- Email: [email protected]
Lack of association between familial Mediterranean fever and angiotensin converting enzyme gene polymorphism
334
Letters to the editor / Joint Bone Spine 73 (2006) 329–337
1. Case report
References
A man born in 1941 received a diagnosis of rheumatoid arthritis (RA) in 1960. The limited disease activity was well controlled by an antimalarial in combination with 5–10 mg of prednisone per day. In late 2000, after an increase in the prednisone dosage, he experienced Staphylococcus aureus septicemia and septic arthritis of the elbow. In April 2002, worsening of the joint symptoms prompted add-on therapy with IL-1Ra (anakinra), 100 mg/day. Il-1Ra was preferred over a TNFα antagonist because of the history of severe infection. Satisfactory disease control was achieved. In June 2004, total hip arthroplasty on the right was followed by an uneventful postoperative recovery. In January 2005, a biopsy of a pigmented skin lesion behind the right ear showed malignant melanoma. The IL-1Ra was stopped. Because the lymph nodes draining the tumor area were enlarged, extensive excision with node dissection was performed. Metastases were identified in several cervical nodes and in the right parotid gland. The stage was T3a, N3, M1. The RA was stable with a rheumatoid factor titer of 15 U/ml, negative tests for antinuclear antibodies, and radiological fusion of the carpal bones. The patient was positive for HLA DRB1*04,13. Adjuvant chemotherapy with fotemustine (100 mg/m2) was given.
[1] Geborek P, Bladström A, Turesson C, Gulfe A, Petersson IF, Saxsne T, et al. Tumor necrosis factor blockers do not increase overall tumor risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 2005;64:699–703. [2] Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N, et al. Risks of solid cancers in patients with rheumatoid arthritis and following treatment with TNF antagonists. Ann Rheum Dis 2005;64:1421–6. [3] La E, Rundhaug JE, Fischer SM. Role of intracellular interleukin-1 antagonist in skin carcinogenesis. Mol Carcinog 2001;30:218–23. [4] Bar D, Apte RN, Voronov E, Dinarello CA, Cohen S. A continuous delivery system of IL-1 receptor antagonist reduces angiogenesis and inhibits tumor development. FASEB J 2004;18:161–3. [5] McKenzie RC, Oran A, Dinarello CA, Sauder DN. Interleukin-1 receptor antagonist inhibits subcutaneous B 16 melanoma growth in vivo. Anticancer Res 1996;16:437–41. [6] Weinreich DM, Elaraj DM, Puhlmann M, Hewitt SM, Carroll NM, Feldman ED, et al. Effect of interleukin 1 receptor antagonist gene transduction on human melanoma xenografts in nude mice. Cancer Res 2003;63: 5957–61.
2. Discussion Metastatic malignant melanoma occurred in our patient after 2½ years of IL-1Ra therapy for RA. The only additional cause of immunodepression was prednisone therapy in daily dosages no greater than 10 mg. The occurrence of solid cancer or lymphoma is a potential source of concern in patients receiving biologic agents to treat inflammatory diseases such as RA. Registries have been established, although most of the data pertain to TNFα antagonists. With current follow-ups, there is no evidence indicating an increase in the incidence of solid cancer [1,2]. IL-1Ra was introduced more recently, so that the number of exposed patient is smaller. We are not aware of previous reports of malignant melanoma during IL-1Ra therapy in the international literature or the French drug surveillance registry. IL-1 is a proinflammatory cytokine that stimulates angiogenesis and promotes tumor growth and metastatic dissemination. IL-1Ra blocks these effects, thereby inhibiting the proliferation of skin tumor cell lines [3,4], inhibiting the growth of murine melanoma cells [5], and reducing the in vivo growth and metastatic potential of human melanoma xenografts, which constitutively produce IL-1 [6]. Conventional disease-modifying anti-rheumatic drugs are not known to increase the risk of melanoma. Although the occurrence of melanoma in our patient may have been coincidental, the development of metastatic malignant melanoma during IL-1Ra therapy is an atypical event that contradicts current pathophysiological concepts. Our case emphasizes the importance of postmarketing surveillance and of registries for side effects of new treatments.
