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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 12  |  Issue : 1  |  Page : 31-37

Effect of anti-tumor necrosis factor alpha therapy on bone health and biomarkers of bone turnover in Indian patients with ankylosing spondylitis


1 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Medicine, AIIMS, New Delhi, India

Date of Web Publication23-Feb-2017

Correspondence Address:
Shefali Khanna Sharma
Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, 458, Sector 37-A, Chandigarh - 160. 036
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-3698.199131

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  Abstract 

Background: We evaluated the relationship between bone mineral density (BMD) and biomarkers of bone turnover in ankylosing spondylitis (AS) patients treated with anti-tumor necrosis factor alpha (TNF-α) agents.
Methods: Fifty-one AS patients were screened, of which 27 were started on anti-TNF therapy in accordance to the assessment of AS guidelines. Detailed assessments of erythrocyte sedimentation ratio (ESR), Bath AS disease activity index (BASDAI), Bath AS functional index (BASFI), Bath AS metrological index (BASMI), AS disease activity score-ESR, and AS quality of life (AsQOL) questionnaire were done at baseline and 6 months. Vitamin D, parathyroid hormone, and osteocalcin were measured along with BMD of the lumbar spine, anteroposterior (AP) and lateral view, and hip.
Results: Out of 27 patients, 12 patients had osteoporosis. At 6 months, significant improvements were seen for BASDAI (mean 2.33 ± 1.08, P < 0.01), BASFI (3 ± 1.31, P < 0.01), BASMI (3 ± 3.05,P = 0.019), and AsQOL (4 ± 3.02, P < 0.01) and these correlated with a decrease in ESR (15.6 ± 10.8,P = 0.01) at 6 months. The mean increase in BMD at the neck of femur, total hip, and lumbar AP view was 3.2% (P = 0.007), 3.1% (P = 0.004), and 2.5% (P < 0.001), respectively. The serum alkaline phosphatase level increased from a mean value of 190.3 ± 70.8 IU/ml at baseline to 225.4 ± 59.8 IU/ml, which was statistically significant at the 6-month follow-up (P = 0.006). The serum osteocalcin levels showed an increasing trend from a mean value of 2.32 ± 1.6 ng/ml at baseline to 3.32 ± 3.02 ng/ml at 6 months.
Conclusion: Anti-TNF-α has a beneficial effect on bone metabolism resulting in improved bone formation.

Keywords: Ankylosing spondylitis, anti-tumor necrosis factor alpha, bone health


How to cite this article:
Sharma SK, Mohanan S, Sharma SK. Effect of anti-tumor necrosis factor alpha therapy on bone health and biomarkers of bone turnover in Indian patients with ankylosing spondylitis. Indian J Rheumatol 2017;12:31-7

How to cite this URL:
Sharma SK, Mohanan S, Sharma SK. Effect of anti-tumor necrosis factor alpha therapy on bone health and biomarkers of bone turnover in Indian patients with ankylosing spondylitis. Indian J Rheumatol [serial online] 2017 [cited 2017 Nov 25];12:31-7. Available from: http://www.indianjrheumatol.com/text.asp?2017/12/1/31/199131


  Introduction Top


Ankylosing spondylitis (AS) is a progressive inflammatory arthritis characterized by an impaired bone metabolism. Simultaneous with the formation of new bone, leading to syndesmophytes and ankylosis, osteoporosis is also a prominent feature. The incidence of osteoporosis varies between 18.7% and 62%.[1] Its prevalence increases with disease duration [2] and is seen more in patients with advanced bony changes.[3]

Bone loss usually occurs early in the disease course, the mean duration is around 10 years, and it correlates with the degree of inflammation.[4] The receptor activator of nuclear factor kappa (RANK)-RANKL-osteoprotegerin system plays an integral role in the activation of osteoclasts,[5] and this in turn is stimulated by tumor necrosis factor alpha (TNF-α). Complications include vertebral compression fracture occurring at an event rate of 10.3%–16.7% over a 30-year period compared to 3.4% for population controls.[3],[4]

