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TNFα inhibition in psoriatic arthritis: cause for hope
Joint Bone Spine 2001 ; 68 : 106-8 © 2001 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S1297319X01002573/EDI
EDITORIAL
TNFα inhibition in psoriatic arthritis: cause for hope Laurent Zabraniecki, Bernard Fournié* Service de Clinique de Rhumatologie, CHU Purpan, 31059 Toulouse Cedex, France
advances in psoriatic arthritis / etanercept / infliximab / TNFα
Since the seminal description of psoriatic arthritis by Alibert in 1818 [1], the concept of psoriatic arthropathy has been clarified, and recent studies have produced classification criteria that seem satisfactory, although they require confirmation by further studies [2]. However, the pathophysiology of psoriatic arthritis remains poorly understood. The disease is probably multifactorial, being caused by a combination of environmental, immunological, and genetic factors that have not yet been clearly identified. Although T-lymphocytes are crucial to the immunological mechanisms that underlie both the joint and the skin lesions, no links between these two disease expressions have been identified, and the T-cell receptors involved are different [3]. Advances have been greatest in the area of genetics. The HLA B16-B17 haplotypes are probably involved in psoriatic arthritis, whereas studies of genes conferring susceptibility to the skin lesions have found a strong association with HLA CW 6. There is evidence incriminating several genes and loci (Psors 1 to 5), particularly on chromosome 6 at 6 p 21.3, where the HLA system is located. The genes involved are of the MICA type (MHC Class I Chain Related gene A) and seem to be located between HLA B and HLA C [4]. Uncertainty also surrounds the cellular mechanisms involved, although various mediators of inflammation have been implicated: IL-6, IL-10, the IL-2 soluble receptors, and the IL-1 receptor antagonists have been found in higher levels in sera from patients with psoriatic arthritis than from healthy controls; the levels of the last two factors were proportional to skin disease severity and to the * Correspondence and reprints. E-mail address: fournié[email protected] (B. Fournié).
swollen joint count, respectively. [5] Tumor necrosis factor alpha (TNFα) seems to be a key mediator in psoriasis. The effects of TNFα include endothelial cell activation (TNFα and vascular endothelial growth factor have been implicated in the genesis of rheumatoid synovial lesions), fibroblast division, increased matrix metalloproteinase production, and increased production of IL-1, IL-6, and IL-8. TNFα is produced not only by macrophages and some synoviocytes but also by keratinocytes and activated skin histiocytes [6]. More recently, in situ hybridization studies have detected the messenger RNA of TNFα in sacroiliac joint biopsies from patients with ankylosing spondylitis [7], i.e., in an enthesis. Thus, TNFα has been found in the three territories involved by psoriasis: the skin, the entheses, and the synovium. Two TNFα inhibitors are theoretically available, etanercept (the soluble TNFα receptor) and infliximab (a chimeric monoclonal antibody). The few published studies suggest that both agents may be highly effective in psoriatic arthritis. ETANERCEPT (ENBRELt) Yazici et al. reported the results of an open-label study in ten patients with severe psoriatic arthritis refractory to three previous second-line treatments [8]. These seven men and three women were aged 26 to 49 years and had a mean disease duration of 8.2 years. They were given etanercept in a dosage of 25 mg twice a week. Follow-up was 12 months. After 3 months, five of the ten patients were considered to be in clinical remission. Concomitant treatments had been stopped by four patients and reduced by two others. A noticeable overall improvement in the
Advances in psoriatic arthritis
Health Assessment Questionnaire score (HAQ) was noted in eight of the ten patients. After 12 months, eight patients had a good response; among them, two had returned to work and five had resumed previous athletic activities. Of the four patients with severe skin disease at baseline, three were in clinical remission of their skin lesions after 12 months. Two patients had stopped etanercept therapy, one because of inefficacy and the other, who had diabetes mellitus, because of osteomyelitis. Mease et al. reported a randomized, double-blind placebo-controlled study of etanercept in a dosage of 25 mg twice a week for three months [9]. The study included 60 patients with psoriatic arthritis, 34 men and 26 women, with a mean age of 45 years and a mean disease duration of 11 years. All 60 patients had active arthritis at baseline. Efficacy was evaluated based on the ACR20, ACR50, and ACR70 criteria; the Psoriatic Arthritis Response Criteria (PsARC); and the Psoriasis Area and Severity Index (PASI). After three months, marked improvements were found in the arthritis (PsARC, 87% vs 23%; and ACR20, 73% vs 13%) and skin disease (PASI, 46% vs 9%; PASI of 75 in 26% of