Daniel Wendling* Rheumatology Department, Minjoz Teaching Hospital, 25030 Besançon, France E-mail address: [email protected] (D. Wendling). François Aubin Dermatology Federation, Saint-Jacques Teaching Hospital, 25030 Besançon, France Received 18 June 2005; accepted 18 August 2005 Available online 28 February 2006 *Corresponding
author.
1297-319X/$ - see front matter © Elsevier SAS. All rights reserved. doi:10.1016/j.jbspin.2005.08.004
Lack of association between familial Mediterranean fever and angiotensin converting enzyme gene polymorphism Keywords: Familial Mediterranean fever; Renin–angiotensin Angiotensin converting enzyme gene polymorphism
system;
1. Introduction Familial Mediterranean fever (FMF) is an autosomal recessive disorder of unknown etiology. Although our understanding of the pathogenesis and genetics of FMF has greatly enhanced after the discovery of the MEFV/marenostrin gene, genetic susceptibility to FMF can not be solely attributed to the mutations in MEFV/marenostrin gene [1]. Hence, identification of other susceptibility loci is currently awaited. FMF is characterized by recurrent serosal, synovial and/or cutaneous inflammation. Moreover, those patients have subclinical inflammation in the attack-free periods [2]. Recent advances demonstrated that angiotensin II is an important component of the inflammatory response [3]. Angiotensin convert-
Letters to the editor / Joint Bone Spine 73 (2006) 329–337
ing enzyme (ACE) hydrolyses inactive angiotensin I into active angiotensin II. Thus ACE plays a regulatory role in the renin– angiotensin system (RAS). A polymorphism of the ACE gene has recently been described that affects circulating and tissue levels of the ACE [4,5]. In this study, we aimed to investigate the frequency of the different alleles of the ACE gene in a cohort of Turkish patients with FMF in an attempt to identify genetic susceptibility loci for FMF other than MEFV/marenostrin gene. 2. Methods Fifty patients with FMF (25 females and 25 males, ranging in age from 16 to 53; mean 31.0 years) and 30 healthy subjects (15 females and 15 males, ranging in age from 20 to 45; mean 31.2 years) were enrolled in this study. There was no difference between the two groups regarding age and sex distribution. The mean duration of symptoms was 13.5 years (min– max: 2–40 years). All of the patients demonstrated peritonitis attacks. Fortyeight of the patients (96%) had fever. Other clinical features in the patients were as follows: arthritis in 20 patients (40%), pleuritis in 10 patients (20%), pericarditis in one patient (2%) and erysipelas-like erythema in one patient (2%). Three patients had been complicated with vasculitis (6%) [two patients Henoch-Schönlein purpura (HSP), and one patient polyartheritis nodosa (PAN)]. Clinical characteristics of the patients were given in Table 1. ACE genotypes were determined by polymerase chain reaction, as previously described in [6]. 3. Results The distribution of DD, ID and II genotypes of the ACE gene were 12 (24%), 28 (56%) and 10 (20%) for patients with FMF, and nine (30%), 16 (53.3%) and five (16.7%) for healthy controls, respectively (Table 2). There was no significant difference between the groups (χ2, P > 0.05). Table 1 Clinical features of patients with FMF (N = 50) Type of clinical manifestation Abdominal pain Fever Arthritis Pleuritis Vasculitis Pericarditis Erysipelas-like erythema
Frequency 50 48 20 10 3 1 1
% 100 96 40 20 6 2 2
Table 2 The distribution of ACE gene polymorphism among patients with FMF and healthy controls ACE gene polymorphism DD genotype ID genotype II genotype Total
FMF patients 12 (24%) 28 (56%) 10 (20%) 50 (100%)
Healthy control 9 (30%) 16 (53.3%) 5 (16.7%) 30 (100%)
335
