical and Experimental Dermatology (2015) 40, pp309–312
Acknowledgements We thank Dr S. Doty for her valuable assistance in editing the manuscript.
References 1 Chaouat Y, Aron-Brnetiere R, Faures B et al. Une nouvelle entite: le rheumatisme fibloblastique. Rev Rhum Mal Osteoartic 1980; 47: 345–51. 2 Taccari E, Teodori S, Zoppini A. Fibroblastic rheumatism of the elderly. Histopathological, ultrastructural data and problems of differential diagnosis. Rev Rhum Mal Osteoartic 1987; 54: 463. 3 Marconi IML, Rivitti-Machado MC, Sotto MN et al. Fibroblastic rheumatism. Clin Exp Dermatol 2008; 34: 29–32. 4 Lee JM, Sundel RP, Liang MG. Fibroblastic rheumatism: case report and review of the literature. Pediatr Dermatol 2002; 19: 532–5. 5 Fam AG, Hanna W, Mak V et al. Fibroblastic rheumatism: clinical and histologic evolution of cutaneous manifestations. J Rheumatol 1998; 25: 2261– 6. 6 du Toit R, Schneider JW, Whitelaw DA. Fibroblastic rheumatism. J Clin Rheumatol 2006; 12: 201–3. 7 Romas E, Finlay M, Woodruff T. The arthropathy of fibroblastic rheumatism. Arthritis Rheum 1997; 40: 183– 7. 8 Paupitz JA, de Carvalho JF. Good clinical response to methotrexate treatment in a patient with fibroblastic rheumatism. Rheumatol Int 2012; 32: 1789– 91. 9 Gottfried E, Kunz-Schughart LA, Weber A et al. Expression of CD68 in non myeloid cell types. Scand J Immunol 2008; 67: 453–63. 10 Ferm VH, Carpenter SJ. Developmental malformations resulting from the administration of lead salts. Exp Mol Pathol 1967; 7: 208–13.
ª 2014 British Association of Dermatologists
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
