- Email: [email protected]
Efficacy of tocilizumab in refractory giant cell arteritis
Joint Bone Spine 79 (2012) 317–318
Available online at
www.sciencedirect.com
Case report
Efficacy of tocilizumab in refractory giant cell arteritis Julien Vinit ∗ , Philip Bielefeld , Géraldine Muller , Jean-Franc¸ois Besancenot Service de médecine interne et maladies systémiques, hôpital Général, University Hospital of Dijon, 3, rue Faubourg-Raines, 21033 Dijon cedex, France
a r t i c l e
i n f o
Article history: Accepted 29 November 2011 Available online 27 January 2012 Keywords: Therapeutic Methotrexate Interleukin-6 blockade Steroids Ileitis
a b s t r a c t Giant cell arteritis is the most frequent form of vasculitis characterized by a high risk of vascular thrombosis. Major complications are blindness and other vascular ischemia but bowel ischemic involvement is rare. Treatment is based on long-term steroid therapy with numerous side effects. The efficacy of immunosuppressive drugs like azathioprine methotrexate or anti-tumor necrosis factor antibodies appears to be too low to reduce the use of steroids. Th17 lymphocytes and interleukin-6 play an important role in pathogenesis of giant cell arteritis. We report here a case of effective interleukin-6 blocker in the treatment of refractory giant cell arteritis with ileitis and high-dose steroid dependence despite 2 years of treatment with steroids and methotrexate. After infusions of tocilizumab, no relapse at 6 months was found despite the decrease in corticosteroids. © 2011 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Giant-cell arteritis (GCA) is an immune-mediated vaculitis characterized by granulomatous infiltrates in the walls of medium-size and large arteries including the aorta and often the external carotid arteries. It is a frequent disease with a prevalence of 200 cases per 100,000 and an annual incidence varying between 20 and 30 per 100,000 persons [1,2]. GCA affects people over 50 years of age. High dose of glucocorticoids (GC) remain the initial treatment recommended [2–5]. They remove headaches, rhizomelic pain, weight loss, elevated inflammatory markers and reduce the risk of vascular accidents such as blindness and artery occlusion. The side effects of GC therapy indicate that lower dosages and shorter treatment durations would be desirable, thus generating interest in drugs that may reduce GC requirements. However, there is no consensus about the optimal starting dose, duration, or tapering schedule, and current recommendations are based on expert opinion. Vasculitis relapses or steroid dependence may occur when GC dosages are decreased. This leads to long-term high-dose treatment and high cumulative doses, which are associated with substantial toxicity and morbidity like osteoporosis, infection and cardiovascular diseases. The EULAR recommends that an immunosuppressive agent should be considered for use in large vessel vasculitis as adjunctive therapy and specially in GCA [5]. The effectiveness of immunosuppressive drugs such as methotrexate (MTX) [2,4,6] and azathioprine (AZA), as well as TNF-blocking agents [2,4], in controlling the disease and thus allowing reductions in the use of steroids have been studied.
∗ Corresponding author. Tel.: +33 3 80 29 37 73; fax: +33 3 80 29 52 68. E-mail address: [email protected] (J. Vinit).
MTX was shown a moderated effectiveness. The usefulness of AZA remains controversial and infliximab and etanercept (TNF-blocking agents) were unable to induce and maintain disease remission. The French study with adalimumab (oral communication) appears to show that the drug is not effective in this indication. Interleukin 6 (IL-6) is an important pro-inflammatory cytokine, one of the most important mediators of fever and of the acute phase response in infection and inflammatory diseases. IL-6 is implicated in the pathogenesis of GCA [7,8]. IL-6 levels are elevated in active disease, and correlate with the acute phase response. In addition, corticosteroids result in decreased levels of IL-6 [9]. Current evidence indicates that IL-6 may be a good target molecule to induce remission in GCA. Indeed, levels of IL-6 were found higher in patients who relapse compared to non-relapsers [10]. We report here a case of the clinical efficacy of an IL-6 blockade agent.