An interesting observation was that all patients complicated with vasculitis had at least one D allele (one of the patients with HSP had the DD genotype, the other patient with HSP and the patient with PAN had ID genotype). 4. Discussion Intensive research in the last decade has led to the concept that the RAS, apart from being a circulating endocrine system, is also an organ- and tissue-based system that performs paracrine/autocrine functions. Angiotensin II, the dominant effector peptide of the RAS, is now considered to be a true cytokine that plays active roles in the inflammatory response [7]. Angiotensin II regulates the expression of adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), and facilitates cell-to-cell interactions. Angiotensin II itself is also chemotactic for neutrophils. Increased monocyte chemoattractant protein and interleukin (IL)-8, in association with angiotensin II are potent chemoattractant proteins for monocyte/macrophages and neutrophils [3,8]. Angiotensin II also increases proinflammatory mediators including TNF-α and IL-6 [8]. Moreover, inflammatory cells express all the components of the RAS, and can produce angiotensin II. One of the early responses to inflammation is an upregulation of angiotensinogen levels. The monocytes/ macrophages present at inflammatory sites have high ACE activity [3]. On the other hand, inhibition of ACE could interfere with some proinflammatory functions of neutrophils and reduces soluble VCAM-1 [9]. Taken together, angiotensin II seems to be involved in the activation, migration and chemotaxis of monocytes and polymorphonuclear leukocytes (PNLs) in inflammatory conditions. Inflammation is an essential integral part of FMF. The at tacks are characterized by acute inflammation of the serosal and/or synovial membranes. Moreover, there is an ongoing inflammatory activity present even in the attack-free periods of FMF [2]. The discovery of the MEFV/marenostrin gene has greatly enlightened the pathogenesis and genetics of FMF. On the other hand, there are some FMF cases with typical clinical manifestations for FMF and lacking the known mutations of MEFV/marenostrin, while others with MEFV/marenostrin mutations without clinical findings of the disease. Accordingly, there could be additional genes causing FMF other than the MEFV/marenostrin [1]. ACE is the regulatory component of the RAS and hydrolyses inactive angiotensin I into active angiotensin II. The plasma and tissue ACE levels are genetically determined by a polymorphism in the ACE gene that is created by the insertion (I allele) or deletion (D allele) of a 287-base pair DNA sequence within intron 16 [4,5]. Furthermore, ACE levels in human T lymphocytes are influenced by ACE polymorphism [10]. Therefore, the ACE gene polymorphism might be suggested as a good candidate for the determination of genetic susceptibility to FMF. In this study we investigated a possible association between the ACE gene polymorphism and FMF. However, there was no difference in the distribution of the different alleles of the ACE gene in FMF patients compared with the controls.
336
Letters to the editor / Joint Bone Spine 73 (2006) 329–337
Three of the FMF patients were complicated with vasculitic disorders (two patients with HSP, and one patient with PAN). Interestingly, all of them had at least one D allele of the ACE gene. Presence of the D allele was previously associated with the development of cardiovascular disorders and the severity of renal involvement in HSP, although conflicting data exist [11– 13]. However, since the incidence of the II polymorphism is low in both FMF patients without vasculitis and healthy controls, this observation could be a simple coincidence. In conclusion, our study suggested that there is no association between the ACE gene polymorphism and development of FMF. However, investigating the ACE gene polymorphism in FMF patients carrying different MEFV gene mutations, and also in FMF patients with no known MEFV mutation would be more informative for the role of the ACE gene in the pathogenesis of FMF (either as a modifier of the MEFV gene or a second susceptibility gene involved in the FMF phenotype). Moreover ACE gene polymorphism can also be investigated in increased number of FMF patients who are complicated with vasculitis in order to see whether the D allele of the ACE gene is associated with the vascular component of FMF. References [1]
