|Year : 2022 | Volume
| Issue : 1 | Page : 10-15
Prospective study of patients with inflammatory back pain, clinical characteristics and treatment response in ankylosing spondylitis in two centers of rheumatology in South India
Subramanian Nallasivan1, Dhivya Thiyagarajan2, Abirami Manivannan3
1 Consultant Rheumatologist, Velammal Medical College Hospital and Research Institute, Madurai and Shifa Hospitals, Tirunelveli, Tamil Nadu, India
2 Post Graduate Trainee in Anasthesiology, Velammal Medical College Hospital and Research Institute, Madurai, Tamil Nadu, India
3 Post Graduate Trainee in Surgery, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
|Date of Submission||16-Jun-2021|
|Date of Acceptance||22-Oct-2021|
|Date of Web Publication||25-Feb-2022|
Dr. Subramanian Nallasivan
Department of Rheumatology and Medicine, Consultant Rheumatologist, Velammal Medical College Hospital, Anuppanadi, Madurai, Tamilnadu
Source of Support: None, Conflict of Interest: None
Introduction: Ankylosing spondylitis is inflammatory arthritis affecting the spine and peripheral joints more commonly in men of 15 years to 40 years of age and is a part of the spectrum of diseases called spondyloarthropathy. Psoriasis, uveitis, ulcerative colitis, and inflammatory bowel disease form part of the systemic manifestations. There exists a long delay between the onset of inflammatory back pain and being diagnosed with ankylosing spondylitis.
Methodology: We set out to study the clinical profile, diagnosis, and management of patients with spondyloarthritis (SpA) prospectively and follow-up over 2 years period. All patients who had inflammatory back pain and diagnosed to have SpA were included in this prospective study in two different centers of Rheumatology. Clinical characteristics, magnetic resonance imaging (MRI)-spine and sacroiliac joints, disease activity using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and early treatment response were assessed. Other investigations including bloods, X-rays, and screening for biologics were done as and when indicated. We used both synthetic Disease-Modifying AntiRheumatic Drugs (DMARDS) and biosimilars as per the British Society of Rheumatology guidelines and patient choice. Patients were reviewed every 3 months for 1–2 years. The response to treatment was assessed and compared with other studies.
Results: Forty -two patients were studied in this 2 years period (15 patients out of 57 lost to follow up). All patients had the diagnosis of ankylosing spondylitis as per Assessment of Spondylo Arthritis international Society (ASAS Score) criteria and MRI evidence of sacroiliitis and 22 patients had peripheral synovitis. HLA-B27 was positive in 11/19 patients. Eleven patients had been on anti-Tumor Necrosis Factor (TNF) drugs and 26 patients were on DMARDs. At the end of 24 weeks, disease activity indices including BASDAI and BASFI were low in remission and statistically significant. At the end of 2 years, most of them were in remission and 81% were continuing to work and maintain productivity. Patients who underwent treatment with biosimilar TNFs showed a significant reduction in disease activity and achieved remission earlier, as evidenced by BASDAI and BASFI scores, compared to others who were on DMARDS and supportive therapy. The usage of DMARDS was more than biosimilar drugs as they are expensive.
Conclusion: This study shows the real-world data on the diagnosis and management of patients with ankylosing spondylitis, achieving remission, and maintaining the work-life balance. Early diagnosis with MRI and appropriate intervention with DMARDS are the important factors in this study.
