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Interleukin-1: a new therapeutic target for ankylosing spondylitis?
Joint Bone Spine 72 (2005) 357–358 http://france.elsevier.com/direct/BONSOI/
Editorial
Interleukin-1: a new therapeutic target for ankylosing spondylitis? Keywords: Interleukin-1; Interleukin-1 receptor antagonist; Anakinra; Ankylosing spondylitis
1. Introduction The dramatic success of TNF-a in the treatment of ankylosing spondylitis (AS) and other spondyloarthropathies [1,2] has fueled research into other cytokines as potential candidates for targeted immunotherapy. A promising cytokine target is interleukin-1 (IL-1), which is known to play a role in chronic inflammatory joint disease, most notably rheumatoid arthritis [3]. IL-1 may seem of limited relevance to AS, as it appears more closely linked to joint destruction than to joint inflammation [3]. Furthermore, local biological mechanisms differ between rheumatoid arthritis and AS. Nevertheless, recent data indicate a need for reappraising the classic pathophysiological concepts and for considering IL-1 as a potential treatment target in patients with AS.
2. Theoretical rationale and experimental data Few studies have investigated the IL-1 system in AS. IL-1b production by polymorphonuclear cells in response to phytohemagglutinin was significantly (P = 0.002) greater in 27 AS patients than in 24 healthy controls, whereas levels were similar for TNF-a and IL-10 [4]. No correlations were identified between cytokine production levels and clinical variables such as the Bath AS functional index (BASFI) or the Bath AS disease activity index (BASDAI). In a study of 18 patients with AS and inflammation (median C-reactive protein [CRP], 31.7 mg/l), Gabay et al. [5] found no decrease in circulating levels of IL-1 receptor antagonist (IL-1Ra) as compared to the control group, whereas serum IL-1Ra was increased in 20 patients with rheumatoid arthritis and in 21 patients with lupus. Claudepierre et al. [6] reported mild IL-1b elevation and marked IL-1Ra elevation in plasma samples from a group of 21 patients with spondyloarthropathies; however, the levels were not correlated with disease activity parameters (pain, morning stiffness, erythrocyte sedimentation rate [ESR], or CRP). Braun et al. [7] examined sacroiliac joint biopsy specimens from five patients with AS. In three of these patients, tests included cytokine messenger RNA (mRNA) detection by situ hybridization. The inflammatory infiltrates contained 1297-319X/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.jbspin.2004.10.013
large amounts of TNF-a mRNA but no IL-1 mRNA. Genetic studies have demonstrated an association between IL-1Ra gene polymorphism and AS, supporting a role for IL-1 and IL-1Ra in this disease [8–11]. In aggregate, these data are consistent with a relative, qualitative, or functional, deficiency in IL-1Ra in patients with AS. Under this hypothesis, administration of IL-1Ra may have beneficial effects in AS.
3. Preliminary clinical data Two open-label pilot studies of anakinra (IL-1Ra) have just been reported [12,13]. Both studies evaluated the shortand medium-term clinical and magnetic resonance imaging (MRI) responses to subcutaneous anakinra, 100 mg/day, in patients with active AS. In the study by Emery and colleagues [12], anakinra was given for 3 months to nine patients with a mean age of 45 years and mean disease duration of 18 years. Mean baseline values for CRP (31 mg/l), BASDAI (5.63), and BASFI (5.88) indicated active AS. After 3 months, significant improvements were noted in disease activity (BASDAI), function (BASFI), quality of life (ASQoL), and tests for inflammation (ESR and CRP). Two-thirds of patients met ASAS20 response criteria. MRI was obtained in eight patients at baseline and after 3 months; of the 38 inflammatory enthesitis lesions seen at baseline (seven at the sacroiliac joints and 31 at the lumbar spine), 23 (61%) resolved completely (n = 7) or improved (n = 16) after 3 months of treatment. The other study of anakinra was done by Haibel et al. [13] in 20 patients with AS refractory to nonsteroidal antiinflammatory drugs. Mean age was 39 years, mean disease duration was 16 years, and mean baseline BASDAI was 5.8. Anakinra was given for 24 weeks. Efficacy criteria were the BASDAI, BASFI, Bath AS Metrology Index (BASMI), global evaluations by the physician and patient, and peripheral joint involvement. The sacroiliac joints and/or spine were assessed by dynamic MRI with gadolinium injection at baseline in 15 patients and at study completion in 10 patients. Response rates after 6 months were 26% for ASAS 20, 21% for ASAS 40, and 10% for ASAS 70. In the intention-to-treat analysis, 21% of patients had an at least 50% BASDAI improvement after 6 months, whereas the CRP level and MRI score were unchanged. In
358
Editorial / Joint Bone Spine 72 (2005) 357–358
the overall study population, no improvements were noted for the mean BASDAI, BASFI, BASMI, pain score, or global evaluations. As in the previous study, anakinra was well tolerated, with however a high rate of injection-site reactions.