Ben-Chetrit E, Levy M. Enigmas in familial Mediterranean fever (FMF). Clin Exp Rheumatol 2001;19:S1–5 (Suppl 24). [2] Kiraz S, Ertenli I, Arici M, Calguneri M, Haznedaroglu I, Celik I, et al. Effects of colchicine on inflammatory cytokines and selectins in familial Mediterranean fever. Clin Exp Rheumatol 1998;16:721–4. [3] Ruiz-Ortega M, Lorenzo O, Suzuki Y, Ruperez M, Egido J. Proinflammatory actions of angiotensins. Curr Opin Nephrol Hypertens 2001;10: 321–9. [4] Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343–6. [5] Danser AH, Schalekamp MA, Bax WA, van den Brink AM, Saxena PR, Riegger GA, et al. Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation 1995;92: 1387–8. [6] Ozturk MA, Calguneri M, Kiraz S, Ertenli I, Ozbalkan Z, Onat AM, et al. Angiotensin converting enzyme gene polymorphism in Behçet’s disease. Clin Rheumatol 2004;23:142–6. [7] Haznedaroğlu IC, Öztürk MA. Towards the understanding of the local hematopoietic bone marrow renin–angiotensin system. Int J Biochem Cell Biol 2003;35:876–80. [8] Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, et al. Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int Suppl 2002;82:12–22. [9] Rahman ST, Lauten WB, Khan QA, Navalkar S, Parthasarathy S, Khan BV. Effects of eprosartan versus hydrochlorothiazide on markers of vascular oxidation and inflammation and blood pressure (renin–angiotensin system antagonists, oxidation, and inflammation). Am J Cardiol 2002;89:686–90. [10] Costerousse O, Allegrini J, Lopez M, Alhenc-Gelas F. Angiotensin Iconverting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in T-lymphocytes. Biochem J 1993;290:33–40. [11] Lindpaintner K, Pfeffer MA, Kreutz R, Stampfer MJ, Grodstein F, LaMotte F, et al. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med 1995;332:706–11. [12] Yoshioka T, Xu YX, Yoshida H, Shiraga H, Muraki T, Ito K. Deletion polymorphism of the angiotensin converting enzyme gene predicts per-
sistent proteinuria in Henoch-Schönlein purpura nephritis. Arch Dis Child 1998;79:394–9. [13] Amoroso A, Danek G, Vatta S, Crovella S, Berrino M, Guarrera S, et al. Polymorphisms in angiotensin-converting enzyme gene and severity of renal disease in Henoch-Schönlein patients. Nephrol Dial Transplant 1998;13:3184–8.
Öztürk Meral Çalgüneri Department of Rheumatology, Faculty of Medicine, Hacettepe University, Ankara, Turkey M. Akif Öztürk* Department of Rheumatology, Faculty of Medicine, Gazi University, Ankara, Turkey E-mail address: [email protected] (M.A. Öztürk). Sedat Kiraz İhsan Ertenli A. Mesut Onat Kemal Üreten Zeynep Özbalkan Department of Rheumatology, Faculty of Medicine, Hacettepe University, Ankara, Turkey İbrahim C. Haznedaroğlu Department of Hematology, Faculty of Medicine, Hacettepe University, Ankara, Turkey Received 15 April 2005; accepted 19 August 2005 Available online 01 December 2005 *Corresponding author. Tel.: +90 312 395 1065. 1297-319X/$ - see front matter © Elsevier SAS. All rights reserved. doi:10.1016/j.jbspin.2005.08.001
Erythema nodosum and lung cancer Keywords: Erythema nodosum; Cancer
Lung cancer is the most common cause of paraneoplastic syndromes. These may occur as the presenting manifestation, coincide with a recurrence, or develop at the terminal phase. A broad spectrum of paraneoplastic disorders occurs in association with lung cancer. The target organ may be the blood, nervous system, bone, endocrine glands, or skin. Paraneoplastic skin diseases known to occur in patients with lung cancer include woolly hypertrichosis, erythema gyratum repens, acrokeratosis (Basex syndrome), dermatomyositis, and Sweet syndrome [1,2]. We report a case of recurrent erythema nodosum in a patient with lung cancer. This 43-year-old male nonsmoker had no history of disease except for allergic rhinitis. He presented with a 2-month history of erythema nodosum over the shins that had failed to respond to indomethacin or potassium iodide. A nagging cough with blood-tinged sputum antedated the skin lesions by 1 month.