Keywords: Ankylosing spondylitis, anti-tumor necrosis factor, bath ankylosing spondylitis disease activity index, bath ankylosing spondylitis functional index, biosimilars, inflammatory back pain
|How to cite this article:|
Nallasivan S, Thiyagarajan D, Manivannan A. Prospective study of patients with inflammatory back pain, clinical characteristics and treatment response in ankylosing spondylitis in two centers of rheumatology in South India. Indian J Rheumatol 2022;17:10-5
|How to cite this URL:|
Nallasivan S, Thiyagarajan D, Manivannan A. Prospective study of patients with inflammatory back pain, clinical characteristics and treatment response in ankylosing spondylitis in two centers of rheumatology in South India. Indian J Rheumatol [serial online] 2022 [cited 2022 May 27];17:10-5. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/1/10/338447
| Introduction|| |
Spondyloarthritis (SpA) is a spectrum of inflammatory arthritides in which ankylosing spondylitis is common with a worldwide prevalence of up to 0.9% including women. Its etiology and pathogenesis are not yet fully understood. SpA is a family of systemic inflammatory rheumatic diseases that have been extensively reported and studied from India over the last four decades. The epidemiological studies estimate the prevalence of SpA to be 7–9/10,000 persons., Several years may pass between the onset of symptoms and definite diagnosis. This delay is most likely due to low awareness of AS or SpA among non rheumatologist and the fact that X-ray evidence of sacroiliitis is a late feature of the disease. Computed tomography and magnetic resonance imaging (MRI) can detect AS lesions earlier and with greater consistency than plain radiography, but these methods are not routinely employed due to poor resource settings. MRI enables the detection of approximately 75% more cases of early sacroiliitis that would otherwise have been missed by plain radiography. New therapies such as the tumor necrosis factor (TNF) inhibitors have transformed the treatment paradigm in AS, especially for those patients with aggressive disease. Thus, the development of clinical methods to assess response to therapy has become a priority. This study focuses on measuring the degree of disease activity, job retention, and morbidity in patients with AS in outpatient settings, and monitoring the response to treatment with nonsteroidal anti-inflammatory drugs (NSAIDS), Disease-modifying antirheumatic drugs (DMARDS), and TNF inhibitors, to achieve remission and quality of life.
- To study the clinical profile, diagnosis, management, and time to achieve remission of patients with SpA and long-term follow-up with disease activity indices
- To assess the outcome of patients on biosimilars in the treatment of ankylosing spondylitis.
| Methodology|| |
This was a prospective study of patients with inflammatory back pain due to ankylosing spondylitis. Prior approval from Institutional Ethical Committee was obtained Vide. VMCIEC/03/2017 dated April 04, 2017.
All consecutive patients who had inflammatory back pain and diagnosed to have SpA by ASAS criteria (Assessment of SpA International society) were included in this prospective study in two different centers' of Rheumatology over 2 1/2 year period (recruitment 18 months and follow up for 12 months). We started from April 2017 and completed by December 2019. Clinical assessment was made by the rheumatologist following ASAS criteria.
All patients who were pregnant, who were living far, who had degenerative disc disease and TB spine.
After obtaining informed consent, clinical characteristics, bloods-erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), disease activity using Bath Ankylosing spondylitis disease activity index and functional index (BASDAI, BASFI), and drug treatment were entered on to the data collection proforma. MRI Imaging of spine and sacroiliac joint (SIJ) (STIR sequences) was used in this study during the first visit for identifying inflammatory changes–sacroiliitis and other features. After the initial assessment, all patients were managed as per BSR (British Society of Rheumatology) guidance. Once diagnosis confirmed, Sulfasalazine was started for most patients, and Methotrexate or Leflunomide was used for patients with peripheral arthritis (risk of developing connective tissue disease if patients positive for ANA take sulfasalazine).
Most patients were started on NSAIDs and intramuscular methylprednisolone 80 mg or prednisolone 10 mg orally daily for 1 week.
During the review consultation, patients were offered treatment escalation - second line DMARDS, TNF blockers etc. after BASDAI and BASFI scores as per BSR guidelines. Prebiologic screening with chest X-ray, bloods, viral serology, and counseling was done. Patients were reviewed every 3 months and compliance to the protocol was stressed. The response to treatment was assessed and compared with other studies.
The data were analyzed using SPSS 23.0 version (Statistical package for the social sciences version 23.0) by IBM and in year 2015. and variance was found using analysis of variance tool for repeated measures. P < 0.05 was considered to be statistically significant.
| Results|| |
We enrolled 57 patients, but 15 patients were excluded due to attrition-(who lost to follow up or were <3 months of follow-up). Out of 42 patients, 37 were male and 5 were female (7.4: 1-M: F) with a mean age of 33.5 years.
These patients presented with back pain, stiff back, for weeks to months, unable to squat or bend forward and and also driving difficulties due to neck pain. Eight patients reported buttock pain. Patients also presented with knee and ankle synovitis. Sleep was affected and had morning stiffness too.
All had the diagnosis of SpA under ASAS criteria, MRI spine and SIJ showing evidence of inflammation. MRI imaging included lumbar spine, SIJ STIR images, and disc changes were reviewed. Marrow edema, vertebral corner lesions and fatty lesions, spinal ligament ossifications scored in favour of ankylosing spondylitis. The changes in patients who had degenerative changes like osteophytes, disc dehydration were insignificant.