[5]
Gabay C, Cakir N, Moral F, Roux-Lombard P, Meyer O, Dayer JM, et al. Circulating levels of tumor necrosis factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with disease activity. J Rheumatol 1997;24:303–8.
[6]
Claudepierre P, Rymer JC, Authier FJ, Allanore Y, Larget-Piet B, Gherardi R, et al. A relationship between TGF-b1 or IL-6 plasma levels and clinical features of spondyloarthropathies. Br J Rheumatol 1997;36:400–1.
[7]
Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbst H, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacro iliac joint specimens from patients with ankylosing spondylitis. Arthritis Rheum 1995;38:499–505.
[8]
Mc Garry F, Neilly J, Anderson N, Sturrock R, Field M. A polymorphism within the interleukin 1 receptor antagonist (IL-1RA) gene is associated with ankylosing spondylitis. Rheumatology 2001;40:1359–64.
[9]
Van der Paardt M, Crusius JBA, Garcia-Gonzales MA, Baudoin P, Kostense PJ, Alizadeh BZ, et al. Interleukin-1b receptor antagonist gene polymorphisms in ankylosing spondylitis. Rheumatology 2002; 41:1419–23.
4. Discussion The evidence supporting IL-1Ra therapy in AS remains shaky. Although plasma cytokine levels are know to be unreliable in patients with chronic inflammatory diseases, the few available data are partly conflicting, indicating a need for further research. Furthermore, plasma levels of IL-1b and IL-1Ra were not correlated with parameters reflecting clinical activity (BASDAI) or biological inflammation (CRP). The clinical findings from the two open-label studies available to date [12,13] are disappointing in comparison to the dramatic efficacy of TNF-a antagonists in AS. Only onefourth of patients responded to 6 months of anakinra [13], whereas response rates in studies of TNF-a antagonists exceeded 60% [1]. The small number of patients in these two studies [12,13] should be borne in mind, but far better results were obtained in early open-label trials of TNF-a antagonists in similarly small populations with comparable patterns of AS. In addition, discordances exist between the findings from the two studies: thus, the activity index, functional index, CRP level, and MRI score improved in the 3-month study [12] but remained virtually unchanged in the 6-month study [13], although baseline patient characteristics were similar in the two studies. These preliminary open-label clinical studies do not warrant a conclusion that anakinra is effective in AS and indicate a need for a carefully conducted controlled study. References [1] [2] [3]
[4]
Wendling D, Toussirot E. Anti TNF-a therapy in ankylosing spondylitis. Expert Opin Pharmacother 2004;5:1497–507. Wendling D. Anti-TNFa therapy in spondyloarthropathy: deciding who to treat. Joint Bone Spine 2003;70:401–3. Dayer JM. The saga of the discovery of IL-1 and TNF and their specific inhibitors in the pathogenesis and treatment of rheumatoid arthritis. Joint Bone Spine 2002;69:123–32. Vazquez Del Mercado M, Garcia-Gonzales A, Munoz-Valle JF, Garcia-Iglesias T, Martinez-Bonilla G, Bernard, Medina G, et al. Interleukin 1b (IL-1b), IL-10, tumor necrosis factor-a and cellular proliferation index in peripheral blood mononuclear cells in patients with ankylosing spondylitis. J Rheumatol 2002;29:522–6.
[10] Maksymowych WP, Reeve JP, Reveille JD, Akey JM, Buenviage H, O’Brien L, et al. High-throughput single-nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Arthritis Rheum 2003;48:2011–8. [11] Timms AE, Crane AM, Sims AM, Cordell HJ, Bradbury LA, AbbottCoyne MR, et al. The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis. Am J Hum Genet 2004;75:587–95. [12] Tan AL, Marzo-Ortega H, O’Connor P, Fraser A, Emery P, McGonagle D. Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study. Ann Rheum Dis 2004;63:1041–5. [13] Haibel H, Rudwaleit M, Listing J, Sieper J. Open-label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann Rheum Dis 200564:296–8.
Daniel Wendling * Rheumatology Department, J. Minjoz Teaching Hospital, 25030 Besançon, France E-mail address: [email protected] (D. Wendling). Received 23 August 2004; accepted 15 October 2004 Available online 03 February 2005 * Corresponding author. Tel.: +33 3 81 66 82 41; fax: +33 3 81 66 86 86.