Letters to the editor / Joint Bone Spine 73 (2006) 329–337
1. Case report
References
A man born in 1941 received a diagnosis of rheumatoid arthritis (RA) in 1960. The limited disease activity was well controlled by an antimalarial in combination with 5–10 mg of prednisone per day. In late 2000, after an increase in the prednisone dosage, he experienced Staphylococcus aureus septicemia and septic arthritis of the elbow. In April 2002, worsening of the joint symptoms prompted add-on therapy with IL-1Ra (anakinra), 100 mg/day. Il-1Ra was preferred over a TNFα antagonist because of the history of severe infection. Satisfactory disease control was achieved. In June 2004, total hip arthroplasty on the right was followed by an uneventful postoperative recovery. In January 2005, a biopsy of a pigmented skin lesion behind the right ear showed malignant melanoma. The IL-1Ra was stopped. Because the lymph nodes draining the tumor area were enlarged, extensive excision with node dissection was performed. Metastases were identified in several cervical nodes and in the right parotid gland. The stage was T3a, N3, M1. The RA was stable with a rheumatoid factor titer of 15 U/ml, negative tests for antinuclear antibodies, and radiological fusion of the carpal bones. The patient was positive for HLA DRB1*04,13. Adjuvant chemotherapy with fotemustine (100 mg/m2) was given.
[1] Geborek P, Bladström A, Turesson C, Gulfe A, Petersson IF, Saxsne T, et al. Tumor necrosis factor blockers do not increase overall tumor risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 2005;64:699–703. [2] Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N, et al. Risks of solid cancers in patients with rheumatoid arthritis and following treatment with TNF antagonists. Ann Rheum Dis 2005;64:1421–6. [3] La E, Rundhaug JE, Fischer SM. Role of intracellular interleukin-1 antagonist in skin carcinogenesis. Mol Carcinog 2001;30:218–23. [4] Bar D, Apte RN, Voronov E, Dinarello CA, Cohen S. A continuous delivery system of IL-1 receptor antagonist reduces angiogenesis and inhibits tumor development. FASEB J 2004;18:161–3. [5] McKenzie RC, Oran A, Dinarello CA, Sauder DN. Interleukin-1 receptor antagonist inhibits subcutaneous B 16 melanoma growth in vivo. Anticancer Res 1996;16:437–41. [6] Weinreich DM, Elaraj DM, Puhlmann M, Hewitt SM, Carroll NM, Feldman ED, et al. Effect of interleukin 1 receptor antagonist gene transduction on human melanoma xenografts in nude mice. Cancer Res 2003;63: 5957–61.
2. Discussion Metastatic malignant melanoma occurred in our patient after 2½ years of IL-1Ra therapy for RA. The only additional cause of immunodepression was prednisone therapy in daily dosages no greater than 10 mg. The occurrence of solid cancer or lymphoma is a potential source of concern in patients receiving biologic agents to treat inflammatory diseases such as RA. Registries have been established, although most of the data pertain to TNFα antagonists. With current follow-ups, there is no evidence indicating an increase in the incidence of solid cancer [1,2]. IL-1Ra was introduced more recently, so that the number of exposed patient is smaller. We are not aware of previous reports of malignant melanoma during IL-1Ra therapy in the international literature or the French drug surveillance registry. IL-1 is a proinflammatory cytokine that stimulates angiogenesis and promotes tumor growth and metastatic dissemination. IL-1Ra blocks these effects, thereby inhibiting the proliferation of skin tumor cell lines [3,4], inhibiting the growth of murine melanoma cells [5], and reducing the in vivo growth and metastatic potential of human melanoma xenografts, which constitutively produce IL-1 [6]. Conventional disease-modifying anti-rheumatic drugs are not known to increase the risk of melanoma. Although the occurrence of melanoma in our patient may have been coincidental, the development of metastatic malignant melanoma during IL-1Ra therapy is an atypical event that contradicts current pathophysiological concepts. Our case emphasizes the importance of postmarketing surveillance and of registries for side effects of new treatments.