HLA B27 antigen was positive in 11 (out of 19 patients in whom the test was done) using the polymerase chain reaction (PCR) method. Raised ESR was present in 24 out of 42 patients, while CRP was elevated in 17 out of 42 patients. Mean scores are depicted in [Table 1]. BASDAI and BASFI scores were recorded at the time of diagnosis, 4 weeks, 12 weeks 24 weeks, 52 weeks, and 2 years, and have shown improvement as in [Table 2] and [Table 3].
|Table 2: Statistical analysis of bath ankylosing spondylitis functional index scores during the treatment course|
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|Table 3: Statistical analysis of bath ankylosing spondylitis disease activity index scores over the treatment course|
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NSAIDS were used at the time of diagnosis and during subsequent visits, conventional DMARDs and Biosimilar anti TNF drugs were used to treat these patients. Sulfasalazine was the drug used in 22 patients while Methotrexate and Leflunomide were used in four each [Graph 1]. Second DMARDs were used for patients who either failed or had intolerance to first-line drugs. Ten patients used Adalimumab biosimilar drug and one patient used etanercept. Those patients who had bio DMARDS used minimal NSAIDs and no steroids and no flares.
Criteria for remission included BASDAI score less than or equal to 2, BASFI score <2.4, absence of active arthritis or enthesitis or extra-articular manifestations in the last 6 months.
Our results show that by 24 weeks, most patients achieve remission with mean BASDAI 2.26(SD-0.701) and mean BASFI 2.45 (SD-0.772). at the end of 2 years mean BASDAI 2.33 (SD-1.817) and mean BASFI 2.07 (SD -1.599). both were statistically significant [Graph 2].
Extra-articular manifestations including uveitis, dactylitis, iridocyclitis, and heel pain (plantar fascitis) were observed in 22 patients. The most common site of enthesitis was plantar fasciitis.
Use of biosimilars
Eleven out of 42 needed Biosimilars and adalimumab was used for 10 patients. Etanercept was used for one. Two patients are continuing on biosimilar injections for 4 years now and others on an average have used 4–6 doses.
[Table 4] illustrates that mean disease activity was high at diagnosis and biosimilar drugs were added to oral DMARDS at 12 weeks and since 24 weeks, they have maintained remission until 104 weeks. Disease remission rate and job retention were high in our study with 81% in work with a mean follow-up of 1 year.
| Discussion|| |
Spondyloarthropathy involves the spine, SIJ and peripheral joints and also associated with extra-articular manifestations such as uveitis, iritis, psoriasis, enthesitis, and inflammatory bowel disease. Out of the 57 patients diagnosed with AS and enrolled for the study the male-to-female ratio was about 7:1 in contrast to trends suggested by Agarwal and Malaviya and other studies., All females presented in their early thirties while males had their presentations in mid-twenties suggesting an early onset of the disease among the males. It could also be because women tend to disregard back pain as simple and use conservative treatment.
The impact of the inflammatory disease can be variable resulting in chronic pain and debility hence early diagnosis and treatment are important. Serum biomarkers have been used in assessing disease activity, treatment response, and as predictors of radiographic severity., We found that elevated ESR, CRP were seen in about 57% of patients with AS, with mean ESR 26.4 mm and CRP 14 mg/dl, implying inflammatory activity was present. 19 patients had tested for HLA B27 antigen using the PCR method, (cost issues). 11 were found to be positive. PCR method was used. 11/19 (57%) positivity for HLA B27 suggests low positive rate however 43% patients couldnt test due to high cost. HLA B27 positivity is associated with more severe disease clinically and radiographically. Haridas et al. study showed positivity in 21% in south Indian population while B27 alleles showed more than 70% positivity.
MRI is being used increasingly to diagnose radiographic AS while a separate group of patients have been classified as nonradiographic AS. All study patients had MRI spine and SIJ with 72% showing bilateral sacroiliitis and hip joint effusion. Five patients had ankylosed spine and bony sclerosis of SIJ which suggests the chronic nature of this disease. Other inflammatory changes reported include supraspinalis tendonitis, cervical facet joint edema, and atlanto-occipital joint space narrowing, and extraskeletal presentations such as dactylitis, uveitis, patellar bursitis, and trochanteric bursitis. The presence of syndesmophytes, male sex, HLA B27 positivity, high CRP, and smoking have been identified as strong risk factors for radiological damage.
The functional index (BASFI) and the subjective activity index (BASDAI) are strongly inter-correlated when assessing AS severity, both by their absolute values and by the Ankylosing Spondylitis Disease Activity Score.,
Our results show, that, by 24 weeks, all patients achieve remission with mean BASDAI 2.26 (SD-0.701) and mean BASFI 2.45 (SD-0.772). At the end of 2 years, mean BASDAI 2.33,(SD-1.817). mean BASFI 2.07 (SD-1.599), both these indices were statistically significant (P < 0.001). This is comparable to 2009 study done by Agarwal and Malaviya.
