Letters to the Editor
Rheumatology 2014;53:23122314 doi:10.1093/rheumatology/keu344 Advance Access publication 17 September 2014
Treatment of ErdheimChester disease with canakinumab
2312
Rheumatology key message .
Canakinumab can be used as a treatment option for ErdheimChester disease.
Funding: None. Disclosure statement: The authors have declared no conflicts of interest.
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ at University of California, San Francisco on December 11, 2014
SIR, ErdheimChester disease (ECD) is a rare nonLangerhans systemic histiocytosis, characterized histologically by typical xanthogranulomatous infiltration of tissues by foamy CD68+ and CD1a histiocytes. ECD typically involves bilateral symmetrical cortical osteosclerosis of the diaphyseal and metaphyseal regions in the long bones and infiltration of other organs [1]. The pathophysiology of the disease is not well understood. Recent studies have found a high prevalence of the BRAF V600E mutation among ECD patients [2]. Only a small number of cases, several hundred adult cases and seven paediatric cases, have been reported in the medical literature [1]. Advances in the treatment are complicated by the rarity of the disease, rendering the conduction of controlled trials impossible. Advances in treatment of this disease are therefore based on reports of cases and case series. Several treatments have been administered to ECD patients in order to achieve remission or at least stabilization [1]. IFN-a therapy provides sustainable stabilization of the disease in most cases [1] and the BRAF inhibitor vemurafenib has efficacy in patients positive for the BRAF V600E mutation [3]. Targeting of IL-1 signalling has recently emerged as another treatment option. Daily s.c. injection with anakinra, a recombinant, non-glycosylated homologue of the human IL-1 receptor antagonist that competitively inhibits binding of IL-1a and IL-1b to the IL-1 receptor, has shown clinical benefit in some patients [48]. However, a previous report of two adult patients suggested that the clinical benefit of anakinra may be mediated by IL-1a blockade [4]. Therefore physicians may hesitate to use the long-acting molecule canakinumab, a human IgG1 monoclonal antibody selectively directed against IL-1b. Here we report the efficacy of canakinumab in maintaining remission after switching from anakinra. A 10-year-old girl with histologically confirmed ECD in bone biopsies was successfully treated with anakinra as second-line treatment after IFN-a [5], which became inefficacious after 10 months of treatment. In this patient the disease presented with recurrent fever, elevated ESR, increased CRP, bone pain and failure to thrive. Bone X-ray found multiple osteolytic and osteosclerotic lesions in the femurs, tibia and pelvis. Whole-body MRI showed a high-intensity signal of the skeletal bone marrow in fatsuppressed T2-weighted image, retroperitoneal infiltration and diffuse low-intensity signal in the metadiaphyses. The patient did not carry the BRAF V600E mutation. Treatment with anakinra allowed resolution of fever and bone pain, normalization of ESR and CRP and weight and height gain [5]. After 12 months of anakinra treatment with ongoing good clinical and biological benefit, the patient refused to go on with daily s.c. injections, which were painful
despite prior application of topical anaesthetic cream [EMLA (lidocaine and prilocaine)]. Treatment with canakinumab was discussed and the patient and her parents agreed to this treatment. Anakinra treatment was replaced by canakinumab (2 mg/kg/8 weeks). During the following 8 months all clinical and biological (blood cell counts, ESR, CRP) signs of disease activity remained normal (Fig. 1A). The frequency of injection was then decreased to every 10 weeks. Nine weeks and 6 days after the last injection the patient was admitted to the hospital with fever, anaemia (haemoglobin 10.1 g/dl), thrombocytopenia (93 000/ mm3), elevated ESR (50 mm/h) and elevated CRP (77 mg/l) (Fig. 1A). This clinical and biological picture was similar to disease flares in the past, suggesting disease relapse. Laboratory investigations for bacterial and viral infection were negative. Cytokine measurement of unstimulated peripheral blood mononuclear cells (PBMC) compared with healthy controls (n = 8) showed increased levels of IL-1b (11-fold) and TNF-a (22-fold) (Fig. 1B). After stimulation with lipopolysaccharide (LPS), the patient’s PBMCs compared with controls produced greater amounts of IL-1b (1.8-fold) and TNF-a (4.8-fold), even though the differences were less important than in unstimulated cells (Fig. 1B). No significant differences were found in unstimulated and LPS-stimulated PBMCs with respect to IL-6 (Fig. 1B). The patient was treated again with injection of canakinumab (2 mg/kg). Within 4 days fever disappeared and CRP, ESR and blood cell counts progressively normalized (Fig. 1A). During the follow-up period of 22 months under treatment with canakinumab (2 mg/kg/8 weeks), no clinical or biological signs of disease were observed. The girl started and completed her puberty and her growth parameters entered the normal developmental curves. However, little change was observed with regard to MRI images of retroperitoneal infiltration and bone marrow (Fig. 1C). No significant side effects were observed. In conclusion, this observation suggests that canakinumab, a long half-life molecule, may be used as a treatment option for ECD, especially in patients who respond to anakinra and in whom compliance problems occur. The clinical benefit obtained by selective blockade of IL-1b observed here suggests that the efficacy of IL-1-targeting drugs in ECD may be, at least in some patients, mediated by inhibition of IL-1b rather than IL-1a.
Letters to the Editor
FIG. 1 Biological and MRI changes during treatment with canakinumab
Downloaded from http://rheumatology.oxfordjournals.org/ at University of California, San Francisco on December 11, 2014
(A) CRP and ESR during treatment with anakinra and canakinumab. (B) Cytokine production of PBMCs with or without LPS stimulation. (C) Comparative images of whole-body MRI before treatment with anakinra, 12 months after treatment with anakinra and 12 months and 28 months after treatment with canakinumab. Whole-body MRI, frontal view; T2weighted images with fat suppression. Coronal fat-suppressed T2-weighted images show high signal intensity in the bone marrow, hepatosplenomegaly and infiltration of the retroperitoneum from renal pedicles to the aortic bifurcation and multiple adenomegalies.
www.rheumatology.oxfordjournals.org
2313
Letters to the Editor
Tu-Anh Tran1, Danie`le Pariente2, Corinne Guitton3, Adriana Delwail4, Mouna Barat-Houari5 and Ulrich Meinzer6 1
References 1 Mazor RD, Manevich-Mazor M, Shoenfeld Y. ErdheimChester disease: a comprehensive review of the literature. Orphanet J Rare Dis 2013;8:137. 2 Haroche J, Charlotte F, Arnaud L et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 2012;120:27003. 3 Haroche J, Cohen-Aubart F, Emile JF et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory ErdheimChester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 2013;121:1495500. 4 Aouba A, Georgin-Lavialle S, Pagnoux C et al. Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease. Blood 2010;116:40706. 5 Tran TA, Pariente D, Lecron JC et al. Treatment of pediatric Erdheim-Chester disease with interleukin-1-targeting drugs. Arthritis Rheum 2011;63:40312. 6 Aubert O, Aouba A, Deshayes S et al. Favorable radiological outcome of skeletal Erdheim-Chester disease involvement with anakinra. Joint Bone Spine 2013;80:2067. 7 Courcoul A, Vignot E, Chapurlat R. Successful treatment of Erdheim-Chester disease by interleukin-1 receptor antagonist protein. Joint Bone Spine 2014;81:1757. 8 Killu AM, Liang JJ, Jaffe AS. Erdheim-Chester disease with cardiac involvement successfully treated with anakinra. Int J Cardiol 2013;167:e1157.