No formal guidelines are available for the detection and treatment of osteoporosis in AS, and most patients are young men who are less likely to be screened. Evidence-based recommendations advocate optimal control of disease activity to prevent bone loss. Calcium, Vitamin D supplements, and bisphosphonates have been used in managing osteoporosis in AS. However, the safety and cost efficacy of long-term therapy with bisphosphonates in young individuals are a matter of concern. Visvanathan et al. conducted the largest randomized, placebo-controlled trial on AS patients and demonstrated the favorable effects of infliximab on bone mineral density (BMD) and markers of bone metabolism in 279 patients of AS.[6]

The therapeutic response, disease outcomes, and adverse effects of biological therapy on AS patients in India have not been adequately studied. This single-center study is the first among the lot observing the bone metabolism in Indian AS patients receiving anti-TNF therapy. We assessed the treatment effect on disease activity and inflammation and simultaneous changes in BMD and markers of bone formation.


  Methods Top


AS patients fulfilling the modified New York criteria,[7] equal to or above the age of 18 years were recruited from the Rheumatology and Medicine outpatient departments at the All India Institute of Medical Sciences, New Delhi. The decision to start them on anti-TNF therapy was taken in accordance with the assessment of AS (ASAS) workgroup guidelines. Detailed baseline assessment, comorbidity assessment, blood investigations, and radiological studies for disease assessment were done. Patients who had other coexistent rheumatological diseases, had contraindications for biological therapy, were on medications that significantly altered bone metabolism, had previously received anti-TNF-α agents in the past 1 year, or had definite risk factors for osteoporosis such as chronic alcoholism, smoking, and endocrine disorders were excluded from the study.

The disease activity and its severity were assessed using the bath AS disease activity index (BASDAI), bath AS functional index (BASFI), and AS quality of life (AsQOL) questionnaire as subjective indices and the bath AS metrological index (BASMI) and AS disease activity score (ASDAS)-erythrocyte sedimentation ratio (ESR) as objective indices. The ASAS 40 improvement criteria were also assessed for subjective quantification of improvement. ESR, by the modified Westergren method, was used as a biochemical marker to assess disease activity. The bone health was assessed at baseline by measuring serum calcium and phosphorous, serum alkaline phosphatase (ALP), serum 25-hydroxy Vitamin D (radioimmunoassay [RIA], DiaSorin Ltd., Minnesota, USA), and serum parathormone (RIA, DiaSorin Ltd., Minnesota, USA). Serum osteocalcin (enzyme-linked immunosorbent assay, DIAsource ImmunoAssays, Belgium) was used as the marker for bone formation. The BMD was quantified by dual X-ray absorptiometry scan of the right hip-joint and lumbar spine (anteroposterior [AP] and lateral views) using the Hologic QDR 4500A bone densitometry machine. The bone density was expressed as bone mineral content (grams) per area density (centimeter square). Osteopenia and osteoporosis were defined according to the WHO criteria as T-score between −2.5 and −1 and T-score of <−2.5, respectively. The BASDAI, BASFI, BASMI, ASDAS, ESR, serum ALP, serum osteocalcin, and BMD were measured further at 6 months of treatment as parameters for statistical analysis.

Anti-tumor necrosis factor alpha therapy

Before treatment, the prevalence of latent tuberculosis infection (LTBI) was documented using tuberculin skin testing (TST), and when positive (>10 mm), patients were started on isoniazid and rifampicin for 6 months. They were recruited for anti-TNF therapy only after at least 1 month of LTBI treatment was completed. Anti-TNF therapy included either infliximab or etanercept. Infliximab was given at a dose of 3–5 mg/kg by intravenous infusion at baseline, 2 weeks, 6 weeks, and then 8 weekly. Etanercept was given at a dose of 50 mg once weekly or 25 mg twice weekly, by the subcutaneous route. The anti-inflammatory drug regimen and calcium supplements (400–800 mg of elemental calcium per day), which the patients were receiving before being enrolled, were continued during the study period. A reassessment was done at 4 weeks and then 2-monthly. If there was no adequate response, defined as a decrease in BASDAI by 2 points by the 12th week, anti-TNF therapy was stopped. However, in one of the patients, there was no response with infliximab and the drug was stopped. In view of rapid deterioration, etanercept was started to which the patient responded. The patients were also excluded if they had any serious infectious complication during the study.