2. Case report A 63-year-old woman consulted for impaired general health with weight loss and asthenia, peripheral arthritis and headache. She described serious abdominal pain in the right lower quadrant. Laboratory tests revealed major chronic inflammatory syndrome, ESR: 90 mm at the first hour, C-reactive protein (CRP): 150 mg/L and anemia of chronic disease. Immunological tests (rheumatoid factor, cyclic citrullinated peptide antibodies, anti-cytoplasm antibodies to polynuclear neutrophils, anti-nuclear antibodies) and tumor markers were normal. Serology and blood cultures were negative. Chest and abdominal tomodensitometry showed no abnormalities. Temporal artery biopsy revealed a typical giant cell granuloma with destruction of the internal elastic lamina, and the diagnosis of GCA was made. GC therapy was quickly started and led
1297-319X/$ – see front matter © 2011 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2011.11.008
318
J. Vinit et al. / Joint Bone Spine 79 (2012) 317–318
to dramatic improvements in symptoms. After 2 years of treatment and despite the introduction of 20 mg per week of MTX, the patient was steroid-dependent at around 20 mg per day of cortisone with the reappearance of inflammatory joint pain and severe abdominal pain associated with a rise in inflammation markers with ESR between 25 to 40 mm at the first hour and CRP at around 25–30 mg/L and fibrinogen around 4.5 g/L. Abdominal pains seemed to depend on schedule of lunch with increase during digestion. Abdominal tomodensitometry showed distal ileitis with edema and wall thickening. An arterial occlusion was not shown. Investigations for infection remained negative (stool culture and infectious serology). Ileo-gastroscopy and colonoscopy with biopsies were normal. Antibiotics were not effectiveness but ileitis was steroid-sensitive. We have concluded to a possible paroxystic bowel ischemia due to GCA and small arterial digestive involvement like described in the literature [11]. Many relapses were seen with decreased doses of GC. Finally, the patient was treated with an intravenous infusion of tocilizumab according to the protocol used in rheumatoid arthritis (8 mg/kg every 4 weeks). With the first dose, the inflammation was completely normalized (ESR 3 mm at the first hour, fibrinogen 2.5 g/L, CRP < 3 mg/L) and the patient was able to resume the reduction in steroid doses. After three infusions, the patient required only 5 mg of prednisone per day. No relapse has occurred 6 months after the last infusion. 3. Discussion GCA is characterized by lymphocyte infiltration arteries. The important role of TH17 lymphocytes in the pathogenesis of GCA is well documented [12]. IL-17-producing Th17 cells are sensitive to GC-mediated suppression [13]. IL-6 is the main cytokine involved in the orientation of TH17 cells [14] and improves the balance between Treg cells and TH17 lymphocytes. These data support the potential interest of anti-IL-6 drugs such as tocilizumab in this disease. Only a few reports about the use of tocilizumab to induce remission or to reduce GCs have been published [12,13] but the drug seems to be effective [15,16]. Similar observations are needed before a randomized study can be initiated to determine the role of IL-6 blockade biotherapy in the
treatment of GCA. The poor efficacy of other immunosuppressive drugs may justify the use of this new biotherapy as an alternative therapy to induce remission or to reduce the use of steroids. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Richards BL, March L, Gabriel SE. Epidemiology of large-vessel vasculidities. Best Pract Res Clin Rheumatol 2010;24:871–83. [2] Devauchelle-Pensec V, Jousse S, Destombe C, et al. Epidemiology, imaging, and treatment of giant cell arteritis. Joint Bone Spine 2008;75:267–72. [3] Gonzalez-Gay MA, Martinez-Dubois C, Agudo M, et al. Giant cell arteritis: epidemiology, diagnosis, and management. Curr Rheumatol Rep 2010;12:436–42. [4] Masson C. Therapeutic approach to giant cell arteritis. Joint Bone Spine 2011, doi:10.1016/j.jbspin.2011.09.015. [5] Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2009;68:318–23. [6] Spies CM, Burmester GR, Buttgereit F. Methotrexate treatment in large vessel vasculitis and polymyalgia rheumatica. Clin Exp Rheumatol 2010;28:S172–7. [7] Emilie D, Liozon E, Crevon MC, et al. Production of interleukin 6 by granulomas of giant cell arteritis. Hum Immunol 1994;39:17–24. [8] Roche NE, Fulbright JW, Wagner AD, et al. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum 1993;36:1286–94. [9] Weyand CM, Fulbright JW, Hunder GG, et al. Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum 2000;43:1041–8. [10] Garcia-Martinez A, Hernandez-Rodriguez J, Espigol-Frigole G, et al. Clinical relevance of persistently elevated circulating cytokines (tumor necrosis factor alpha and interleukin-6) in the long-term follow-up of patients with giant cell arteritis. Arthritis Care Res 2010;62:835–41. [11] Scola CJ, Li C, Upchurch KS. Mesenteric involvement in giant cell arteritis. An underrecognized complication? Analysis of a case series with clinicoanatomic correlation. Medicine (Baltimore) 2008;87:45–51. [12] Weyand CM, Younge BR, Goronzy JJ. IFN-gamma and IL-17: the two faces of T-cell pathology in giant cell arteritis. Curr Opin Rheumatol 2011;23:43–9. [13] Deng J, Younge BR, Olshen RA, et al. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation 2010;121:906–15. [14] Kimura A, Kishimoto T. Th17 cells in inflammation. Int Immunopharmacol 2011;11:319–22. [15] Sciascia S, Rossi D, Roccatello D. Interleukin 6 blockade as steroid-sparing treatment for 2 patients with giant cell arteritis. J Rheumatol 2011;38:2080–1. [16] Seitz M, Reichenbach S, Bonel HM, et al. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly 2011;141:w13156, doi:10.4414/smw.2011.13156.
Available online at
www.sciencedirect.com
Case report
Efficacy of tocilizumab in refractory giant cell arteritis Julien Vinit ∗ , Philip Bielefeld , Géraldine Muller , Jean-Franc¸ois Besancenot Service de médecine interne et maladies systémiques, hôpital Général, University Hospital of Dijon, 3, rue Faubourg-Raines, 21033 Dijon cedex, France
a r t i c l e
i n f o
Article history: Accepted 29 November 2011 Available online 27 January 2012 Keywords: Therapeutic Methotrexate Interleukin-6 blockade Steroids Ileitis
a b s t r a c t Giant cell arteritis is the most frequent form of vasculitis characterized by a high risk of vascular thrombosis. Major complications are blindness and other vascular ischemia but bowel ischemic involvement is rare. Treatment is based on long-term steroid therapy with numerous side effects. The efficacy of immunosuppressive drugs like azathioprine methotrexate or anti-tumor necrosis factor antibodies appears to be too low to reduce the use of steroids. Th17 lymphocytes and interleukin-6 play an important role in pathogenesis of giant cell arteritis. We report here a case of effective interleukin-6 blocker in the treatment of refractory giant cell arteritis with ileitis and high-dose steroid dependence despite 2 years of treatment with steroids and methotrexate. After infusions of tocilizumab, no relapse at 6 months was found despite the decrease in corticosteroids. © 2011 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Giant-cell arteritis (GCA) is an immune-mediated vaculitis characterized by granulomatous infiltrates in the walls of medium-size and large arteries including the aorta and often the external carotid arteries. It is a frequent disease with a prevalence of 200 cases per 100,000 and an annual incidence varying between 20 and 30 per 100,000 persons [1,2]. GCA affects people over 50 years of age. High dose of glucocorticoids (GC) remain the initial treatment recommended [2–5]. They remove headaches, rhizomelic pain, weight loss, elevated inflammatory markers and reduce the risk of vascular accidents such as blindness and artery occlusion. The side effects of GC therapy indicate that lower dosages and shorter treatment durations would be desirable, thus generating interest in drugs that may reduce GC requirements. However, there is no consensus about the optimal starting dose, duration, or tapering schedule, and current recommendations are based on expert opinion. Vasculitis relapses or steroid dependence may occur when GC dosages are decreased. This leads to long-term high-dose treatment and high cumulative doses, which are associated with substantial toxicity and morbidity like osteoporosis, infection and cardiovascular diseases. The EULAR recommends that an immunosuppressive agent should be considered for use in large vessel vasculitis as adjunctive therapy and specially in GCA [5]. The effectiveness of immunosuppressive drugs such as methotrexate (MTX) [2,4,6] and azathioprine (AZA), as well as TNF-blocking agents [2,4], in controlling the disease and thus allowing reductions in the use of steroids have been studied.