Editorial
Interleukin-1: a new therapeutic target for ankylosing spondylitis? Keywords: Interleukin-1; Interleukin-1 receptor antagonist; Anakinra; Ankylosing spondylitis
1. Introduction The dramatic success of TNF-a in the treatment of ankylosing spondylitis (AS) and other spondyloarthropathies [1,2] has fueled research into other cytokines as potential candidates for targeted immunotherapy. A promising cytokine target is interleukin-1 (IL-1), which is known to play a role in chronic inflammatory joint disease, most notably rheumatoid arthritis [3]. IL-1 may seem of limited relevance to AS, as it appears more closely linked to joint destruction than to joint inflammation [3]. Furthermore, local biological mechanisms differ between rheumatoid arthritis and AS. Nevertheless, recent data indicate a need for reappraising the classic pathophysiological concepts and for considering IL-1 as a potential treatment target in patients with AS.
2. Theoretical rationale and experimental data Few studies have investigated the IL-1 system in AS. IL-1b production by polymorphonuclear cells in response to phytohemagglutinin was significantly (P = 0.002) greater in 27 AS patients than in 24 healthy controls, whereas levels were similar for TNF-a and IL-10 [4]. No correlations were identified between cytokine production levels and clinical variables such as the Bath AS functional index (BASFI) or the Bath AS disease activity index (BASDAI). In a study of 18 patients with AS and inflammation (median C-reactive protein [CRP], 31.7 mg/l), Gabay et al. [5] found no decrease in circulating levels of IL-1 receptor antagonist (IL-1Ra) as compared to the control group, whereas serum IL-1Ra was increased in 20 patients with rheumatoid arthritis and in 21 patients with lupus. Claudepierre et al. [6] reported mild IL-1b elevation and marked IL-1Ra elevation in plasma samples from a group of 21 patients with spondyloarthropathies; however, the levels were not correlated with disease activity parameters (pain, morning stiffness, erythrocyte sedimentation rate [ESR], or CRP). Braun et al. [7] examined sacroiliac joint biopsy specimens from five patients with AS. In three of these patients, tests included cytokine messenger RNA (mRNA) detection by situ hybridization. The inflammatory infiltrates contained 1297-319X/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.jbspin.2004.10.013
large amounts of TNF-a mRNA but no IL-1 mRNA. Genetic studies have demonstrated an association between IL-1Ra gene polymorphism and AS, supporting a role for IL-1 and IL-1Ra in this disease [8–11]. In aggregate, these data are consistent with a relative, qualitative, or functional, deficiency in IL-1Ra in patients with AS. Under this hypothesis, administration of IL-1Ra may have beneficial effects in AS.
3. Preliminary clinical data Two open-label pilot studies of anakinra (IL-1Ra) have just been reported [12,13]. Both studies evaluated the shortand medium-term clinical and magnetic resonance imaging (MRI) responses to subcutaneous anakinra, 100 mg/day, in patients with active AS. In the study by Emery and colleagues [12], anakinra was given for 3 months to nine patients with a mean age of 45 years and mean disease duration of 18 years. Mean baseline values for CRP (31 mg/l), BASDAI (5.63), and BASFI (5.88) indicated active AS. After 3 months, significant improvements were noted in disease activity (BASDAI), function (BASFI), quality of life (ASQoL), and tests for inflammation (ESR and CRP). Two-thirds of patients met ASAS20 response criteria. MRI was obtained in eight patients at baseline and after 3 months; of the 38 inflammatory enthesitis lesions seen at baseline (seven at the sacroiliac joints and 31 at the lumbar spine), 23 (61%) resolved completely (n = 7) or improved (n = 16) after 3 months of treatment. The other study of anakinra was done by Haibel et al. [13] in 20 patients with AS refractory to nonsteroidal antiinflammatory drugs. Mean age was 39 years, mean disease duration was 16 years, and mean baseline BASDAI was 5.8. Anakinra was given for 24 weeks. Efficacy criteria were the BASDAI, BASFI, Bath AS Metrology Index (BASMI), global evaluations by the physician and patient, and peripheral joint involvement. The sacroiliac joints and/or spine were assessed by dynamic MRI with gadolinium injection at baseline in 15 patients and at study completion in 10 patients. Response rates after 6 months were 26% for ASAS 20, 21% for ASAS 40, and 10% for ASAS 70. In the intention-to-treat analysis, 21% of patients had an at least 50% BASDAI improvement after 6 months, whereas the CRP level and MRI score were unchanged. In
358
Editorial / Joint Bone Spine 72 (2005) 357–358
the overall study population, no improvements were noted for the mean BASDAI, BASFI, BASMI, pain score, or global evaluations. As in the previous study, anakinra was well tolerated, with however a high rate of injection-site reactions.
