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Extended report
Long-term effects of infliximab on bone and cartilage turnover markers in patients with rheumatoid arthritis
  1. F Chopin1,
  2. P Garnero2,
  3. A le Henanff3,
  4. F Debiais4,
  5. A Daragon5,
  6. C Roux6,
  7. J Sany7,
  8. D Wendling8,
  9. C Zarnitsky9,
  10. P Ravaud3,
  11. T Thomas1
  1. 1
    Inserm Unit 890, University Hospital of St-Etienne, France
  2. 2
    Inserm Unit 664 and Molecular Markers, Synarc, Lyon, France
  3. 3
    Hôpital Bichat, Paris, France
  4. 4
    University Hospital of Poitiers, France
  5. 5
    University Hospital of Rouen, France
  6. 6
    Hôpital Cochin, Paris, France
  7. 7
    Hôpital Lapeyronie, Montpellier, France
  8. 8
    University Hospital of Besançon, France
  9. 9
    Groupe Hospitalier du Havre, France
  1. Professor T Thomas, INSERM U890, Rheumatology Department, University Hospital, Boulevard Pasteur, 42055 SAINT-ETIENNE Cedex2, France; thierry.thomas{at}univ-st-etienne.fr

Abstract

Background: Rheumatoid arthritis (RA) is associated with systemic bone loss, subchondral bone erosion and cartilage degradation under the control of pro-inflammatory cytokines, including tumour necrosis factor α (TNFα). Therefore, we tested the hypothesis that administration of infliximab, an anti-TNFα drug in the treatment of RA, would modulate systemic and local bone resorption and reduce cartilage degradation.

Methods: We performed a prospective study of a multicentric cohort of 48 women, mean (SD) age 54.2 (12.1) years old, with severe RA for 11.4 (7.8) years, who started infliximab after failure of other disease-modifying antirheumatic drugs. At baseline and 6, 22 and 54 weeks after initiating Infliximab therapy we measured the following biochemical markers: pro-collagen serum type I N-terminal propeptide (PINP), a marker of bone formation; serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), a marker of cathepsin K-mediated bone collagen degradation believed to reflect systemic bone resorption; serum C-terminal cross-linked telopeptide of type I collagen (ICTP), an index of matrix metalloprotease (MMP) mediated type I collagen degradation reflecting preferential joint metabolism; and urinary CTX-II a biochemical markers of cartilage degradation. Total hip and lumbar spine bone mineral density (BMD) was assessed at baseline, and after 6 and 12 months by dual-energy x-ray absorptiometry (DXA). No patient received bisphosphonates while 77% were under oral glucocorticoids.

Results: BMD remained stable over 1 year. Serum CTX-I levels rapidly decreased by 19% and 28% at week 6 and week 22, respectively (analysis of variance (ANOVA) p = 0.032) values returning to pre-treatment level at week 54. By contrast, ICTP levels progressively declined with a maximal 25% decrease at week 54 (ANOVA p = 0.028). By contrast, PINP levels remained stable over time, which led to a 30 to 40% improvement in bone remodelling balance, as assessed by the ratios PINP/CTX and PINP/ICTP (p<0.05). There was no significant change of urinary CTX-II in the whole population, but a slight decrease (ANOVA p = 0.041) in those with pre-treatment levels above the upper limit of normal range.

Conclusions: In summary, the improvement in the formation/resorption marker ratio suggests beneficial systemic and local bone effects of infliximab in patients with RA.

https://doi.org/10.1136/ard.2007.076604

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    Rheumatoid arthritis (RA) is an autoimmune disease characterised by a progressive destruction of periarticular and joint structures, including subchondral bone loss, associated with a more generalised osteoporosis. There is growing evidence that subchondral bone erosions play a critical role in joint destruction, as blockade of the RANK-ligand pathway in animal arthritis models was able to prevent bony erosions and articular damage without any changes in inflammatory activity of the disease.1–3

    It is also clearly established that RA is associated with a generalised osteoporosis, which goes beyond just epiphyseal bone loss secondary to joint inflammation. The causes of this osteoporosis are multifactorial, including corticosteroids side effects as well as reduced physical activity and disease process itself.4–7 The cellular mechanisms leading to this bone loss are under the control of pro-inflammatory cytokines such as tumour necrosis factor α (TNFα), and interleukin (IL)-1 and IL-6, which are abundantly produced in the inflammatory synovium and its vicinity.8 Therefore, we proposed the working hypothesis that infliximab therapy in severe RA may improve RA-related bone alterations with a better bone balance between resorption and formation. These results may derive from different effects including direct control of inflammatory mechanisms, reduction of corticosteroid use and increase level activity secondary to improved health status.