patients in the TNFα group vs 0% in the placebo group). At the last meeting of the American College of Rheumatology (ACR) in Philadelphia, Mease reported the six-month results of an open-label study: 87% of the patients had achieved ACR20 criteria, 63% ACR50 criteria, and 33% ACR70 criteria; the PASI was improved by 62%; in the methotrexate-treated subset, 25% of patients stopped methotrexate and 43% reduced the dosage; and in the glucocorticoid-treated subset, 44% stopped glucocorticoid therapy and 67% reduced the dosage. Finally, Aboulafia described the results of etanercept therapy for psoriatic arthritis in an HIV-positive patient [10]; although remarkably effective, the drug had to be stopped because of serious infectious side effects. INFLIXIMAB (REMICADEt) Infliximab has been used according to the same schedule as in rheumatoid arthritis but at a dosage of 5 mg/kg instead of 10 mg/kg. In an open-label study of 21 patients with spondyloarthropathy, including eight with psoriatic arthritis, Van Den Bosh et al. reported improvements as early as the third day in the joint involvement as assessed globally by the patient and physician, as well as in the
107
erythrocyte sedimentation rate and C-reactive protein level [11]. The beneficial effects on peripheral and axial manifestations persisted through the sixth week. Improvements were noted in the visual analogue scale score and in spinal parameters such as the finger-tofloor distance, the occiput-to-wall distance and chest expansion. The psoriasis improved also, as shown by the mean PASI values of 0.72 at baseline, 0.44 after two weeks, 0.16 after six weeks, and 0.105 after 14 weeks. At the last meeting of the European League Against Rheumatism (EULAR), Antoni presented a poster [12] showing that three infusions of infliximab (on weeks 0, 2, and 6) produced excellent results in ten patients with severe active psoriatic arthritis. At the tenth week, all ten patients met ACR50 criteria and 70% met ACR70 criteria. Improvements were 90% for the visual analogue scale score, 80% for the Health Assessment Questionnaire score, and 71% for the PASI. The laboratory evidence of inflammation was less marked. In the minority of patients who had magnetic resonance imaging (MRI) scans, the postgadolinium enhancement denoting enthesitis decreased markedly as compared to baseline. Similarly, in a study of active ankylosing spondylitis treated with infliximab, Brandt [13] described the results of spinal MRI in five patients. Three patients had evidence of discitis at baseline. In two of these patients, marked improvements were seen on the follow-up MRIs obtained after 6 weeks of treatment. Nine of the ten patients in this study had a 50% decrease in back pain. Preliminary results from an open-label study reported by Gorman at the last ACR meeting suggest that etanercept may also improve back pain in patients with ankylosing spondylitis. In our department, we have used infliximab in a few patients with severe psoriatic arthritis. Dramatic improvements in the skin and joint symptoms were noted as early as after the second infusion. Taken in aggregate, these data are extremely promising: TNFα inhibitors improve the skin lesions, the peripheral joint manifestations (perhaps preventing radiological destruction, as in rheumatoid arthritis), and the enthesitis. The favorable effects on MRI evidence of discitis suggest that TNFα inhibitors may prevent the development of intervertebral ankylosis. Thus, the indications for TNFα inhibitor therapy will probably be extended to psoriatic arthritis. However, several issues remain unsettled. TNFα inhibitors treat the symptoms of psoriatic arthritis, not the cause. Studies are needed to determine which patients are most
108
L. Zabraniecki, B. Fournié
likely to benefit from TNFα inhibitor therapy, when the treatment should be started, and what the optimal dosage and treatment duration are. Studies of these issues will face two major obstacles: the high cost of TNFα inhibitors and the lack of long-term safety data. TNFα inhibitors interact with the immune system, modifying the capacity of the body to ward off infection and cancer and to prevent the development of autoimmunity. Clearly, further studies are needed. At long last, a treatment effective even on the axial manifestations of psoriatic arthritis will probably be available soon. At what cost? REFERENCES 1 Alibert JL. Précis théorique et pratique sur les maladies de la peau. Paris: Caille et Ranvier; 1818. 2 Fournié B, Crognier L, Arnaud C, Zabraniecki L, LascauLefebvre V, Marc V, et al. Proposed classification criteria of psoriatic arthritis. A preliminary study in 260 patients. Rev Rhum [Engl Ed] 1999 ; 66 : 446-56. 3 Pitzalis C, Cauli A, Pipitone N, Smith C, Barker J, Marchesoni A, et al. Cutaneous lymphocyte antigen-positive T lymphocytes preferentially migrate to the skin but not to the joint in psoriatic arthritis. Arthritis Rheum 1996 ; 39 : 137-45. 4 Burden AD. Identifying a gene for psoriasis on chromosome 6 (Psors 1). Br J Dermatol 2000 ; 143 : 237-43.