Rheumatology 2014;53:23142315 doi:10.1093/rheumatology/keu374 Advance Access publication 18 September 2014
Remission of rheumatoid arthritis on brentuximab vedotin SIR, RA is characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone
2314
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ at University of California, San Francisco on December 11, 2014
Department of Pediatrics, Nıˆmes University Hospital, Nıˆmes, INSERM U 844, University of Montpelier 1, Montpellier, 2 Department of Pediatric Radiology, 3Department of Pediatrics, Assistance Publique Hoˆpitaux de Paris, Biceˆtre University Hospital, Le Kremlin Biceˆtre, 4University of Poitiers, Laboratoire Inflammation, Tissus Epithe´liaux et Cytokines (LITEC) Poitiers, 5Laboratory of Genetics, Rare and Autoinflammatory Diseases, Department of Genetics, LBM Montpellier University Hospital, INSERM U844, Montpellier and 6Department of General Pediatrics and Internal Medicine, Assistance Publique Hoˆpitaux de Paris, Robert Debre´ University Hospital, University of Paris, Paris, France. Accepted 30 June 2014 Correspondence to: Tu-Anh Tran, Department of Pediatrics, Nıˆmes University Hospital, 1 place du Pr Debre´, Nıˆmes 30029, France. E-mail: [email protected]
destruction and systemic manifestations, e.g. cardiovascular, pulmonary and neoplastic complications [1]. Both the innate and adaptive immune pathways contribute to synovial pathology; cytokines such as TNF and IL-6, among others, play a central role in the pathogenesis. Indeed, DMARDs targeted against some of these cytokines, socalled biologics, are routinely used in practice today. Nevertheless, current therapies occasionally fail or produce only partial responses, and sustained remission is rarely achieved [1]. Further, the emergence of infections, e.g. tuberculosis, and certain autoimmune syndromes, e.g. lupus, have occasionally been associated with TNF antagonists, the most commonly used class among currently available biologics [2]. There exists, therefore, a substantial unmet need for novel therapies, preferably with new mechanisms of action. Here we describe a case of complete, sustained remission of RA on the novel CD30-directed antibodydrug conjugate (ADC) brentuximab vedotin [BV (ADCETRIS); Seattle Genetics, Bothell, WA, USA). To our knowledge this has not previously been reported in the literature. A 76-year-old female presented with a 6 month history of fevers, chills, night sweats and a 20 lb weight loss. She had a 10 year history of RA maintained on infliximab (300 mg every 8 weeks) and oral MTX (15 mg/wk) with approximately 23 prednisone-requiring flares annually. PET suggested a stage IV lymphoma. A pathological diagnosis of classical Hodgkin’s lymphoma was made, as immunohistochemical staining was positive for CD15, CD30 and Pax5. She was enrolled in a phase II clinical trial of BV, 1.8 mg/kg i.v. every 3 weeks (NCT01716806). Eight weeks prior to starting BV, her rheumatologist recommended increasing the frequency of infliximab administration, noting a wearing off effect [morning stiffness, arthralgia, 10 swollen and tender joints and a 28-joint DAS with CRP (DAS28-CRP) of 6.35 (high disease activity)], but both DMARDs had to be discontinued as requirements for trial eligibility. Steroids were not co-administered. A complete metabolic remission (by PET) of her stage IVB lymphoma was achieved after just two cycles of therapy [3]. Notably, her RA went into clinical remission as well at this time. Six weeks after completing 16 cycles (10.5 months) of BV, her RA continues to be in remission (DAS28-CRP 1.93). Therapy with BV was discontinued after 16 cycles due to progressive peripheral neuropathy. CT continued to show no evidence of recurrence of Hodgkin’s lymphoma. The surface expression of CD30, a transmembrane glycoprotein belonging to the TNF receptor superfamily, appears to be restricted to both normal and neoplastic cells of T and B lineage within the immune system [4]. Increased concentrations of soluble CD30 (sCD30), formed after cleavage of the extracellular domain of CD30, have been detected in various conditions, e.g. CD30+ malignancies, viral infections and immune-mediated inflammatory processes such as CTDs, vasculitis and RA [4]. The consequences of CD30 interaction with its ligand, CD30L, are poorly understood; CD30 activation may well depend upon cell and tissue type, with effects ranging from cell proliferation and activation to apoptosis and control of Treg function; reverse signalling, i.e. signal transduction to
Rheumatology 2014;53:23122314 doi:10.1093/rheumatology/keu344 Advance Access publication 17 September 2014
Treatment of ErdheimChester disease with canakinumab
2312
Rheumatology key message .