Daniel Wendling* Rheumatology Department, Minjoz Teaching Hospital, 25030 Besançon, France E-mail address: [email protected] (D. Wendling). François Aubin Dermatology Federation, Saint-Jacques Teaching Hospital, 25030 Besançon, France Received 18 June 2005; accepted 18 August 2005 Available online 28 February 2006 *Corresponding
author.
1297-319X/$ - see front matter © Elsevier SAS. All rights reserved. doi:10.1016/j.jbspin.2005.08.004
Lack of association between familial Mediterranean fever and angiotensin converting enzyme gene polymorphism Keywords: Familial Mediterranean fever; Renin–angiotensin Angiotensin converting enzyme gene polymorphism
system;
1. Introduction Familial Mediterranean fever (FMF) is an autosomal recessive disorder of unknown etiology. Although our understanding of the pathogenesis and genetics of FMF has greatly enhanced after the discovery of the MEFV/marenostrin gene, genetic susceptibility to FMF can not be solely attributed to the mutations in MEFV/marenostrin gene [1]. Hence, identification of other susceptibility loci is currently awaited. FMF is characterized by recurrent serosal, synovial and/or cutaneous inflammation. Moreover, those patients have subclinical inflammation in the attack-free periods [2]. Recent advances demonstrated that angiotensin II is an important component of the inflammatory response [3]. Angiotensin convert-
Letters to the editor / Joint Bone Spine 73 (2006) 329–337
ing enzyme (ACE) hydrolyses inactive angiotensin I into active angiotensin II. Thus ACE plays a regulatory role in the renin– angiotensin system (RAS). A polymorphism of the ACE gene has recently been described that affects circulating and tissue levels of the ACE [4,5]. In this study, we aimed to investigate the frequency of the different alleles of the ACE gene in a cohort of Turkish patients with FMF in an attempt to identify genetic susceptibility loci for FMF other than MEFV/marenostrin gene. 2. Methods Fifty patients with FMF (25 females and 25 males, ranging in age from 16 to 53; mean 31.0 years) and 30 healthy subjects (15 females and 15 males, ranging in age from 20 to 45; mean 31.2 years) were enrolled in this study. There was no difference between the two groups regarding age and sex distribution. The mean duration of symptoms was 13.5 years (min– max: 2–40 years). All of the patients demonstrated peritonitis attacks. Fortyeight of the patients (96%) had fever. Other clinical features in the patients were as follows: arthritis in 20 patients (40%), pleuritis in 10 patients (20%), pericarditis in one patient (2%) and erysipelas-like erythema in one patient (2%). Three patients had been complicated with vasculitis (6%) [two patients Henoch-Schönlein purpura (HSP), and one patient polyartheritis nodosa (PAN)]. Clinical characteristics of the patients were given in Table 1. ACE genotypes were determined by polymerase chain reaction, as previously described in [6]. 3. Results The distribution of DD, ID and II genotypes of the ACE gene were 12 (24%), 28 (56%) and 10 (20%) for patients with FMF, and nine (30%), 16 (53.3%) and five (16.7%) for healthy controls, respectively (Table 2). There was no significant difference between the groups (χ2, P > 0.05). Table 1 Clinical features of patients with FMF (N = 50) Type of clinical manifestation Abdominal pain Fever Arthritis Pleuritis Vasculitis Pericarditis Erysipelas-like erythema
Frequency 50 48 20 10 3 1 1
% 100 96 40 20 6 2 2
Table 2 The distribution of ACE gene polymorphism among patients with FMF and healthy controls ACE gene polymorphism DD genotype ID genotype II genotype Total
FMF patients 12 (24%) 28 (56%) 10 (20%) 50 (100%)
Healthy control 9 (30%) 16 (53.3%) 5 (16.7%) 30 (100%)
335
