G Model
ARTICLE IN PRESS
BONSOI-4008; No. of Pages 3
Joint Bone Spine xxx (2014) xxx–xxx
Available online at www.sciencedirect.com
Case report
Repair of radiographic hip joint in juvenile rheumatoid arthritis patients treated with etanercept plus methotrexate Anouck Remy ∗ , Bernard Combe Department of Rheumatology, Lapeyronie Hospital, Montpellier I University, Montpellier, France
a r t i c l e
i n f o
Article history: Accepted 14 March 2014 Available online xxx Keywords: Rheumatoid arthritis Repair Joint space narrowing Hip TNF inhibitors
a b s t r a c t For patients suffering from rheumatoid arthritis (RA), structural damage, i.e. bone erosion and joint space narrowing, is a major factor leading to functional disability. Negative radiographic progression has been shown in joints, especially in RA patients treated with tumor necrosis factor alpha (TNF␣) inhibitors in combination with methotrexate. Bone erosion repair in small joints have been observed but only one study selected large weight-bearing joints. We reported 2 cases of patients with severe seropositive juvenile RA who shown improvement of joint space narrowing and subchondral erosion in hip joint when treated with etanercept in combination with methotrexate for at least 1 year. Two Japanese cases were also published but with different TNF inhibitors. The mechanisms of bone erosion or joint space narrowing repair are unclear. One study investigated whether bone erosions in rheumatoid arthritis patients show evidence of repair in metacarpophalangeal joints when treated with TNF inhibitors and MTX. These results suggested that repair in RA emerged from the bone marrow and the endosteal lining rather than the periosteal compartment. No study investigated joint space narrowing repair in hip joint in rheumatoid arthritis patients. Larger studies needed to confirm joint space narrowing improvement in hip joint in patients treated with TNF inhibitors and to explain the mechanisms of repair. © 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
For patients suffering from rheumatoid arthritis (RA), structural damage, i.e. bone erosion and joint space narrowing (JSN), is a major factor leading to functional disability. Tumor necrosis factor alpha (TNF␣) inhibitors remarkably reduce RA disease activity and inhibit radiographic progression. Several trials have shown negative radiographic progression scores, which suggest the concept of “joint repair” [1–3]. These negative scores in the modified Sharp score were in agreement with what experts judged as less damage [4]. Furthermore, it was shown that negative scores occur almost exclusively either in joints without inflammation or in joints with improved inflammation, and also preferentially when patients were treated with the combination of methotrexate (MTX) and a TNF-blocker arm [5]. All these data suggest that negative scores are an indication of repair of the erosive process. The same analyses have been performed with JSN as the outcome measure and exactly similar results were obtained [6]. We report two patients with severe juvenile RA who were treated with etanercept (ETN) plus MTX, in which there was
∗ Corresponding author. Département de rhumatologie, CHU Lapeyronie, 191, avenue du Doyen Gaston-Giraud, 34295 Montpellier cedex 5, France. Tel.: +33 4 67 33 87 10. E-mail address: [email protected] (A. Remy).