Canakinumab can be used as a treatment option for ErdheimChester disease.
Funding: None. Disclosure statement: The authors have declared no conflicts of interest.
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ at University of California, San Francisco on December 11, 2014
SIR, ErdheimChester disease (ECD) is a rare nonLangerhans systemic histiocytosis, characterized histologically by typical xanthogranulomatous infiltration of tissues by foamy CD68+ and CD1a histiocytes. ECD typically involves bilateral symmetrical cortical osteosclerosis of the diaphyseal and metaphyseal regions in the long bones and infiltration of other organs [1]. The pathophysiology of the disease is not well understood. Recent studies have found a high prevalence of the BRAF V600E mutation among ECD patients [2]. Only a small number of cases, several hundred adult cases and seven paediatric cases, have been reported in the medical literature [1]. Advances in the treatment are complicated by the rarity of the disease, rendering the conduction of controlled trials impossible. Advances in treatment of this disease are therefore based on reports of cases and case series. Several treatments have been administered to ECD patients in order to achieve remission or at least stabilization [1]. IFN-a therapy provides sustainable stabilization of the disease in most cases [1] and the BRAF inhibitor vemurafenib has efficacy in patients positive for the BRAF V600E mutation [3]. Targeting of IL-1 signalling has recently emerged as another treatment option. Daily s.c. injection with anakinra, a recombinant, non-glycosylated homologue of the human IL-1 receptor antagonist that competitively inhibits binding of IL-1a and IL-1b to the IL-1 receptor, has shown clinical benefit in some patients [48]. However, a previous report of two adult patients suggested that the clinical benefit of anakinra may be mediated by IL-1a blockade [4]. Therefore physicians may hesitate to use the long-acting molecule canakinumab, a human IgG1 monoclonal antibody selectively directed against IL-1b. Here we report the efficacy of canakinumab in maintaining remission after switching from anakinra. A 10-year-old girl with histologically confirmed ECD in bone biopsies was successfully treated with anakinra as second-line treatment after IFN-a [5], which became inefficacious after 10 months of treatment. In this patient the disease presented with recurrent fever, elevated ESR, increased CRP, bone pain and failure to thrive. Bone X-ray found multiple osteolytic and osteosclerotic lesions in the femurs, tibia and pelvis. Whole-body MRI showed a high-intensity signal of the skeletal bone marrow in fatsuppressed T2-weighted image, retroperitoneal infiltration and diffuse low-intensity signal in the metadiaphyses. The patient did not carry the BRAF V600E mutation. Treatment with anakinra allowed resolution of fever and bone pain, normalization of ESR and CRP and weight and height gain [5]. After 12 months of anakinra treatment with ongoing good clinical and biological benefit, the patient refused to go on with daily s.c. injections, which were painful
despite prior application of topical anaesthetic cream [EMLA (lidocaine and prilocaine)]. Treatment with canakinumab was discussed and the patient and her parents agreed to this treatment. Anakinra treatment was replaced by canakinumab (2 mg/kg/8 weeks). During the following 8 months all clinical and biological (blood cell counts, ESR, CRP) signs of disease activity remained normal (Fig. 1A). The frequency of injection was then decreased to every 10 weeks. Nine weeks and 6 days after the last injection the patient was admitted to the hospital with fever, anaemia (haemoglobin 10.1 g/dl), thrombocytopenia (93 000/ mm3), elevated ESR (50 mm/h) and elevated CRP (77 mg/l) (Fig. 1A). This clinical and biological picture was similar to disease