Statistical analysis

This is an open-labeled, uncontrolled, prospective single-center study. Quantitative variables (BMD, blood parameters, and disease activity indices) are summarized by mean and standard deviation at each measurement points. For the final analysis, only those patients were included who had received standard treatment till that time point, i.e. 6-month, and these were analyzed. The paired t-test was used to compare the changes in mean values from the baseline to 6 months. To compare the change in values from the median (nonparametric test), the Friedman analysis was used, and the Wilcoxon-signed rank test was used for individual comparisons. Categorical variables (such as side effects) were summarized by frequency. A P < 0.05 was taken as being significant and all data were analyzed using STATA statistical software version 9.0.

Ethical approval

The study was approved by the ethics committee of the institute. Informed written consent was obtained from all patients prior to their enrollment in this study.


  Results Top


A total of 51 patients with AS were screened over a period of 16 months. Twenty-seven patients fulfilled the inclusion criteria and were enrolled into the study. Of the 27 study patients, 23 completed 6 months of follow-up. Four patients were excluded either because of complications (n = 2), change in treatment plan (n = 1), or loss to follow-up (n = 1). The baseline parameters of the 27 patients who were included are given in [Table 1]. The baseline disease activity parameters have been listed in [Table 2]. The mean and standard deviation of the overall T-score was 2.11 ± 1.27 at baseline. The baseline BMD measured at the lumbar spine and hip joint are given in [Table 3]. Out of 27 patients, 12 patients (44%) had osteoporosis, and a total 22 patients (81.5%) had objective bone loss (including both osteopenia and osteoporosis), according to the WHO classification. Twenty-three patients (85%) received infliximab therapy and five patients received etanercept injections. This is because one patient received infliximab for 3 doses but due to lack of response was switched to etanercept.
Table 1: Baseline characteristics of 27 patients of Ankylosing spondylitis

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Table 2: Mean values of the various disease activity parameters in the 27 patients of AS at baseline

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Table 3: Comparison of various parameters from baseline to 6 months for 23 patients with ankylosing spondylitis who were put on anti-TNF alpha therapy

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Effect of anti-tumor necrosis factor therapy on disease activity, function, metrology, and quality of life

At 6 months, significant improvements were seen in BASDAI (51.1%, P < 0.001), BASFI (43.5%, P < 0.001), BASMI (20.1%, P < 0.001), and AsQOL (51.7%, P < 0.001). Similarly, it was seen that the ESR decreased from a mean value of 49 ± 28.5–20.2 ± 18.5 (P < 0.001) at 6 months (P < 0.001) [Table 3]. The ASDAS-ESR also decreased from a baseline mean of 4.13 ± 0.81–2.19 ± 0.88 at 6 months (P < 0.001). BASDAI 50 response (i.e., the number of people who had a decrease of BASDAI by 50% of the baseline value) was attained by 52.2% of the study population by 6 months. ASAS 40 improvement was attained in 74% of the study population (n = 20).

Effect of anti-tumor necrosis factor therapy on bone mineral density

The BMD at the hip joint and lumbar AP views showed significant improvement while that at the lumbar lateral view showed a trend in improvement but did not reach statistical significance. The mean increases at the lumbar AP, lumbar lateral, hip joint-neck of femur, and hip joint-total views were 2.52%, 4.99%, 3.16%, and 3.07%, respectively.

Effect of anti-tumor necrosis factor therapy on markers of bone metabolism

The serum ALP level increased from a mean value of 190.3 ± 70.8 IU/ml at baseline to 225.4 ± 59.8 IU/ml, which was statistically significant at the 6-month follow-up (P = 0.006). The serum osteocalcin levels increased from a mean value of 2.32 ± 1.6 ng/ml at baseline to 3.32 ± 3.02 ng/ml at 6 months; however, this was not statistically significant.