Before the advent of biologic agents, treatment for AS was limited to using NSAIDS and DMARDS like sulfasalazine. Toward the end of the 20th century, TNF-α was found to be overexpressed in the SIJ tissues in patients with Ankylosing Spondylitis. Since 2003, biologic drugs have been licensed to use in patients with SpA. Currently, there are six biological agents approved for use in Ankylosing Spondylitis, including five monoclonal antibodies (i.e., infliximab, adalimumab, certolizumab pegol, golimumab, and secukinumab) and a soluble TNF receptor, etanercept. These drugs and their biosimilar agents have transformed the treatment paradigm in AS, especially for those with aggressive disease and associated extra-articular manifestations.
Though the biologicals have been effective in patients with Ankylosing Spondylitis, their high cost is the major hindrance for their use in majority of Indian patients who have to shell out from their pocket. This had been highlighted by Singhal and colleagues showing many Asian Indian patients with ASpA were deprived of the benefits of these agents. Hence, biosimilar drugs were used and are increasingly being accepted across the world not only for ankylosing spondylitis but also in other conditions.
In our study, we followed multidisciplinary approach for management that included counseling, physiotherapy, NSAIDS, DMARD, intramuscular steroids, and biosimilars. Ten patients were on Adalimumab and 1 patient was on Etanercept. Patients who were on biosimilars showed a reduction in their disease activity in all except one (10/11) and achieved remission in 4 months to 6 months during the follow-up while they continued on DMARDs and physiotherapy. This was similar to Bruner et al. l in 2014. One patient had undergone total hip replacement in our study. One patient was drug free after 4 cycles of biosimilar therapy. Recent insights into the immune mediators of the inflammatory cascade have resulted in targeted treatment strategies in patients with SpAs. Castillo-Gallego et al. have thrown more light on the bioDMARDS including Interleukin (IL)-17 blockers, and IL-22 monoclonal antibodies in achieving effective disease control and remission in patients with SpAs.
The extra articular features like uveitis and enthesitis responded to DMARDs and topical eye preparations. It may be possible that inflammatory bowel disease was not found in this cohort due to early aggressive therapy for ankylosing spondylitis and achieve remission. With the advent of various immune cytokine blockers the clinicians are able to give good quality of care and QoL to the patients.
Patients who can continue their work and maintain their economic activities were supported for job retention. Our follow-up consultations suggested that patients were able to retain their job and were satisfied. Disease remission and job retention were high in our study with 81% in work with a mean follow-up of 1 year.
This study shows the real-world data on spondyloarthritis over 2 years, with tight control of disease activity despite social, financial, and physical impediments. Better communication with patients and family by the team of doctors and nurses might have helped to achieve this and continued follow-up and using low-cost DMARDS in SpA would be an effective strategy and tool for further research in developing countries.
First is the limited study population so we cannot make generalizations. Affordability was the reason for the low rate of testing of the HLA B27 antigen. Second, biologics and biosimilars usage has been restricted due to financial constraints. Follow-up imaging might have added more value in reinforcing the remission. Third, the dose of NSAIDS could have helped to analyze the long-term implications. Monitoring of inflammatory mediators could also have helped to assess the duration to achieve biochemical remission along with BASDAI and BASFI.
Within these limitations, our patients responded reasonably well to the strategies employed and managed to work and adopt work-life balance and keep productivity.
| Conclusion|| |
SpA is increasing in incidence and patients still reach the specialists late (average of 25 months after the onset of symptoms) and have a reduced quality of life and loss of productivity due to work disability and sickness absenteeism. NSAIDS and DMARDS work well, however, Biosimilars do have a role in selected patients. Remission is good and job retention is high in our cohort with good quality of life. This study shows the real-world data on SpA, with tight control of disease activity despite social, financial, and physical impediments. Using low-cost DMARDs in SpA and diagnosis using MRI at the start for diagnosis would have contributed to effective control of arthritis in SpA and further research is warranted in developing countries.
We thank all our patients and family members who had spent time for this study, Mr Vijay. Patients and family members, Mr. Vijay Anto, Assistant professor cum statistician in community medicine department, and Dr. Mariappan, Consultant Radiologist in Velammal medical college hospital, Madurai.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]