radiological evidence of reparative changes of a previously damaged hip joint. 1. Case 1 A 18-year-old-women, diagnosis with RA at 15 years of age, was treated with synthetic disease modifying antirheumatic drugs (DMARDs) included methotrexate (MTX) since 2001. Rheumatoid factor and anti-citrullinated peptide antibody (ACPA) were positive. Her bone mass index in september 2001 was 19.8 kg/m2 and remained stable. In March 2002, she had pain in the left hip joint with no joint limitation. ETN was started in combination with MTX and corticosteroids (10 mg/day) in December 2002, because of high disease activity and important biological inflammation (erythrocyte sedimentation rate [ESR] 90 mm and C-reactive protein [CRP] 5.4 mg/L). Due to pain and disability, a hip arthroplasty was discussed. On X-ray, a joint space narrowing of the left hip was shown in 2002 and 2003 (Fig. 1a), with subchondral cysts of the femoral head and subchondral bone sclerosis. With ETN and MTX, RA remission based on Disease Activity Score in 28 joints was achieved and hip pain disappeared progressively during the first year of therapy. Corticosteroids were stopped in December 2003. Biological inflammation was also reduced and CRP became negative since
doi:10.1016/j.jbspin.2014.03.006 1297-319X/© 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Remy A, Combe B. Repair of radiographic hip joint in juvenile rheumatoid arthritis patients treated with etanercept plus methotrexate. Joint Bone Spine (2014), doi:10.1016/j.jbspin.2014.03.006
G Model BONSOI-4008; No. of Pages 3
ARTICLE IN PRESS A. Remy, B. Combe / Joint Bone Spine xxx (2014) xxx–xxx
2
Fig. 1. Radiographic images of the left hip joint in 2003 (a), in 2005 (b) and in 2009 (c) from rheumatoid arthritis patient treated by etanercept. a: joint space narrowing and subchondral cysts of femoral head and subchondral bone sclerosis; b: improvement of joint space and cysts disappeared, osteophytosis; c: widening of joint space and osteophytosis.
2004. Radiographic images of the left hip joint on 2005 (Fig. 1b) and 2009 (Fig. 1c) showed widening joint space and removal cysts of the femoral head but osteophyte appeared. In 2012, she is still treated with ETN and MTX but do not have any more clinical or radiographic symptoms of hip arthritis. 2. Case 2 A 20-year-old-women was treated with MTX for juvenile RA, diagnosed at 13 years of age. She was positive for rheumatoid factor and ACPA. She began ETN in combination with MTX in April 2005. At this date, ESR was 43 mm and CRP 0.7 mg/L. Radiographic images on the right hip joint in 2005 showed widening joint space but hip pain disappeared. Corticosteroids were only used 7 days in January 2007. In January 2008, inflammatory right hip pain reappeared and radiological examination showed already complete loss of the joint space, erosive changes in the femoral head and acetabulum and subchondral cysts and bone sclerosis (Fig. 2a and b). Based on Disease Activity Score in 28 joints and expert decision, RA remission was achieved but mechanical right hip pain still remained. Since January 2008, CRP became negative. In 2009 X-ray, space joint of the right hip improved with less subchondral cysts and bone sclerosis but with osteophyte formation (Fig. 2c and d). On 2010, her bone mass index was 20.2 kg/m2 . These 2 cases showed JSN repair of large weight-bearing joints in young patients with severe juvenile RA who achieved clinical remission during a combined treatment with ETN and MTX.
Fig. 2. Radiographic images of hip joint (face and profile) in 2008 (a, b) and in 2009 (c, d) from juvenile chronic arthritis patient treated by etanercept. a and b: complete loss of joint space and subchondral cysts of femoral head and subchondral bone sclerosis of right hip joint; c and d: improvement of joint space and cysts, osteophytosis appeared of right hip joint.