    Bone matrix is mainly composed of type I collagen, and the type I collagen telopeptide fragments CTX-I and ICTP that are present in the serum are currently considered as the most sensitive markers of bone resorption.9 These two telopeptide fragments are released from bone type I collagen by different enzymatic pathways.10 11 ICTP is generated by matrix metalloproteases (MMPs), whose activity plays an important role in collagen degradation associated with RA.12 By contrast, CTX-I is efficiently generated by cathepsin K, which is the key osteoclastic enzyme for systemic bone resorption,13 but not by MMPs. The use of these two biological markers may help to better decipher the mechanisms of bone erosion and the clinical management of patients with RA.

    Among the various biochemical markers of cartilage breakdown, measurement of type II collagen C-terminal cross-linked telopeptides (CTX-II) appears as the most sensitive to detect these cartilage damages in RA.14 Indeed, studies have shown in patients with RA that increased levels of urinary CTX-II were highly predictive of a rapid joint degradation assessed by x ray follow-up within a period of 1–5 years, independently from other bio-clinical indexes.15–17 We sought to determine their pattern of response under infliximab therapy in correlation to bone turnover markers (BTM). In fact, there is no published data so far on the effects of anti-TNF treatment on biochemical markers of type II collagen degradation in patients with RA and their relationships with the changes in bone turnover. The aims of our study were therefore to analyse the effects of infliximab on markers of bone and cartilage metabolism in patients with RA under treatment and followed prospectively for 1 year.

    PATIENTS AND METHODS

    Patients

    We conducted a prospective, multi-centric open study in a population of women <80 years old, having a severe RA non-responding to first-level disease-modifying antirheumatic drug (DMARD) class (hydroxychloroquine, leflunomide, methotrexate or salazopyrine) who started infliximab therapy. We did not include women with confounding factors such as concomitant bone diseases (including Paget, osteomalacia, hyperparathyroidism and other endocrinopathies with bone alterations), chronic alcoholism and treatments with bone effects such as bisphosphonates, hormonal replacement therapy, anabolic steroids or calcitonin but corticosteroids. The protocol was approved by the Ethical Committee of the Loire area.

    A total of 48 women (mean (SD) age 54.2 (12.1)), having severe RA, resistant to DMARDs (methotrexate in half of cases) for 11.4 (7.8) years, were included in the study prior receiving the first injection of infliximab; 62.5% of them were postmenopausal women (n = 30) while only 12.5% were current smokers (n = 6). In accordance with selection criteria, no patient had received bisphosphonates even though two patients had a prevalent clinical vertebral fracture, and 77% of them had corticosteroid therapy at baseline with a mean daily dose of 10 mg/day.

    At baseline, mean (SD) RA clinical activity was characterised by 100.7 (73.6) min of morning stiffness, 9.6 (7.4) painful joints and 7.2 (5.4) swollen joints. Mean (SD) erythrocyte sedimentation rate (ESR) was 36.8 (26.3) mm.

    Infliximab was administered following recommended protocol with intravenous (IV) infusion over 2 h at 3 mg/kg dose, at weeks 0, 2, and 6, and then every 8 weeks. Whenever permitted by tolerance at baseline, infliximab was combined with the previously prescribed DMARDs. No change in DMARD treatment occurred over the duration of the study.

    Biologic parameters measurements

    We measured serum levels of pro-collagen type I N-terminal propeptide (PINP), a marker of bone formation by an automated assay (PINP, ELeccys, Roche Diagnostics, Meylan, France). For bone resorption, degradation products of the C-terminal telopeptide of collagen type I released by cathepsin K (CTX-I, Serum Crosslaps, Roche Diagnostics) or MMPs (ICTP, ICTP RIA, Orion Diagnostica, Espoo, Finland) were analysed. Blood draws were performed before 9:00 AM in fasting patients at baseline and then at weeks 0, 6, 22 and 54.

    We also measured urinary CTX-II (Cartilaps, Nordic Biosciences, Herlev, Denmark) in second morning void urines of fasting patients, at baseline and then at week 6 and week 22.

    All assays have intra and inter assay coefficient of variation below 10%. All measurements were performed in a centralised laboratory (Synarc, Lyon France) in a single batch to reduce analytical variation.

    Bone mineral density measurement

    Bone mineral density (BMD) was measured at total hip and lumbar spine by dual-energy x-ray absorptiometry (DXA) at baseline and after 6 and 12 months of treatment. Reproducibility of BMD measurements at hip and spine were ∼1%.

    Evaluation of RA activity

    The activity of RA and response to infliximab therapy was evaluated by clinical parameters including morning stiffness duration, Ritchie index, count of painful and swollen joints, as well as biological parameters (ESR and C-reactive protein (CRP)). Quality of life and physical activity status were appreciated by Health Assessment Questionnaire (HAQ) and Huet-Léger questionnaire respectively.18 The Huet questionnaire is an easy, rapidly administered tool that is highly correlated with VO2max. All parameters were measured at baseline and then at weeks 6, 22 and 54.