An interesting observation was that all patients complicated with vasculitis had at least one D allele (one of the patients with HSP had the DD genotype, the other patient with HSP and the patient with PAN had ID genotype). 4. Discussion Intensive research in the last decade has led to the concept that the RAS, apart from being a circulating endocrine system, is also an organ- and tissue-based system that performs paracrine/autocrine functions. Angiotensin II, the dominant effector peptide of the RAS, is now considered to be a true cytokine that plays active roles in the inflammatory response [7]. Angiotensin II regulates the expression of adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), and facilitates cell-to-cell interactions. Angiotensin II itself is also chemotactic for neutrophils. Increased monocyte chemoattractant protein and interleukin (IL)-8, in association with angiotensin II are potent chemoattractant proteins for monocyte/macrophages and neutrophils [3,8]. Angiotensin II also increases proinflammatory mediators including TNF-α and IL-6 [8]. Moreover, inflammatory cells express all the components of the RAS, and can produce angiotensin II. One of the early responses to inflammation is an upregulation of angiotensinogen levels. The monocytes/ macrophages present at inflammatory sites have high ACE activity [3]. On the other hand, inhibition of ACE could interfere with some proinflammatory functions of neutrophils and reduces soluble VCAM-1 [9]. Taken together, angiotensin II seems to be involved in the activation, migration and chemotaxis of monocytes and polymorphonuclear leukocytes (PNLs) in inflammatory conditions. Inflammation is an essential integral part of FMF. The at tacks are characterized by acute inflammation of the serosal and/or synovial membranes. Moreover, there is an ongoing inflammatory activity present even in the attack-free periods of FMF [2]. The discovery of the MEFV/marenostrin gene has greatly enlightened the pathogenesis and genetics of FMF. On the other hand, there are some FMF cases with typical clinical manifestations for FMF and lacking the known mutations of MEFV/marenostrin, while others with MEFV/marenostrin mutations without clinical findings of the disease. Accordingly, there could be additional genes causing FMF other than the MEFV/marenostrin [1]. ACE is the regulatory component of the RAS and hydrolyses inactive angiotensin I into active angiotensin II. The plasma and tissue ACE levels are genetically determined by a polymorphism in the ACE gene that is created by the insertion (I allele) or deletion (D allele) of a 287-base pair DNA sequence within intron 16 [4,5]. Furthermore, ACE levels in human T lymphocytes are influenced by ACE polymorphism [10]. Therefore, the ACE gene polymorphism might be suggested as a good candidate for the determination of genetic susceptibility to FMF. In this study we investigated a possible association between the ACE gene polymorphism and FMF. However, there was no difference in the distribution of the different alleles of the ACE gene in FMF patients compared with the controls.
336
Letters to the editor / Joint Bone Spine 73 (2006) 329–337
Three of the FMF patients were complicated with vasculitic disorders (two patients with HSP, and one patient with PAN). Interestingly, all of them had at least one D allele of the ACE gene. Presence of the D allele was previously associated with the development of cardiovascular disorders and the severity of renal involvement in HSP, although conflicting data exist [11– 13]. However, since the incidence of the II polymorphism is low in both FMF patients without vasculitis and healthy controls, this observation could be a simple coincidence. In conclusion, our study suggested that there is no association between the ACE gene polymorphism and development of FMF. However, investigating the ACE gene polymorphism in FMF patients carrying different MEFV gene mutations, and also in FMF patients with no known MEFV mutation would be more informative for the role of the ACE gene in the pathogenesis of FMF (either as a modifier of the MEFV gene or a second susceptibility gene involved in the FMF phenotype). Moreover ACE gene polymorphism can also be investigated in increased number of FMF patients who are complicated with vasculitis in order to see whether the D allele of the ACE gene is associated with the vascular component of FMF. References [1]