Some trials and case studies reported bone erosion repair in small joints (hand, feet, sometimes wrist), mainly during adalimumab (ADA) [7–9] or etanercept [4,5] therapies. By contrast, only one study evaluated large weight-bearing joints (69 hip joints, 63 knee joints, and 81 ankle joints excluding joints with preceding surgery) of 42 consecutive RA patients [10]. Structural damage to the weight-bearing joints was assessed using the Larsen scoring method at baseline and at 1 year of TNF-blocking therapies. At 1 year, 94% of the joints and 81% of the patients showed no apparent radiographic progression. However, analysis of individual joints indicated that hip and knee joints with moderate to advanced pre-existing damage resulted in radiographic progression even after TNF-blocking therapies [10]. Furthermore, two Japanese publications reported reparative radiographic hip joint in RA with TNF-blocking therapies. Nagare et al. reported a case of radiological improvement of hip joint in a 22-year-old-women with juvenile RA treated by infliximab (IFX) then ETN because of loss of efficacy of IFX [11]. Momohara et al. also observed widening space joint of the right hip in a 46-year-old-man, diagnosed with RA at 29 years of age, treated by ADA whereas space joint narrowing remained through when previously treated with non-biological DMARDs [12]. Repair of radiographic hip joint was shown in juvenile RA in three case reports (our two cases and one Japanese). It is commonly believed that juvenile RA has less destructive potential that adult RA with the possibility of improvement in radiographic joint damage. But one recent study showed that structural peripheral damage is as common and as severe in young adults with juvenile RA as in adults with RA. Moreover, hip radiographic damage was more frequently detected in juvenile RA patients with a higher risk of bilateral hip damage. Hip replacement was needed in 36% of juvenile RA patients [13]. Thereby repair of radiographic hip joint could be explained by anti-TNF treatment in our cases reports. Nevertheless the mechanisms of bone erosion or JSN repair are unclear. Finzel et al. investigated whether bone erosions in RA patients show evidence of repair [14]. An in-depth analysis of the change in the dimension of each single erosion in metacarpophalangeal joints 2–4 of the right hands was performed in a group of 30 RA patients treated with TNF inhibitors and MTX after 1 year of treatment using high-resolution CT scanning. They also sequentially assessed sclerosis of each individual lesion as well as their exact width and depth during TNF inhibitors therapy and compared these results with 21 RA patients treated with MTX monotherapy. In this study, repair was based on a decrease in the depth of the lesions and were exclusively found in erosions, which showed evidence of bone apposition (sclerosis) at baseline or at follow-up. Importantly, evidence of repair was most pronounced in deeper lesions and virtually absent in more shallow bone erosions. This observation suggested that repair in RA emerged from the bone marrow and the endosteal lining rather than the periosteal compartment [14]. These results highlighted the skeletal effects of TNF and its pharmacological inhibition. TNF was considered as a potent downregulator of osteoblast differentiation and an inducer of bone resorption thus, creating a local imbalance between bone formation and resorption. This negative influence of TNF on bone was of key relevance for synovial tissue to elicit bone resorption. TNF blockade may restore bone balance in addition to blocking synovitis and may thus facilitate repair. No clinical trial investigated mechanisms of JSN improvement, especially in large weight-baring joints, such as hip joint. However, experimental study showed healing of joint damage in arthritic transgenic mice. Anti-TNF treatment for 6 weeks significantly reduced cartilage degradation and improved proteoglycan content of cartilage in transgenic mice. Cartilage degradation was maintained in young mice, which developed signs of arthritis at 7 or 8 weeks of age in comparison with baseline and aged mice. These mice were disease-free with 10 mg/kg weekly of monoclonal
Please cite this article in press as: Remy A, Combe B. Repair of radiographic hip joint in juvenile rheumatoid arthritis patients treated with etanercept plus methotrexate. Joint Bone Spine (2014), doi:10.1016/j.jbspin.2014.03.006
G Model BONSOI-4008; No. of Pages 3
ARTICLE IN PRESS A. Remy, B. Combe / Joint Bone Spine xxx (2014) xxx–xxx
anti-TNF antibody starting at 4 weeks of age and stopped at 24 weeks. Repair of cartilage was age dependent: reversal of cartilage degradation after anti-TNF treatment was observed in young mice but not in aged mice [15]. These experimental results could support the repair of hip cartilage that was observed in our cases reports of patients with juvenile RA. Furthermore, a case report investigated whether reparative radiological changes in hip joint indicate a true healing of joint. Sakuma et al. observed a case of radiological improvement of hip joint in a 51-year-old-women with juvenile RA diagnosed at 7 years of age. The treatment was not reported but disease activity indicated clinical remission. Because the patient had still pain and disability due to hip involvement and was satisfied by prior joint replacements, a total hip joint replacement was decided. During the surgical procedure, most of the femoral head surface was noted to be eburnated with only partial covering by fibrous tissue. This tissue was identified microscopically as fibrous cartilage. This finding suggests that radiologic healing could correlate with the presence of partially fibrous cartilage at the repaired joint [16]. Additional studies are needed to confirm that JSN repair may occur in large joints in patients with juvenile RA treated with TNF inhibitors to explain the mechanisms of this JSN improvement and to determine the true nature of the anatomic and microscopic changes that correlate with the observed radiological changes in RA. Disclosure of interest AR has no conflict of interest. BC has received honorarium from Abbvie, Merck, Pfizer, UCB. References [1] Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586–93.