flares in the past, suggesting disease relapse. Laboratory investigations for bacterial and viral infection were negative. Cytokine measurement of unstimulated peripheral blood mononuclear cells (PBMC) compared with healthy controls (n = 8) showed increased levels of IL-1b (11-fold) and TNF-a (22-fold) (Fig. 1B). After stimulation with lipopolysaccharide (LPS), the patient’s PBMCs compared with controls produced greater amounts of IL-1b (1.8-fold) and TNF-a (4.8-fold), even though the differences were less important than in unstimulated cells (Fig. 1B). No significant differences were found in unstimulated and LPS-stimulated PBMCs with respect to IL-6 (Fig. 1B). The patient was treated again with injection of canakinumab (2 mg/kg). Within 4 days fever disappeared and CRP, ESR and blood cell counts progressively normalized (Fig. 1A). During the follow-up period of 22 months under treatment with canakinumab (2 mg/kg/8 weeks), no clinical or biological signs of disease were observed. The girl started and completed her puberty and her growth parameters entered the normal developmental curves. However, little change was observed with regard to MRI images of retroperitoneal infiltration and bone marrow (Fig. 1C). No significant side effects were observed. In conclusion, this observation suggests that canakinumab, a long half-life molecule, may be used as a treatment option for ECD, especially in patients who respond to anakinra and in whom compliance problems occur. The clinical benefit obtained by selective blockade of IL-1b observed here suggests that the efficacy of IL-1-targeting drugs in ECD may be, at least in some patients, mediated by inhibition of IL-1b rather than IL-1a.
Letters to the Editor
FIG. 1 Biological and MRI changes during treatment with canakinumab
Downloaded from http://rheumatology.oxfordjournals.org/ at University of California, San Francisco on December 11, 2014
(A) CRP and ESR during treatment with anakinra and canakinumab. (B) Cytokine production of PBMCs with or without LPS stimulation. (C) Comparative images of whole-body MRI before treatment with anakinra, 12 months after treatment with anakinra and 12 months and 28 months after treatment with canakinumab. Whole-body MRI, frontal view; T2weighted images with fat suppression. Coronal fat-suppressed T2-weighted images show high signal intensity in the bone marrow, hepatosplenomegaly and infiltration of the retroperitoneum from renal pedicles to the aortic bifurcation and multiple adenomegalies.
www.rheumatology.oxfordjournals.org
2313
Letters to the Editor
Tu-Anh Tran1, Danie`le Pariente2, Corinne Guitton3, Adriana Delwail4, Mouna Barat-Houari5 and Ulrich Meinzer6 1
References 1 Mazor RD, Manevich-Mazor M, Shoenfeld Y. ErdheimChester disease: a comprehensive review of the literature. Orphanet J Rare Dis 2013;8:137. 2 Haroche J, Charlotte F, Arnaud L et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 2012;120:27003. 3 Haroche J, Cohen-Aubart F, Emile JF et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory ErdheimChester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 2013;121:1495500. 4 Aouba A, Georgin-Lavialle S, Pagnoux C et al. Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease. Blood 2010;116:40706. 5 Tran TA, Pariente D, Lecron JC et al. Treatment of pediatric Erdheim-Chester disease with interleukin-1-targeting drugs. Arthritis Rheum 2011;63:40312. 6 Aubert O, Aouba A, Deshayes S et al. Favorable radiological outcome of skeletal Erdheim-Chester disease involvement with anakinra. Joint Bone Spine 2013;80:2067. 7 Courcoul A, Vignot E, Chapurlat R. Successful treatment of Erdheim-Chester disease by interleukin-1 receptor antagonist protein. Joint Bone Spine 2014;81:1757. 8 Killu AM, Liang JJ, Jaffe AS. Erdheim-Chester disease with cardiac involvement successfully treated with anakinra. Int J Cardiol 2013;167:e1157.