Ben-Chetrit E, Levy M. Enigmas in familial Mediterranean fever (FMF). Clin Exp Rheumatol 2001;19:S1–5 (Suppl 24). [2] Kiraz S, Ertenli I, Arici M, Calguneri M, Haznedaroglu I, Celik I, et al. Effects of colchicine on inflammatory cytokines and selectins in familial Mediterranean fever. Clin Exp Rheumatol 1998;16:721–4. [3] Ruiz-Ortega M, Lorenzo O, Suzuki Y, Ruperez M, Egido J. Proinflammatory actions of angiotensins. Curr Opin Nephrol Hypertens 2001;10: 321–9. [4] Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343–6. [5] Danser AH, Schalekamp MA, Bax WA, van den Brink AM, Saxena PR, Riegger GA, et al. Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation 1995;92: 1387–8. [6] Ozturk MA, Calguneri M, Kiraz S, Ertenli I, Ozbalkan Z, Onat AM, et al. Angiotensin converting enzyme gene polymorphism in Behçet’s disease. Clin Rheumatol 2004;23:142–6. [7] Haznedaroğlu IC, Öztürk MA. Towards the understanding of the local hematopoietic bone marrow renin–angiotensin system. Int J Biochem Cell Biol 2003;35:876–80. [8] Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, et al. Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int Suppl 2002;82:12–22. [9] Rahman ST, Lauten WB, Khan QA, Navalkar S, Parthasarathy S, Khan BV. Effects of eprosartan versus hydrochlorothiazide on markers of vascular oxidation and inflammation and blood pressure (renin–angiotensin system antagonists, oxidation, and inflammation). Am J Cardiol 2002;89:686–90. [10] Costerousse O, Allegrini J, Lopez M, Alhenc-Gelas F. Angiotensin Iconverting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in T-lymphocytes. Biochem J 1993;290:33–40. [11] Lindpaintner K, Pfeffer MA, Kreutz R, Stampfer MJ, Grodstein F, LaMotte F, et al. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med 1995;332:706–11. [12] Yoshioka T, Xu YX, Yoshida H, Shiraga H, Muraki T, Ito K. Deletion polymorphism of the angiotensin converting enzyme gene predicts per-
sistent proteinuria in Henoch-Schönlein purpura nephritis. Arch Dis Child 1998;79:394–9. [13] Amoroso A, Danek G, Vatta S, Crovella S, Berrino M, Guarrera S, et al. Polymorphisms in angiotensin-converting enzyme gene and severity of renal disease in Henoch-Schönlein patients. Nephrol Dial Transplant 1998;13:3184–8.
Öztürk Meral Çalgüneri Department of Rheumatology, Faculty of Medicine, Hacettepe University, Ankara, Turkey M. Akif Öztürk* Department of Rheumatology, Faculty of Medicine, Gazi University, Ankara, Turkey E-mail address: [email protected] (M.A. Öztürk). Sedat Kiraz İhsan Ertenli A. Mesut Onat Kemal Üreten Zeynep Özbalkan Department of Rheumatology, Faculty of Medicine, Hacettepe University, Ankara, Turkey İbrahim C. Haznedaroğlu Department of Hematology, Faculty of Medicine, Hacettepe University, Ankara, Turkey Received 15 April 2005; accepted 19 August 2005 Available online 01 December 2005 *Corresponding author. Tel.: +90 312 395 1065. 1297-319X/$ - see front matter © Elsevier SAS. All rights reserved. doi:10.1016/j.jbspin.2005.08.001
Erythema nodosum and lung cancer Keywords: Erythema nodosum; Cancer
Lung cancer is the most common cause of paraneoplastic syndromes. These may occur as the presenting manifestation, coincide with a recurrence, or develop at the terminal phase. A broad spectrum of paraneoplastic disorders occurs in association with lung cancer. The target organ may be the blood, nervous system, bone, endocrine glands, or skin. Paraneoplastic skin diseases known to occur in patients with lung cancer include woolly hypertrichosis, erythema gyratum repens, acrokeratosis (Basex syndrome), dermatomyositis, and Sweet syndrome [1,2]. We report a case of recurrent erythema nodosum in a patient with lung cancer. This 43-year-old male nonsmoker had no history of disease except for allergic rhinitis. He presented with a 2-month history of erythema nodosum over the shins that had failed to respond to indomethacin or potassium iodide. A nagging cough with blood-tinged sputum antedated the skin lesions by 1 month.