3
[2] Klareskog L, van der Heijde D, de Jager JP, et al. TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double blind randomised controlled trial. Lancet 2004;363:675–81. [3] Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. N Engl J Med 2000;343:1594–602. [4] van der Heijde D, Landewé R, Boonen A, et al. Expert agreement confirms that negative changes in hand and foot radiographs are a surrogate for repair in patients with rheumatoid arthritis. Arthritis Res Ther 2007;9:R62. [5] Lukas C, van der Heijde D, Fatenejad S, et al. Repair of erosions occurs almost exclusively in damaged joints without swelling. Ann Rheum Dis 2010;69:851–5. [6] van der Heijde D. Erosions versus joint space narrowing in rheumatoid arthritis: what do we know? Ann Rheum Dis 2011;70:i116–8. [7] Ahn IE, Ju JH, Park SH, et al. Radiologic observation: repair of focal bone erosions after humanized anti-tumor necrosis factor antibody adalimumab therapy in a patient with rheumatoid arthritis. Clin Rheumatol 2010;29:211–3. [8] Ros-Expósito S, Ruiz-Martín JM, Sanz-Frutos P, et al. Bone erosion repair with adalimumab in rheumatoid arthritis. Clin Rheumatol 2010;29:1339–40. [9] Møller Døhn U, Boonen A, Hetland ML, et al. Erosive progression is minimal, but erosion healing rare, in patients with rheumatoid arthritis treated with adalimumab. A 1-year investigator-initiated follow-up study using high-resolution computed tomography as the primary outcome measure. Ann Rheum Dis 2009;68:1585–90. [10] Seki E, Matsushita I, Sugiyama E, et al. Radiographic progression in weightbearing joints of patients with rheumatoid arthritis after TNF-blocking therapies. Clin Rheumatol 2009;28:453–60. [11] Nagare Y, Kinoshita K, Nishisaka F, et al. Remarkable improvement of the hip joint lesion in a patient with rheumatoid arthritis by the treatment with antiTNF-␣ agents. Japn J Clin Immunol 2010;33:272–6. [12] Momohara S, Tanaka E, Iwamoto T, et al. Reparative radiological changes of a large joint after adalimumab for rheumatoid arthritis. Clin Rheumatol 2011;30:591–2. [13] Elhai M, Bazeli R, Freire V, et al. Radiological peripheral involvement in a cohort of patients with polyarticular juvenile idiopathic arthritis at adulthood. J Rheumatol 2013;40:520–7. [14] Finzel S, Rech J, Schmidt S, et al. Repair of bone erosions in rheumatoid arthritis treated with tumour necrosis factor inhibitors is based on bone apposition at the base of the erosion. Ann Rheum Dis 2011;70:1587–93. [15] Shealy DJ, Wooley PH, Emmell E, et al. Anti-TNF-␣ antibody allows healing of joint damage in polyarthritic transgenic mice. Arthritis Res 2002;4:R7. [16] Sakuma Y, Ikari K, Iwamoto T, et al. Reparative radiological changes of the hip joint in rheumatoid arthritis: do these findings indicate the true repair of the joint? Joint Bone Spine 2010;77:278–9.