∗ Corresponding author. Tel.: +33 3 80 29 37 73; fax: +33 3 80 29 52 68. E-mail address: [email protected] (J. Vinit).
MTX was shown a moderated effectiveness. The usefulness of AZA remains controversial and infliximab and etanercept (TNF-blocking agents) were unable to induce and maintain disease remission. The French study with adalimumab (oral communication) appears to show that the drug is not effective in this indication. Interleukin 6 (IL-6) is an important pro-inflammatory cytokine, one of the most important mediators of fever and of the acute phase response in infection and inflammatory diseases. IL-6 is implicated in the pathogenesis of GCA [7,8]. IL-6 levels are elevated in active disease, and correlate with the acute phase response. In addition, corticosteroids result in decreased levels of IL-6 [9]. Current evidence indicates that IL-6 may be a good target molecule to induce remission in GCA. Indeed, levels of IL-6 were found higher in patients who relapse compared to non-relapsers [10]. We report here a case of the clinical efficacy of an IL-6 blockade agent.
2. Case report A 63-year-old woman consulted for impaired general health with weight loss and asthenia, peripheral arthritis and headache. She described serious abdominal pain in the right lower quadrant. Laboratory tests revealed major chronic inflammatory syndrome, ESR: 90 mm at the first hour, C-reactive protein (CRP): 150 mg/L and anemia of chronic disease. Immunological tests (rheumatoid factor, cyclic citrullinated peptide antibodies, anti-cytoplasm antibodies to polynuclear neutrophils, anti-nuclear antibodies) and tumor markers were normal. Serology and blood cultures were negative. Chest and abdominal tomodensitometry showed no abnormalities. Temporal artery biopsy revealed a typical giant cell granuloma with destruction of the internal elastic lamina, and the diagnosis of GCA was made. GC therapy was quickly started and led
1297-319X/$ – see front matter © 2011 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2011.11.008
318
J. Vinit et al. / Joint Bone Spine 79 (2012) 317–318
to dramatic improvements in symptoms. After 2 years of treatment and despite the introduction of 20 mg per week of MTX, the patient was steroid-dependent at around 20 mg per day of cortisone with the reappearance of inflammatory joint pain and severe abdominal pain associated with a rise in inflammation markers with ESR between 25 to 40 mm at the first hour and CRP at around 25–30 mg/L and fibrinogen around 4.5 g/L. Abdominal pains seemed to depend on schedule of lunch with increase during digestion. Abdominal tomodensitometry showed distal ileitis with edema and wall thickening. An arterial occlusion was not shown. Investigations for infection remained negative (stool culture and infectious serology). Ileo-gastroscopy and colonoscopy with biopsies were normal. Antibiotics were not effectiveness but ileitis was steroid-sensitive. We have concluded to a possible paroxystic bowel ischemia due to GCA and small arterial digestive involvement like described in the literature [11]. Many relapses were seen with decreased doses of GC. Finally, the patient was treated with an intravenous infusion of tocilizumab according to the protocol used in rheumatoid arthritis (8 mg/kg every 4 weeks). With the first dose, the inflammation was completely normalized (ESR 3 mm at the first hour, fibrinogen 2.5 g/L, CRP < 3 mg/L) and the patient was able to resume the reduction in steroid doses. After three infusions, the patient required only 5 mg of prednisone per day. No relapse has occurred 6 months after the last infusion. 