5 Elkayam O, Yaron I, Shirazi I, Yaron M, Caspi D. Serum levels of IL-10, IL-6, IL-1ra, and sIL-2R in patients with psoriatic arthritis. Rheumatol Int 2000 ; 19 : 101-5. 6 Starcher B. Role of tumour necrosis factor-α receptors in ultraviolet-induced skin tumours. Br J Dermatol 2000 ; 142 : 1140-7. 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 sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum 1995 ; 38 : 499-505. 8 Yazici Y, Erkan D, Lockshin MD. A preliminary study of etanercept in the treatment of severe, resistant psoriatic arthritis. Clin Exp Rheumatol 2000 ; 18 : 732-4. 9 Mease PJ, Goffe BS, Metz J, Van der Stoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000 ; 356 : 385-90. 10 Aboulafia DM, Bundow D, Wilske K, Ochs UI. Etanercept for the treatment of human immunodeficiency virus-associated psoriatic arthritis. Mayo Clin Proc 2000 ; 75 : 1093-8. 11 Van den Bosch F, Kruithof E, Baeten D, De Keyser F, Mielants H, Veys EM. Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor-α (infliximab) in spondylarthropathy: an open pilot study. Ann Rheum Dis 2000 ; 59 : 428-33. 12 Antoni C, Dechant C, Lorenz HM, Wendlere J, Ogilive A, Lufti M, et al. Successful treatment of psoriatic arthritis with infliximab in an MRI controlled study [abstract]. Ann Rheum Dis 2000 ; 5 (Suppl 1) : 200. 13 Brandt J, Haibel H, Cornely D, Golder W, Gonzalez J, Reddig J. Successful treatment of active ankylosing spondylitis with the anti-tumour necrosis factor-α monoclonal antibody infliximab. Arthritis Rheum 2000 ; 43 : 1346-52.
EDITORIAL
TNFα inhibition in psoriatic arthritis: cause for hope Laurent Zabraniecki, Bernard Fournié* Service de Clinique de Rhumatologie, CHU Purpan, 31059 Toulouse Cedex, France
advances in psoriatic arthritis / etanercept / infliximab / TNFα
Since the seminal description of psoriatic arthritis by Alibert in 1818 [1], the concept of psoriatic arthropathy has been clarified, and recent studies have produced classification criteria that seem satisfactory, although they require confirmation by further studies [2]. However, the pathophysiology of psoriatic arthritis remains poorly understood. The disease is probably multifactorial, being caused by a combination of environmental, immunological, and genetic factors that have not yet been clearly identified. Although T-lymphocytes are crucial to the immunological mechanisms that underlie both the joint and the skin lesions, no links between these two disease expressions have been identified, and the T-cell receptors involved are different [3]. Advances have been greatest in the area of genetics. The HLA B16-B17 haplotypes are probably involved in psoriatic arthritis, whereas studies of genes conferring susceptibility to the skin lesions have found a strong association with HLA CW 6. There is evidence incriminating several genes and loci (Psors 1 to 5), particularly on chromosome 6 at 6 p 21.3, where the HLA system is located. The genes involved are of the MICA type (MHC Class I Chain Related gene A) and seem to be located between HLA B and HLA C [4]. Uncertainty also surrounds the cellular mechanisms involved, although various mediators of inflammation have been implicated: IL-6, IL-10, the IL-2 soluble receptors, and the IL-1 receptor antagonists have been found in higher levels in sera from patients with psoriatic arthritis than from healthy controls; the levels of the last two factors were proportional to skin disease severity and to the * Correspondence and reprints. E-mail address: fournié[email protected] (B. Fournié).