Please cite this article in press as: Remy A, Combe B. Repair of radiographic hip joint in juvenile rheumatoid arthritis patients treated with etanercept plus methotrexate. Joint Bone Spine (2014), doi:10.1016/j.jbspin.2014.03.006
ARTICLE IN PRESS
BONSOI-4008; No. of Pages 3
Joint Bone Spine xxx (2014) xxx–xxx
Available online at www.sciencedirect.com
Case report
Repair of radiographic hip joint in juvenile rheumatoid arthritis patients treated with etanercept plus methotrexate Anouck Remy ∗ , Bernard Combe Department of Rheumatology, Lapeyronie Hospital, Montpellier I University, Montpellier, France
a r t i c l e
i n f o
Article history: Accepted 14 March 2014 Available online xxx Keywords: Rheumatoid arthritis Repair Joint space narrowing Hip TNF inhibitors
a b s t r a c t For patients suffering from rheumatoid arthritis (RA), structural damage, i.e. bone erosion and joint space narrowing, is a major factor leading to functional disability. Negative radiographic progression has been shown in joints, especially in RA patients treated with tumor necrosis factor alpha (TNF␣) inhibitors in combination with methotrexate. Bone erosion repair in small joints have been observed but only one study selected large weight-bearing joints. We reported 2 cases of patients with severe seropositive juvenile RA who shown improvement of joint space narrowing and subchondral erosion in hip joint when treated with etanercept in combination with methotrexate for at least 1 year. Two Japanese cases were also published but with different TNF inhibitors. The mechanisms of bone erosion or joint space narrowing repair are unclear. One study investigated whether bone erosions in rheumatoid arthritis patients show evidence of repair in metacarpophalangeal joints when treated with TNF inhibitors and MTX. These results suggested that repair in RA emerged from the bone marrow and the endosteal lining rather than the periosteal compartment. No study investigated joint space narrowing repair in hip joint in rheumatoid arthritis patients. Larger studies needed to confirm joint space narrowing improvement in hip joint in patients treated with TNF inhibitors and to explain the mechanisms of repair. © 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
For patients suffering from rheumatoid arthritis (RA), structural damage, i.e. bone erosion and joint space narrowing (JSN), is a major factor leading to functional disability. Tumor necrosis factor alpha (TNF␣) inhibitors remarkably reduce RA disease activity and inhibit radiographic progression. Several trials have shown negative radiographic progression scores, which suggest the concept of “joint repair” [1–3]. These negative scores in the modified Sharp score were in agreement with what experts judged as less damage [4]. Furthermore, it was shown that negative scores occur almost exclusively either in joints without inflammation or in joints with improved inflammation, and also preferentially when patients were treated with the combination of methotrexate (MTX) and a TNF-blocker arm [5]. All these data suggest that negative scores are an indication of repair of the erosive process. The same analyses have been performed with JSN as the outcome measure and exactly similar results were obtained [6]. We report two patients with severe juvenile RA who were treated with etanercept (ETN) plus MTX, in which there was
∗ Corresponding author. Département de rhumatologie, CHU Lapeyronie, 191, avenue du Doyen Gaston-Giraud, 34295 Montpellier cedex 5, France. Tel.: +33 4 67 33 87 10. E-mail address: [email protected] (A. Remy).