    Satistical analysis

    Two models of analysis of variance with mixed effects for repeated data were constructed to study variations in biomarkers over the course of time. Analysis of variations over time was performed using analysis of variance (ANOVA) and post-hoc tests for comparison of individual timepoints compared to baseline.

    A subgroup analysis was also conducted based on threshold defined for two parameters: mean daily dose of corticosteroids (ie, ⩽ or >7.5 mg/day between week 0 and week 54) and absolute change in HAQ value (ie, ⩽ or >0.22 minimal change at the individual level (MCID) between week 54 and baseline).

    RESULTS

    Clinical evaluation

    As expected, clinical and biological response to infliximab was obtained as early as 6 weeks after treatment was introduced (data not shown). Patients received a cumulative infliximab dose of 1002 (265.5) mg over 1 year.

    After 1 year of treatment with infliximab, mean physical activity did not change while only 19% (n = 9) continued oral glucocorticoids (table 1).

    View this table:
    Table 1 Evolution over time of physical activity and corticosteroid mean daily dose under infliximab therapy

    Bone mineral density

    At baseline, BMD T-score values were–0.65 (1.53) and–0.66 (1.63) at lumbar spine and total hip respectively. Five patients (10.4%) had osteoporosis (T score ⩽–2.5 at either spine or hip) and 27% (n = 13) had osteopenia (<–2.5 T-score ⩽–1 at either spine or hip). BMD values remained stable after 6 and 12 months (table 2). No difference were observed when subgroups of patients based on daily dose of corticosteroids > or ⩽7.5 mg/day were analysed. Likewise, absolute change in HAQ value, either ⩽ or >0.22 between week 0 and week 54, did not influence BMD over time.

    View this table:
    Table 2 Lumbar spine and hip bome mineral density (BMD) under infliximab therapy

    Bone turnover markers

    Serum CTX-I levels rapidly decreased with treatment (ANOVA for repeated measures p = 0.0032) by a median of 19% (p = 0.014) and 28% (p = 0.0014) after 6 and 22 weeks, respectively, returning back to pre-treatment level after 1 year of treatment (table 3). These changes were similar whether patients had a daily dose of corticosteroids ⩽ or >7.5 mg/day or whether absolute change in HAQ was inferior or superior to MICD between baseline and week 54 evaluation.

    View this table:
    Table 3 Bone and cartilage turnover markers of patients with severe rheumatoid arthritis under infliximab therapy

    Serum ICTP also decreased with treatment with infliximab (ANOVA for repeated measures p = 0.0028) but with a different pattern than serum CTX-I. Indeed, ICTP levels progressively decreased only after 22 weeks (p = 0.0095) down to a maximum of–25% after 1 year of treatment, compared to initial values (p = 0.0093). This decrease was not dependent on daily corticosteroid dose at week 54 whereas a higher decrease was observed in the subgroup defined by HAQ improvement superior to MCID, compared to the subgroup of patients with no such improvement.

    By contrast, serum PINP levels remained stable over time (ANOVA for repeated measures p = 0.63) in the whole population as well as in subgroups. Therefore, the ratios PINP/CTX-I (ANOVA for repeated measures p = 0.018) and PINP/ICTP (ANOVA p = 0.025) increased during infliximab therapy, with peak median percentage changes from baseline of 30% (p<0.001) and 40% (p = 0.015), respectively at week 22 (fig 1).

    Figure 1
    Figure 1 Changes of biochemical markers of bone formation (pro-collagen type I N-terminal propeptide; PINP), markers of bone resorption (CTX-I and ICTP) and their ratio during in patients with severe rheumatoid arthritis under infliximab therapy.

    Cartilage breakdown markers

    Over the whole population, there was no significant change with time in urinary CTX-II (ANOVA repeated measures p = 0.45) (table 3). When analysis was restricted to the 17 patients with high baseline CTX-II levels (upper limit of healthy controls: 95% percentile  = 443 ng/mmol Cr), there was a significant decrease of urinary CTX-II with time (ANOVA p = 0.044). The median decrease was–15.7% (25/75 percentile:–38.4;–2.5%; p = 0.011) and–19.7% (25/75 percentile:–31; 6.2%, p = 0.08) at week 6 and week 22, respectively. Changes in urinary CTX-II at week 22 were significantly associated with changes in serum CTX-I (r = 0.46, p = 0.005) and ICTP (r = 0.46, p = 0.016).