Adverse effects

There was one infusion reaction following infliximab, which resolved on restarting at a slower rate. One patient developed transaminitis which resolved after methotrexate was stopped. Minor upper respiratory tract infections consisting of rhinitis and pharyngitis were reported by two people. Six patients developed serious infectious complications, out of which four patients were diagnosed to have tuberculosis, one as acute hepatitis-A virus infection, and another as acute pyogenic liver abscess. There were no hematological, renal, or other significant adverse effects during the study period for any patient. One patient had worsening of symptoms on therapy.


  Discussion Top


This is the first study in the Indian scenario that observed the effect of anti-TNF-α agents on the BMD, bone metabolism, and disease remission in patients suffering from severe AS. All patients had active disease with severe symptoms and poor quality of life while on standard therapy with nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs (DMARDS). The study showed that anti-TNF therapy significantly improves disease activity in parallel with a progressive improvement in BMD in both the spine and hip regions. The patients were more or less evenly distributed between the age groups of 18–25; 26–35; and 35–50 years with a majority in the younger age groups. Twenty-six out of twenty-seven patients were males. The sample size, study duration, and study design were comparable to previous studies conducted in France and Korea [Table 4].[8],[9],[10],[11] Our study population had a high prevalence of bone loss (81.5%) and 44% (12 out of 27) of them had osteoporosis by the WHO criteria. Previous studies also have reported osteoporosis as a common complication of AS with an incidence between 18.7% and 62%.[1] The mean disease duration of our patients was 8.4 ± 5.2 years and the bone loss was clearly evident due to the disease. The baseline mean Vitamin D levels were in the “insufficient” range (mean - 15.75 ng/ml); this was in concordance with the average normal Vitamin D levels in the North Indian population.[12],[13] Vitamin D supplementation was however not given during the study to avoid confounding of results.
Table 4: Compari son of previous studies with the present study in the evaluation of changes in bone mineral density with anti-TNFtherapy in ankylosing spondylitis patient

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A significant improvement in the absolute values of BMD was seen at the lumbar spine and hip, following anti-TNF therapy.[14],[15] The median percentage increase in BMD values is comparable with similar studies conducted in other countries as compared in [Figure 1]. In the present study, it was noted that the median percentage increases in BMD were higher in the lumbar spine lateral view (+5% at 6 months) than those seen in the AP view (2.5%), thus representing a true improvement in bone mineralization. The study however prospectively demonstrated that increases in BMD may be seen objectively as early as 6 months, in parallel with disease activity remission. The baseline serum osteocalcin levels were low in our population when compared to other studies. The low serum osteocalcin levels implied low osteoblastic activity, and this has been reported in previous studies in AS also.[10],[16] Following anti-TNF therapy, mean serum osteocalcin and ALP levels showed an increasing trend though it was not statistically significant, explained by the short study duration. Although ALP is not a specific marker of bone osteoblastic activity in view of the fact that none of the patients had alteration in liver function during the study period, the source of rising ALP is presumably from the bone. All patients were on calcium supplementation (400 mg elemental calcium per day) since the diagnosis of AS and this was not altered during the study period. Therefore, the increase in osteoblastic activity may be attributed to the specific effects of anti-TNF agents on bone metabolism. It would be difficult to comment on the exact effects of anti-TNF therapy on the structural spinal changes in this particular study as it was too short a study period for such interpretations. A previous study also did not show significant structural improvement with anti-TNF therapy, but a probable retardation in the progression of spinal changes has been objectively shown previously.[17],[18] As also suggested in the present study, early and aggressive control of inflammation appears the best preventive strategy to protect from permanent structural damage.
Figure 1: Comparison of the baseline and 6-month bone mineral densities of 23 patients with ankylosing spondylitis who had received anti-TNF therapy for six months. The increase in bone mineral density is significant at the hip joint (both neck of femur and total values) and at the lumbar spine antero-posterior view. The increases seen in the lumbar lateral view did not reach significant levels. P < 0.05 was taken as significant