radiological evidence of reparative changes of a previously damaged hip joint. 1. Case 1 A 18-year-old-women, diagnosis with RA at 15 years of age, was treated with synthetic disease modifying antirheumatic drugs (DMARDs) included methotrexate (MTX) since 2001. Rheumatoid factor and anti-citrullinated peptide antibody (ACPA) were positive. Her bone mass index in september 2001 was 19.8 kg/m2 and remained stable. In March 2002, she had pain in the left hip joint with no joint limitation. ETN was started in combination with MTX and corticosteroids (10 mg/day) in December 2002, because of high disease activity and important biological inflammation (erythrocyte sedimentation rate [ESR] 90 mm and C-reactive protein [CRP] 5.4 mg/L). Due to pain and disability, a hip arthroplasty was discussed. On X-ray, a joint space narrowing of the left hip was shown in 2002 and 2003 (Fig. 1a), with subchondral cysts of the femoral head and subchondral bone sclerosis. With ETN and MTX, RA remission based on Disease Activity Score in 28 joints was achieved and hip pain disappeared progressively during the first year of therapy. Corticosteroids were stopped in December 2003. Biological inflammation was also reduced and CRP became negative since
doi:10.1016/j.jbspin.2014.03.006 1297-319X/© 2014 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Remy A, Combe B. Repair of radiographic hip joint in juvenile rheumatoid arthritis patients treated with etanercept plus methotrexate. Joint Bone Spine (2014), doi:10.1016/j.jbspin.2014.03.006
G Model BONSOI-4008; No. of Pages 3
ARTICLE IN PRESS A. Remy, B. Combe / Joint Bone Spine xxx (2014) xxx–xxx
2
Fig. 1. Radiographic images of the left hip joint in 2003 (a), in 2005 (b) and in 2009 (c) from rheumatoid arthritis patient treated by etanercept. a: joint space narrowing and subchondral cysts of femoral head and subchondral bone sclerosis; b: improvement of joint space and cysts disappeared, osteophytosis; c: widening of joint space and osteophytosis.
2004. Radiographic images of the left hip joint on 2005 (Fig. 1b) and 2009 (Fig. 1c) showed widening joint space and removal cysts of the femoral head but osteophyte appeared. In 2012, she is still treated with ETN and MTX but do not have any more clinical or radiographic symptoms of hip arthritis. 2. Case 2 A 20-year-old-women was treated with MTX for juvenile RA, diagnosed at 13 years of age. She was positive for rheumatoid factor and ACPA. She began ETN in combination with MTX in April 2005. At this date, ESR was 43 mm and CRP 0.7 mg/L. Radiographic images on the right hip joint in 2005 showed widening joint space but hip pain disappeared. Corticosteroids were only used 7 days in January 2007. In January 2008, inflammatory right hip pain reappeared and radiological examination showed already complete loss of the joint space, erosive changes in the femoral head and acetabulum and subchondral cysts and bone sclerosis (Fig. 2a and b). Based on Disease Activity Score in 28 joints and expert decision, RA remission was achieved but mechanical right hip pain still remained. Since January 2008, CRP became negative. In 2009 X-ray, space joint of the right hip improved with less subchondral cysts and bone sclerosis but with osteophyte formation (Fig. 2c and d). On 2010, her bone mass index was 20.2 kg/m2 . These 2 cases showed JSN repair of large weight-bearing joints in young patients with severe juvenile RA who achieved clinical remission during a combined treatment with ETN and MTX.
Fig. 2. Radiographic images of hip joint (face and profile) in 2008 (a, b) and in 2009 (c, d) from juvenile chronic arthritis patient treated by etanercept. a and b: complete loss of joint space and subchondral cysts of femoral head and subchondral bone sclerosis of right hip joint; c and d: improvement of joint space and cysts, osteophytosis appeared of right hip joint.