    DISCUSSION

    Anti-TNF drugs provide a new standard in the treatment of RA with the objective of disease remission on clinical and radiological levels. Our study demonstrates in a group of patients—naïve for biotherapy and treated with infliximab after failure of conventional DMARDs—that these beneficial effects were associated with improvement of bone metabolism. Indeed, a decrease in bone resorption was observed under infliximab treatment, as documented by a decrease in serum CTX-I and ICTP levels, currently the most sensitive indices of bone degradation.19 20

    The rapid and significant decrease in CTX-I levels observed during the first 6 months of treatment was followed by a return to baseline levels at 1 year. A similar pattern of evolution was described for this biochemical marker in other studies conducted in patients treated for RA21–23 or spondylarthopathy.24 Interestingly, the profile of change of ICTP level was different over time with a delayed decrease, which was significant only after 22 weeks but was amplified with the duration of infliximab therapy. A similar decrease in ICTP levels were reported in a small study in patients with RA treated with infliximab over only 6 weeks.25 Our study is the first one demonstrating a difference in the pattern of changes of these two different type I collagen degradation markers evaluated concurrently in the same population over a long period of treatment. It provides further evidence that these markers actually reflect specific resorption processes. In fact, comparing synovial fluid and serum levels of CTX-I and ICTP in patients with RA, Sassi et al26 showed that synovial fluid/serum ratio was increased for ICTP, but not for CTX-I, indicating preferential local joint production of ICTP. Therefore, ICTP may be more sensitive to detect abnormalities of local joint tissue turnover, which is mediated in part by MMPs activities under the control of various cells including synoviocytes.3 Treatments that inhibit the production and the activity of MMP-1 should limit the formation of new joint erosions and prevent cartilage impairment,27 with important improvement in the long-term functional outcome of some patients with inflammatory arthritis.28 This is consistent with the correlation we observed between ICTP changes under treatment and clinical improvement measured by a significant individual changes in HAQ status (data not shown).

    By contrast, the cathepsin K derived peptide CTX-I may be of particular relevance to investigate systemic alterations of bone resorption, which have been shown to result from increased osteoclastic activity, but also local bone erosion. We suggest that early changes in bone remodelling under infliximab over the whole skeleton was characterised by an uncoupled response with TNFα inhibition inducing decrease in resorption. This was followed by a secondary steady state with higher resorption level to match bone formation. In fact, the latter evaluated by serum PINP levels remained in the normal range, even under treatment. This is somewhat different from a previous study showing an increase in bone formation.23 However, these authors used osteocalcin, a bone formation marker which is largely and directly influenced by corticosteroid therapy,29 in contrast to PINP, which is not.9 Although the reasons for this uncoupling effect remain unclear with for example, no significant change in activity level, 58% of patients under oral glucocorticoids at baseline had stopped this therapy after 54 weeks, a therapeutic change which could participate in sustained level of bone formation rate despite decreased bone resorption. In addition, PINP levels at baseline were in the normal range in our population despite RA-related factors of decreased bone formation. The latter could at least in part explain why BMD values were normal on average at baseline and therefore why no differences were observed in BMD values after 6 and 12 months, even when comparing subgroups of patients defined by daily dose of corticosteroids. Overall, difference in changes of biochemical markers of bone formation and resorption under treatment lead to an improved bone remodelling balance, as suggested by the significant increase in PINP/CTX or PINP/ICTP ratios.

    Over the whole population, infliximab therapy did not decrease urinary CTX-II, a specific biochemical marker of cartilage degradation. However, there was a significant decrease in patients presenting with high pre-treatment values which have been shown to be associated with more rapid progression of radiological damage in patients with RA.15 16 30 Whether the modest decrease of urinary CTX-II with infliximab in patients with high pre-treatment levels will be associated with reduced radiological alterations will require further studies with further radiological evaluation. However, the significant correlation between changes in urinary CTX-II and changes in serum CTX-I and serum ICTP at week 6 and week 22 already suggests a relationship between the effects of infliximab on reducing bone and cartilage degradation.

    In summary, our study suggests beneficial effects of infliximab therapy on bone metabolism in patients with severe RA. The ratio between markers of bone formation and bone resorption increased suggesting improvement of the bone remodelling balance, mainly due to a decrease in bone resorption. The latter was transient at the skeletal level, as documented by serum CTX-I levels, before returning to a new steady state. Conversely, decreased in MMP-mediated type I collagen degradation detected by ICTP, which could rather reflect mainly RA-related subchondral bone resorption, was delayed, but maintained during the 1-year treatment duration. Further studies are needed to evaluate whether these changes in bone turnover markers ratios and cartilage marker levels are predictive of structural effects of infliximab therapy.

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    Footnotes

    • Funding: This study was funded by Schering Plough, France.

    • Competing interests: None.