[5]
Gabay C, Cakir N, Moral F, Roux-Lombard P, Meyer O, Dayer JM, et al. Circulating levels of tumor necrosis factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with disease activity. J Rheumatol 1997;24:303–8.
[6]
Claudepierre P, Rymer JC, Authier FJ, Allanore Y, Larget-Piet B, Gherardi R, et al. A relationship between TGF-b1 or IL-6 plasma levels and clinical features of spondyloarthropathies. Br J Rheumatol 1997;36:400–1.
[7]
Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbst H, et al. Use of immunohistologic and in situ hybridization techniques in the examination of sacro iliac joint specimens from patients with ankylosing spondylitis. Arthritis Rheum 1995;38:499–505.
[8]
Mc Garry F, Neilly J, Anderson N, Sturrock R, Field M. A polymorphism within the interleukin 1 receptor antagonist (IL-1RA) gene is associated with ankylosing spondylitis. Rheumatology 2001;40:1359–64.
[9]
Van der Paardt M, Crusius JBA, Garcia-Gonzales MA, Baudoin P, Kostense PJ, Alizadeh BZ, et al. Interleukin-1b receptor antagonist gene polymorphisms in ankylosing spondylitis. Rheumatology 2002; 41:1419–23.
4. Discussion The evidence supporting IL-1Ra therapy in AS remains shaky. Although plasma cytokine levels are know to be unreliable in patients with chronic inflammatory diseases, the few available data are partly conflicting, indicating a need for further research. Furthermore, plasma levels of IL-1b and IL-1Ra were not correlated with parameters reflecting clinical activity (BASDAI) or biological inflammation (CRP). The clinical findings from the two open-label studies available to date [12,13] are disappointing in comparison to the dramatic efficacy of TNF-a antagonists in AS. Only onefourth of patients responded to 6 months of anakinra [13], whereas response rates in studies of TNF-a antagonists exceeded 60% [1]. The small number of patients in these two studies [12,13] should be borne in mind, but far better results were obtained in early open-label trials of TNF-a antagonists in similarly small populations with comparable patterns of AS. In addition, discordances exist between the findings from the two studies: thus, the activity index, functional index, CRP level, and MRI score improved in the 3-month study [12] but remained virtually unchanged in the 6-month study [13], although baseline patient characteristics were similar in the two studies. These preliminary open-label clinical studies do not warrant a conclusion that anakinra is effective in AS and indicate a need for a carefully conducted controlled study. References [1] [2] [3]
[4]
Wendling D, Toussirot E. Anti TNF-a therapy in ankylosing spondylitis. Expert Opin Pharmacother 2004;5:1497–507. Wendling D. Anti-TNFa therapy in spondyloarthropathy: deciding who to treat. Joint Bone Spine 2003;70:401–3. Dayer JM. The saga of the discovery of IL-1 and TNF and their specific inhibitors in the pathogenesis and treatment of rheumatoid arthritis. Joint Bone Spine 2002;69:123–32. Vazquez Del Mercado M, Garcia-Gonzales A, Munoz-Valle JF, Garcia-Iglesias T, Martinez-Bonilla G, Bernard, Medina G, et al. Interleukin 1b (IL-1b), IL-10, tumor necrosis factor-a and cellular proliferation index in peripheral blood mononuclear cells in patients with ankylosing spondylitis. J Rheumatol 2002;29:522–6.
[10] Maksymowych WP, Reeve JP, Reveille JD, Akey JM, Buenviage H, O’Brien L, et al. High-throughput single-nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Arthritis Rheum 2003;48:2011–8. [11] Timms AE, Crane AM, Sims AM, Cordell HJ, Bradbury LA, AbbottCoyne MR, et al. The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis. Am J Hum Genet 2004;75:587–95. [12] Tan AL, Marzo-Ortega H, O’Connor P, Fraser A, Emery P, McGonagle D. Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study. Ann Rheum Dis 2004;63:1041–5. [13] Haibel H, Rudwaleit M, Listing J, Sieper J. Open-label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann Rheum Dis 200564:296–8.
Daniel Wendling * Rheumatology Department, J. Minjoz Teaching Hospital, 25030 Besançon, France E-mail address: [email protected] (D. Wendling). Received 23 August 2004; accepted 15 October 2004 Available online 03 February 2005 * Corresponding author. Tel.: +33 3 81 66 82 41; fax: +33 3 81 66 86 86.