Some trials and case studies reported bone erosion repair in small joints (hand, feet, sometimes wrist), mainly during adalimumab (ADA) [7–9] or etanercept [4,5] therapies. By contrast, only one study evaluated large weight-bearing joints (69 hip joints, 63 knee joints, and 81 ankle joints excluding joints with preceding surgery) of 42 consecutive RA patients [10]. Structural damage to the weight-bearing joints was assessed using the Larsen scoring method at baseline and at 1 year of TNF-blocking therapies. At 1 year, 94% of the joints and 81% of the patients showed no apparent radiographic progression. However, analysis of individual joints indicated that hip and knee joints with moderate to advanced pre-existing damage resulted in radiographic progression even after TNF-blocking therapies [10]. Furthermore, two Japanese publications reported reparative radiographic hip joint in RA with TNF-blocking therapies. Nagare et al. reported a case of radiological improvement of hip joint in a 22-year-old-women with juvenile RA treated by infliximab (IFX) then ETN because of loss of efficacy of IFX [11]. Momohara et al. also observed widening space joint of the right hip in a 46-year-old-man, diagnosed with RA at 29 years of age, treated by ADA whereas space joint narrowing remained through when previously treated with non-biological DMARDs [12]. Repair of radiographic hip joint was shown in juvenile RA in three case reports (our two cases and one Japanese). It is commonly believed that juvenile RA has less destructive potential that adult RA with the possibility of improvement in radiographic joint damage. But one recent study showed that structural peripheral damage is as common and as severe in young adults with juvenile RA as in adults with RA. Moreover, hip radiographic damage was more frequently detected in juvenile RA patients with a higher risk of bilateral hip damage. Hip replacement was needed in 36% of juvenile RA patients [13]. Thereby repair of radiographic hip joint could be explained by anti-TNF treatment in our cases reports. Nevertheless the mechanisms of bone erosion or JSN repair are unclear. Finzel et al. investigated whether bone erosions in RA patients show evidence of repair [14]. An in-depth analysis of the change in the dimension of each single erosion in metacarpophalangeal joints 2–4 of the right hands was performed in a group of 30 RA patients treated with TNF inhibitors and MTX after 1 year of treatment using high-resolution CT scanning. They also sequentially assessed sclerosis of each individual lesion as well as their exact width and depth during TNF inhibitors therapy and compared these results with 21 RA patients treated with MTX monotherapy. In this study, repair was based on a decrease in the depth of the lesions and were exclusively found in erosions, which showed evidence of bone apposition (sclerosis) at baseline or at follow-up. Importantly, evidence of repair was most pronounced in deeper lesions and virtually absent in more shallow bone erosions. This observation suggested that repair in RA emerged from the bone marrow and the endosteal lining rather than the periosteal compartment [14]. These results highlighted the skeletal effects of TNF and its pharmacological inhibition. TNF was considered as a potent downregulator of osteoblast differentiation and an inducer of bone resorption thus, creating a local imbalance between bone formation and resorption. This negative influence of TNF on bone was of key relevance for synovial tissue to elicit bone resorption. TNF blockade may restore bone balance in addition to blocking synovitis and may thus facilitate repair. No clinical trial investigated mechanisms of JSN improvement, especially in large weight-baring joints, such as hip joint. However, experimental study showed healing of joint damage in arthritic transgenic mice. Anti-TNF treatment for 6 weeks significantly reduced cartilage degradation and improved proteoglycan content of cartilage in transgenic mice. Cartilage degradation was maintained in young mice, which developed signs of arthritis at 7 or 8 weeks of age in comparison with baseline and aged mice. These mice were disease-free with 10 mg/kg weekly of monoclonal
Please cite this article in press as: Remy A, Combe B. Repair of radiographic hip joint in juvenile rheumatoid arthritis patients treated with etanercept plus methotrexate. Joint Bone Spine (2014), doi:10.1016/j.jbspin.2014.03.006
G Model BONSOI-4008; No. of Pages 3
ARTICLE IN PRESS A. Remy, B. Combe / Joint Bone Spine xxx (2014) xxx–xxx
anti-TNF antibody starting at 4 weeks of age and stopped at 24 weeks. Repair of cartilage was age dependent: reversal of cartilage degradation after anti-TNF treatment was observed in young mice but not in aged mice [15]. These experimental results could support the repair of hip cartilage that was observed in our cases reports of patients with juvenile RA. Furthermore, a case report investigated whether reparative radiological changes in hip joint indicate a true healing of joint. Sakuma et al. observed a case of radiological improvement of hip joint in a 51-year-old-women with juvenile RA diagnosed at 7 years of age. The treatment was not reported but disease activity indicated clinical remission. Because the patient had still pain and disability due to hip involvement and was satisfied by prior joint replacements, a total hip joint replacement was decided. During the surgical procedure, most of the femoral head surface was noted to be eburnated with only partial covering by fibrous tissue. This tissue was identified microscopically as fibrous cartilage. This finding suggests that radiologic healing could correlate with the presence of partially fibrous cartilage at the repaired joint [16]. Additional studies are needed to confirm that JSN repair may occur in large joints in patients with juvenile RA treated with TNF inhibitors to explain the mechanisms of this JSN improvement and to determine the true nature of the anatomic and microscopic changes that correlate with the observed radiological changes in RA. Disclosure of interest AR has no conflict of interest. BC has received honorarium from Abbvie, Merck, Pfizer, UCB. References [1] Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586–93.