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The present study is also one of the largest single-center studies looking into the efficacy and side effects of anti-TNF therapy in Indian patients with severe AS. Significant improvements were seen in the mean BASDAI, BASFI, BASMI, ASDAS ESR, and ASAS 40 improvements over the period of 6 months in our cohort of patients. BASDAI 50 response was seen for 12 patients out of 23 (52%) at 6 months. In parallel, there was also a significant decrease in ESR. The major adverse effect noted in this study, as also in previous Indian studies using anti-TNF agents, is a high incidence of tuberculosis. In this study, 4 out of 27 patients (14.8%) developed tuberculosis despite following strict screening and follow-up protocols, out of which two had disseminated tuberculosis. Previous studies conducted in the Indian scenario have shown rates varying from 10.6% to 21% in similar settings.[19],[20] In this study, all the four patients who developed the disease were on infliximab therapy. The less chance for tubercular reactivation with etanercept therapy has been reported in previous studies also.[19]

The present study has provided some interesting observations on the development of tuberculosis, which has not been speculated before in areas of high tubercular endemicity. First, none of the patients who developed tuberculosis following anti-TNF therapy were TST positive at baseline screening. Supposing the pathophysiological mechanism of tuberculosis in this cohort is reactivation of latent bacilli, it suggests that the TST is not sensitive enough to pick up LTBI in the four out of the 22 patients (~18%) who were TST negative at baseline. This makes it an insensitive diagnostic tool in this scenario. This could probably be because these patients were on chronic immunosuppressant therapy (DMARDs). The diagnostic value of TST needs to be studied in larger cohorts in future studies on anti-TNF therapy in high TB prevalent nations like India. In addition, the predictive value and cost-effectiveness of newer modalities such as interferon gamma release assays need to be validated in this scenario. Second, out of the four patients who had developed tuberculosis, two were diagnosed at or after 6 months. This contrasts with the usual observation that reactivation of tuberculosis usually develops early after the start of anti-TNF therapy (i.e., within 4 months).[20] This alerts us of the possibility that acquisition of exogenous infection is an equally important mechanism in the background of high tuberculosis prevalence. In addition, one of the patients had clearly given the history of exposure to an active case around the 6th month of infliximab infusion. However, this could be proven only by DNA fingerprinting studies [21] which are not widely available. Thus, prevention of contact and strict preventive measures should be clearly advised to any patient on anti-TNF therapy. Third, none of the patients who were LTBI positive and therefore received a course of LTBI therapy developed tuberculosis till the end of our study period. There are no guidelines on LTBI treatment in India though the consensus is to screen and treat on the lines advised in the British Thoracic Society guidelines [22] and the National Institute for Health and Clinical Excellence guidelines which advise isoniazid for 9 months. However, recently, failure of monotherapy due to emergence of isoniazid-resistant mycobacterial infection has been reported,[23] making a reconsideration on the present LTBI management guideline necessary, in favor of combination therapy. Drug-induced hepatotoxicity associated with the usage of combination regimens warrants careful screening and monitoring. The regimen in this study included a combination of isoniazid 5 mg/kg and rifampicin 10 mg/kg for duration of 6 months. The results show that LTBI treatment is highly effective in preventing tuberculosis in patients receiving anti-TNF therapy. Larger and well-controlled studies exploring the efficacy of various regimens for LTBI treatment are urgently required in areas where the tuberculosis burden is high.

The limitations of the present study include short duration of follow-up and lack of a control arm. Further studies should look into specific markers of bone resorption such as urine, deoxypyridinoline, and serum C-telopeptide of alpha-1 chain of collagen, which have been shown to correlate better with the bone metabolism than osteocalcin.

The results of this study highlight that anti-TNF therapy for patients with active AS improves the bone density and the beneficial effect on bone metabolism is seen as early as 6 months of treatment. Anti-TNF therapy is effective in inducing remission in patients who are resistant to conventional therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Karberg K, Zochling J, Sieper J, Felsenberg D, Braun J. Osteoporosis in AS. J Rheumatol 2004;31:1981-5.  Back to cited text no. 1
    
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van der Heijde D, Salonen D, Weissman BN, Landewé R, Maksymowych WP, Kupper H, et al. Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Res Ther 2009;11:R127.  Back to cited text no. 16
    
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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