swollen joint count, respectively. [5] Tumor necrosis factor alpha (TNFα) seems to be a key mediator in psoriasis. The effects of TNFα include endothelial cell activation (TNFα and vascular endothelial growth factor have been implicated in the genesis of rheumatoid synovial lesions), fibroblast division, increased matrix metalloproteinase production, and increased production of IL-1, IL-6, and IL-8. TNFα is produced not only by macrophages and some synoviocytes but also by keratinocytes and activated skin histiocytes [6]. More recently, in situ hybridization studies have detected the messenger RNA of TNFα in sacroiliac joint biopsies from patients with ankylosing spondylitis [7], i.e., in an enthesis. Thus, TNFα has been found in the three territories involved by psoriasis: the skin, the entheses, and the synovium. Two TNFα inhibitors are theoretically available, etanercept (the soluble TNFα receptor) and infliximab (a chimeric monoclonal antibody). The few published studies suggest that both agents may be highly effective in psoriatic arthritis. ETANERCEPT (ENBRELt) Yazici et al. reported the results of an open-label study in ten patients with severe psoriatic arthritis refractory to three previous second-line treatments [8]. These seven men and three women were aged 26 to 49 years and had a mean disease duration of 8.2 years. They were given etanercept in a dosage of 25 mg twice a week. Follow-up was 12 months. After 3 months, five of the ten patients were considered to be in clinical remission. Concomitant treatments had been stopped by four patients and reduced by two others. A noticeable overall improvement in the
Advances in psoriatic arthritis
Health Assessment Questionnaire score (HAQ) was noted in eight of the ten patients. After 12 months, eight patients had a good response; among them, two had returned to work and five had resumed previous athletic activities. Of the four patients with severe skin disease at baseline, three were in clinical remission of their skin lesions after 12 months. Two patients had stopped etanercept therapy, one because of inefficacy and the other, who had diabetes mellitus, because of osteomyelitis. Mease et al. reported a randomized, double-blind placebo-controlled study of etanercept in a dosage of 25 mg twice a week for three months [9]. The study included 60 patients with psoriatic arthritis, 34 men and 26 women, with a mean age of 45 years and a mean disease duration of 11 years. All 60 patients had active arthritis at baseline. Efficacy was evaluated based on the ACR20, ACR50, and ACR70 criteria; the Psoriatic Arthritis Response Criteria (PsARC); and the Psoriasis Area and Severity Index (PASI). After three months, marked improvements were found in the arthritis (PsARC, 87% vs 23%; and ACR20, 73% vs 13%) and skin disease (PASI, 46% vs 9%; PASI of 75 in 26% of patients in the TNFα group vs 0% in the placebo group). At the last meeting of the American College of Rheumatology (ACR) in Philadelphia, Mease reported the six-month results of an open-label study: 87% of the patients had achieved ACR20 criteria, 63% ACR50 criteria, and 33% ACR70 criteria; the PASI was improved by 62%; in the methotrexate-treated subset, 25% of patients stopped methotrexate and 43% reduced the dosage; and in the glucocorticoid-treated subset, 44% stopped glucocorticoid therapy and 67% reduced the dosage. Finally, Aboulafia described the results of etanercept therapy for psoriatic arthritis in an HIV-positive patient [10]; although remarkably effective, the drug had to be stopped because of serious infectious side effects. INFLIXIMAB (REMICADEt) Infliximab has been used according to the same schedule as in rheumatoid arthritis but at a dosage of 5 mg/kg instead of 10 mg/kg. In an open-label study of 21 patients with spondyloarthropathy, including eight with psoriatic arthritis, Van Den Bosh et al. reported improvements as early as the third day in the joint involvement as assessed globally by the patient and physician, as well as in the
107