3
[2] Klareskog L, van der Heijde D, de Jager JP, et al. TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double blind randomised controlled trial. Lancet 2004;363:675–81. [3] Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. N Engl J Med 2000;343:1594–602. [4] van der Heijde D, Landewé R, Boonen A, et al. Expert agreement confirms that negative changes in hand and foot radiographs are a surrogate for repair in patients with rheumatoid arthritis. Arthritis Res Ther 2007;9:R62. [5] Lukas C, van der Heijde D, Fatenejad S, et al. Repair of erosions occurs almost exclusively in damaged joints without swelling. Ann Rheum Dis 2010;69:851–5. [6] van der Heijde D. Erosions versus joint space narrowing in rheumatoid arthritis: what do we know? Ann Rheum Dis 2011;70:i116–8. [7] Ahn IE, Ju JH, Park SH, et al. Radiologic observation: repair of focal bone erosions after humanized anti-tumor necrosis factor antibody adalimumab therapy in a patient with rheumatoid arthritis. Clin Rheumatol 2010;29:211–3. [8] Ros-Expósito S, Ruiz-Martín JM, Sanz-Frutos P, et al. Bone erosion repair with adalimumab in rheumatoid arthritis. Clin Rheumatol 2010;29:1339–40. [9] Møller Døhn U, Boonen A, Hetland ML, et al. Erosive progression is minimal, but erosion healing rare, in patients with rheumatoid arthritis treated with adalimumab. A 1-year investigator-initiated follow-up study using high-resolution computed tomography as the primary outcome measure. Ann Rheum Dis 2009;68:1585–90. [10] Seki E, Matsushita I, Sugiyama E, et al. Radiographic progression in weightbearing joints of patients with rheumatoid arthritis after TNF-blocking therapies. Clin Rheumatol 2009;28:453–60. [11] Nagare Y, Kinoshita K, Nishisaka F, et al. Remarkable improvement of the hip joint lesion in a patient with rheumatoid arthritis by the treatment with antiTNF-␣ agents. Japn J Clin Immunol 2010;33:272–6. [12] Momohara S, Tanaka E, Iwamoto T, et al. Reparative radiological changes of a large joint after adalimumab for rheumatoid arthritis. Clin Rheumatol 2011;30:591–2. [13] Elhai M, Bazeli R, Freire V, et al. Radiological peripheral involvement in a cohort of patients with polyarticular juvenile idiopathic arthritis at adulthood. J Rheumatol 2013;40:520–7. [14] Finzel S, Rech J, Schmidt S, et al. Repair of bone erosions in rheumatoid arthritis treated with tumour necrosis factor inhibitors is based on bone apposition at the base of the erosion. Ann Rheum Dis 2011;70:1587–93. [15] Shealy DJ, Wooley PH, Emmell E, et al. Anti-TNF-␣ antibody allows healing of joint damage in polyarthritic transgenic mice. Arthritis Res 2002;4:R7. [16] Sakuma Y, Ikari K, Iwamoto T, et al. Reparative radiological changes of the hip joint in rheumatoid arthritis: do these findings indicate the true repair of the joint? Joint Bone Spine 2010;77:278–9.
Please cite this article in press as: Remy A, Combe B. Repair of radiographic hip joint in juvenile rheumatoid arthritis patients treated with etanercept plus methotrexate. Joint Bone Spine (2014), doi:10.1016/j.jbspin.2014.03.006