Rheumatology 2014;53:23142315 doi:10.1093/rheumatology/keu374 Advance Access publication 18 September 2014
Remission of rheumatoid arthritis on brentuximab vedotin SIR, RA is characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone
2314
www.rheumatology.oxfordjournals.org
Downloaded from http://rheumatology.oxfordjournals.org/ at University of California, San Francisco on December 11, 2014
Department of Pediatrics, Nıˆmes University Hospital, Nıˆmes, INSERM U 844, University of Montpelier 1, Montpellier, 2 Department of Pediatric Radiology, 3Department of Pediatrics, Assistance Publique Hoˆpitaux de Paris, Biceˆtre University Hospital, Le Kremlin Biceˆtre, 4University of Poitiers, Laboratoire Inflammation, Tissus Epithe´liaux et Cytokines (LITEC) Poitiers, 5Laboratory of Genetics, Rare and Autoinflammatory Diseases, Department of Genetics, LBM Montpellier University Hospital, INSERM U844, Montpellier and 6Department of General Pediatrics and Internal Medicine, Assistance Publique Hoˆpitaux de Paris, Robert Debre´ University Hospital, University of Paris, Paris, France. Accepted 30 June 2014 Correspondence to: Tu-Anh Tran, Department of Pediatrics, Nıˆmes University Hospital, 1 place du Pr Debre´, Nıˆmes 30029, France. E-mail: [email protected]
destruction and systemic manifestations, e.g. cardiovascular, pulmonary and neoplastic complications [1]. Both the innate and adaptive immune pathways contribute to synovial pathology; cytokines such as TNF and IL-6, among others, play a central role in the pathogenesis. Indeed, DMARDs targeted against some of these cytokines, socalled biologics, are routinely used in practice today. Nevertheless, current therapies occasionally fail or produce only partial responses, and sustained remission is rarely achieved [1]. Further, the emergence of infections, e.g. tuberculosis, and certain autoimmune syndromes, e.g. lupus, have occasionally been associated with TNF antagonists, the most commonly used class among currently available biologics [2]. There exists, therefore, a substantial unmet need for novel therapies, preferably with new mechanisms of action. Here we describe a case of complete, sustained remission of RA on the novel CD30-directed antibodydrug conjugate (ADC) brentuximab vedotin [BV (ADCETRIS); Seattle Genetics, Bothell, WA, USA). To our knowledge this has not previously been reported in the literature. A 76-year-old female presented with a 6 month history of fevers, chills, night sweats and a 20 lb weight loss. She had a 10 year history of RA maintained on infliximab (300 mg every 8 weeks) and oral MTX (15 mg/wk) with approximately 23 prednisone-requiring flares annually. PET suggested a stage IV lymphoma. A pathological diagnosis of classical Hodgkin’s lymphoma was made, as immunohistochemical staining was positive for CD15, CD30 and Pax5. She was enrolled in a phase II clinical trial of BV, 1.8 mg/kg i.v. every 3 weeks (NCT01716806). Eight weeks prior to starting BV, her rheumatologist recommended increasing the frequency of infliximab administration, noting a wearing off effect [morning stiffness, arthralgia, 10 swollen and tender joints and a 28-joint DAS with CRP (DAS28-CRP) of 6.35 (high disease activity)], but both DMARDs had to be discontinued as requirements for trial eligibility. Steroids were not co-administered. A complete metabolic remission (by PET) of her stage IVB lymphoma was achieved after just two cycles of therapy [3]. Notably, her RA went into clinical remission as well at this time. Six weeks after completing 16 cycles (10.5 months) of BV, her RA continues to be in remission (DAS28-CRP 1.93). Therapy with BV was discontinued after 16 cycles due to progressive peripheral neuropathy. CT continued to show no evidence of recurrence of Hodgkin’s lymphoma. The surface expression of CD30, a transmembrane glycoprotein belonging to the TNF receptor superfamily, appears to be restricted to both normal and neoplastic cells of T and B lineage within the immune system [4]. Increased concentrations of soluble CD30 (sCD30), formed after cleavage of the extracellular domain of CD30, have been detected in various conditions, e.g. CD30+ malignancies, viral infections and immune-mediated inflammatory processes such as CTDs, vasculitis and RA [4]. The consequences of CD30 interaction with its ligand, CD30L, are poorly understood; CD30 activation may well depend upon cell and tissue type, with effects ranging from cell proliferation and activation to apoptosis and control of Treg function; reverse signalling, i.e. signal transduction to