erythrocyte sedimentation rate and C-reactive protein level [11]. The beneficial effects on peripheral and axial manifestations persisted through the sixth week. Improvements were noted in the visual analogue scale score and in spinal parameters such as the finger-tofloor distance, the occiput-to-wall distance and chest expansion. The psoriasis improved also, as shown by the mean PASI values of 0.72 at baseline, 0.44 after two weeks, 0.16 after six weeks, and 0.105 after 14 weeks. At the last meeting of the European League Against Rheumatism (EULAR), Antoni presented a poster [12] showing that three infusions of infliximab (on weeks 0, 2, and 6) produced excellent results in ten patients with severe active psoriatic arthritis. At the tenth week, all ten patients met ACR50 criteria and 70% met ACR70 criteria. Improvements were 90% for the visual analogue scale score, 80% for the Health Assessment Questionnaire score, and 71% for the PASI. The laboratory evidence of inflammation was less marked. In the minority of patients who had magnetic resonance imaging (MRI) scans, the postgadolinium enhancement denoting enthesitis decreased markedly as compared to baseline. Similarly, in a study of active ankylosing spondylitis treated with infliximab, Brandt [13] described the results of spinal MRI in five patients. Three patients had evidence of discitis at baseline. In two of these patients, marked improvements were seen on the follow-up MRIs obtained after 6 weeks of treatment. Nine of the ten patients in this study had a 50% decrease in back pain. Preliminary results from an open-label study reported by Gorman at the last ACR meeting suggest that etanercept may also improve back pain in patients with ankylosing spondylitis. In our department, we have used infliximab in a few patients with severe psoriatic arthritis. Dramatic improvements in the skin and joint symptoms were noted as early as after the second infusion. Taken in aggregate, these data are extremely promising: TNFα inhibitors improve the skin lesions, the peripheral joint manifestations (perhaps preventing radiological destruction, as in rheumatoid arthritis), and the enthesitis. The favorable effects on MRI evidence of discitis suggest that TNFα inhibitors may prevent the development of intervertebral ankylosis. Thus, the indications for TNFα inhibitor therapy will probably be extended to psoriatic arthritis. However, several issues remain unsettled. TNFα inhibitors treat the symptoms of psoriatic arthritis, not the cause. Studies are needed to determine which patients are most
108
L. Zabraniecki, B. Fournié
likely to benefit from TNFα inhibitor therapy, when the treatment should be started, and what the optimal dosage and treatment duration are. Studies of these issues will face two major obstacles: the high cost of TNFα inhibitors and the lack of long-term safety data. TNFα inhibitors interact with the immune system, modifying the capacity of the body to ward off infection and cancer and to prevent the development of autoimmunity. Clearly, further studies are needed. At long last, a treatment effective even on the axial manifestations of psoriatic arthritis will probably be available soon. At what cost? REFERENCES 1 Alibert JL. Précis théorique et pratique sur les maladies de la peau. Paris: Caille et Ranvier; 1818. 2 Fournié B, Crognier L, Arnaud C, Zabraniecki L, LascauLefebvre V, Marc V, et al. Proposed classification criteria of psoriatic arthritis. A preliminary study in 260 patients. Rev Rhum [Engl Ed] 1999 ; 66 : 446-56. 3 Pitzalis C, Cauli A, Pipitone N, Smith C, Barker J, Marchesoni A, et al. Cutaneous lymphocyte antigen-positive T lymphocytes preferentially migrate to the skin but not to the joint in psoriatic arthritis. Arthritis Rheum 1996 ; 39 : 137-45. 4 Burden AD. Identifying a gene for psoriasis on chromosome 6 (Psors 1). Br J Dermatol 2000 ; 143 : 237-43.
5 Elkayam O, Yaron I, Shirazi I, Yaron M, Caspi D. Serum levels of IL-10, IL-6, IL-1ra, and sIL-2R in patients with psoriatic arthritis. Rheumatol Int 2000 ; 19 : 101-5. 6 Starcher B. Role of tumour necrosis factor-α receptors in ultraviolet-induced skin tumours. Br J Dermatol 2000 ; 142 : 1140-7. 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 sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum 1995 ; 38 : 499-505. 8 Yazici Y, Erkan D, Lockshin MD. A preliminary study of etanercept in the treatment of severe, resistant psoriatic arthritis. Clin Exp Rheumatol 2000 ; 18 : 732-4. 9 Mease PJ, Goffe BS, Metz J, Van der Stoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000 ; 356 : 385-90. 10 Aboulafia DM, Bundow D, Wilske K, Ochs UI. Etanercept for the treatment of human immunodeficiency virus-associated psoriatic arthritis. Mayo Clin Proc 2000 ; 75 : 1093-8. 11 Van den Bosch F, Kruithof E, Baeten D, De Keyser F, Mielants H, Veys EM. Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor-α (infliximab) in spondylarthropathy: an open pilot study. Ann Rheum Dis 2000 ; 59 : 428-33. 12 Antoni C, Dechant C, Lorenz HM, Wendlere J, Ogilive A, Lufti M, et al. Successful treatment of psoriatic arthritis with infliximab in an MRI controlled study [abstract]. Ann Rheum Dis 2000 ; 5 (Suppl 1) : 200. 13 Brandt J, Haibel H, Cornely D, Golder W, Gonzalez J, Reddig J. Successful treatment of active ankylosing spondylitis with the anti-tumour necrosis factor-α monoclonal antibody infliximab. Arthritis Rheum 2000 ; 43 : 1346-52.