3. Discussion GCA is characterized by lymphocyte infiltration arteries. The important role of TH17 lymphocytes in the pathogenesis of GCA is well documented [12]. IL-17-producing Th17 cells are sensitive to GC-mediated suppression [13]. IL-6 is the main cytokine involved in the orientation of TH17 cells [14] and improves the balance between Treg cells and TH17 lymphocytes. These data support the potential interest of anti-IL-6 drugs such as tocilizumab in this disease. Only a few reports about the use of tocilizumab to induce remission or to reduce GCs have been published [12,13] but the drug seems to be effective [15,16]. Similar observations are needed before a randomized study can be initiated to determine the role of IL-6 blockade biotherapy in the
treatment of GCA. The poor efficacy of other immunosuppressive drugs may justify the use of this new biotherapy as an alternative therapy to induce remission or to reduce the use of steroids. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Richards BL, March L, Gabriel SE. Epidemiology of large-vessel vasculidities. Best Pract Res Clin Rheumatol 2010;24:871–83. [2] Devauchelle-Pensec V, Jousse S, Destombe C, et al. Epidemiology, imaging, and treatment of giant cell arteritis. Joint Bone Spine 2008;75:267–72. [3] Gonzalez-Gay MA, Martinez-Dubois C, Agudo M, et al. Giant cell arteritis: epidemiology, diagnosis, and management. Curr Rheumatol Rep 2010;12:436–42. [4] Masson C. Therapeutic approach to giant cell arteritis. Joint Bone Spine 2011, doi:10.1016/j.jbspin.2011.09.015. [5] Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2009;68:318–23. [6] Spies CM, Burmester GR, Buttgereit F. Methotrexate treatment in large vessel vasculitis and polymyalgia rheumatica. Clin Exp Rheumatol 2010;28:S172–7. [7] Emilie D, Liozon E, Crevon MC, et al. Production of interleukin 6 by granulomas of giant cell arteritis. Hum Immunol 1994;39:17–24. [8] Roche NE, Fulbright JW, Wagner AD, et al. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum 1993;36:1286–94. [9] Weyand CM, Fulbright JW, Hunder GG, et al. Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum 2000;43:1041–8. [10] Garcia-Martinez A, Hernandez-Rodriguez J, Espigol-Frigole G, et al. Clinical relevance of persistently elevated circulating cytokines (tumor necrosis factor alpha and interleukin-6) in the long-term follow-up of patients with giant cell arteritis. Arthritis Care Res 2010;62:835–41. [11] Scola CJ, Li C, Upchurch KS. Mesenteric involvement in giant cell arteritis. An underrecognized complication? Analysis of a case series with clinicoanatomic correlation. Medicine (Baltimore) 2008;87:45–51. [12] Weyand CM, Younge BR, Goronzy JJ. IFN-gamma and IL-17: the two faces of T-cell pathology in giant cell arteritis. Curr Opin Rheumatol 2011;23:43–9. [13] Deng J, Younge BR, Olshen RA, et al. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation 2010;121:906–15. [14] Kimura A, Kishimoto T. Th17 cells in inflammation. Int Immunopharmacol 2011;11:319–22. [15] Sciascia S, Rossi D, Roccatello D. Interleukin 6 blockade as steroid-sparing treatment for 2 patients with giant cell arteritis. J Rheumatol 2011;38:2080–1. [16] Seitz M, Reichenbach S, Bonel HM, et al. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly 2011;141:w13156, doi:10.4414/smw.2011.13156.