A Prospective Double Blind Placebo Controlled Trial of Combination Disease Modifying Antirheumatic Drugs Vs

Home , Sulfasalazine

al of Arth rn ri u ti o s J Venkatesh et al., J Arthritis 2015, S1 Journal of Arthritis DOI: 10.4172/2167-7921.S1-001 ISSN: 2167-7921

Research Article Open Access A Prospective Double Blind Placebo Controlled Trial of Combination Disease Modifying Antirheumatic Drugs vs. Monotherapy (Sulfasalazine) in Patients with Inflammatory Low Backache in Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy Venkatesh S, Vishad V Viswanath, Deepak Tripathi, Mehtab Ansari and Vikas Agarwal* Department of Clinical Immunology, SGPGIMS, Raebareli road, Lucknow, India

Abstract Inflammatory back pain (IBP) in Ankylosing Spondylitis (AS) and Undifferentiated Spondyloarthritis (UspA) adversely affects the quality of life. Herein combination DMARD vs. sulfasalazine (SSZ) monotherapy was evaluated in treatment of axial symptoms of AS and UspA. Methods: Patients with AS/UspA with disease duration ≤ 8 years, IBP of atleast 6 months duration, and BASDAI ≥ 4 or early morning stiffness ≥ 1 hour despite NSAID therapy for 6 weeks were included. Patients were initiated on SSZ with either combination DMARD [MTX (10 mg escalated by 2.5 mg every week up to 20 mg/week) and HCQS 200 mg/day] or SSZ Monotherapy group [placebo MTX and placebo HCQS]. ASAS20 response was assessed at baseline and at the end of 6 months. Results: Of thirty three patients (31 males) with mean disease duration 39 months and mean BASDAI of 6 at baseline, 27 completed the study (16 in Combination DMARD and 11 in SSZ monotherapy group). ASAS 20 response, was achieved in 68.4% (13/19) and 50% (7/14) in the Combination DMARD and SSZ monotherapy groups (p=0.47), respectively. BASDAI scores decreased significantly in both the groups after therapy. A significant improvement in BASFI, patient pain VAS, patient global disease VAS, HAQ, and MCS of SF-36 was observed in both the groups. In the combination DMARD group, significant improvement in BASMI, FACIT and PCS of SF-36 and decrease in the serum MMP-3 levels was observed following therapy. Conclusion: SSZ monotherapy is equally efficacious as combination DMARD group in a significant proportion of patients with NSAID refractory IBP associated with AS/ USpA.

Keywords: Inflammatory back pain; Spondyloarthritis; Ankylosing factor which influences the quality of life is the extent of entheseal spondylitis; Psoriatic arthritis; Reactive arthritis; Inflammatory bowel involvement and associated stiffness and pain [5]. Besides these, the disease economic impact of loss of productivity due to AS calculated in terms of average annual human capital lost varies from Euros 4227 to Euros Introduction 8862 per patient. Seronegative Spondyloarthropathies (SpA) refer to a group NSAIDS have been the main stay of treatment for these diseases of chronic inflammatory disorders of unknown etiology. With for long. Despite providing good pain relief, they are largely ineffective prevalence between 0.5-2.5 percent, they are among the most common in altering the natural course. However, very often, in spite of therapy, rheumatologic disorders [1]. This is a male predominant disease with pain and discomfort continues in these patients with recurrent a mean age of onset usually in the second and third decade. This exacerbations. includes a heterogeneous group of patients with predominant axial The DMARDs (Disease Modifying Anti Rheumatic Drugs) are skeletal and entheseal involvement to more wide spread peripheral a group of drugs which have come into prominence following their involvement; asymmetric or symmetric oligo/polyarthritis without any remarkable efficacy in the management of rheumatoid arthritis. The axial involvement. The subgroups which come under this terminology major drugs representative of this group are; methotrexate (MTX), includes: Ankylosing Spondylitis (AS), Psoriatic Arthritis, Reactive Arthritis, Inflammatory bowel disease associated arthritis and Undifferentiated Spondyloarthritis (USpA). *Corresponding author: Dr. Vikas Agarwal, Additional Professor, Department of These diseases are major cause of morbidity for the patients, Clinical Immunology, SGPGIMS, Raebareli Road, Lucknow, India, 226014, Tel: causing pain, stiffness, loss of mobility, disability, poor sleep and 915222668812; E-mail: [email protected], [email protected] overall poor quality of life. In a study conducted by Linden et al., it was Received May 20, 2015; Accepted June 16, 2015; Published June 25, 2015 found that work related indices such as percentage of unemployment, Citation: Venkatesh S, Viswanath VV, Tripathi D, Ansari M, Agarwal V (2015) lack of permanence of work, number of sick leaves and early retirement A Prospective Double Blind Placebo Controlled Trial of Combination Disease due to illness were all higher in patients with AS as compared to Modifying Antirheumatic Drugs vs. Monotherapy (Sulfasalazine) in Patients with Inflammatory Low Backache in Ankylosing Spondylitis and Undifferentiated healthy individuals [2]. In another study, it was demonstrated that the Spondyloarthropathy. J Arthritis S1: 001. doi:10.4172/2167-7921.S1-001 quality of life in these patients is worse than cancer and myocardial infarction patients [3]. Amor et al., concluded that predictive factors Copyright: © 2015 Venkatesh S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits of long term outcome could be defined very early after the onset of unrestricted use, distribution, and reproduction in any medium, provided the spondyloarthropathy [4]. It has been demonstrated that a major original author and source are credited.

J Arthritis Arthritis & Pain ISSN: 2167-7921 JAHS, an open access journal Citation: Venkatesh S, Viswanath VV, Tripathi D, Ansari M, Agarwal V (2015) A Prospective Double Blind Placebo Controlled Trial of Combination Disease Modifying Antirheumatic Drugs vs. Monotherapy (Sulfasalazine) in Patients with Inflammatory Low Backache in Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy. J Arthritis S1: 001. doi:10.4172/2167-7921.S1-001

Page 2 of 6 sulfasalazine (SSZ), hydroxychloroquine (HCQ), gold and leflunomide. a definite benefit in halting radiologic progression [18]. Besides, the Of these drugs, the most well studied drug in SpA is SSZ. However, enormous cost incurred at a rate of about Rs 700,000/- (Euros 10000, its efficacy has been variably reported. Dougdas et al., conducted US $ 14000/-) per annum, put it out of reach of the majority of affected a multicenter, 36 week trial, involving 264 patients with evidence of population in India and other third world nations. Added to these, active AS refractory to NSAIDs, defined as morning stiffness of >45 is the increased risk of tuberculosis and fungal infections, a major minutes duration, inflammatory back pain, and patient and physician problem in our country. global assessments of moderate or high disease activity. The primary In this background, there is a severe and pressing need for outcome variable was treatment response based on morning stiffness, alternative safe and effective drugs in the management of these diseases. back pain, and physician and patient global assessments. In this It is here that the combination DMARD therapy assumes importance trial, SSZ was given at a dose of 2 g/day. The trial found SSZ to be as a potential safe and cheaper alternative. It has been demonstrated no more effective than placebo; treatment response rates were 38.2% that SpA is a TNF-α driven disease process. Though the level of this for SSZ versus 36.1% for placebo. Significant treatment efficacy was cytokine has been found to be quite high in the synovial and entheseal not shown for any of the following four outcome measures used to biopsies, they do not cause commensurate increase in the serum levels. define treatment response: physician global assessment (SSZ, 53.4% It has been shown that one of the mechanisms of action of conventional vs. placebo, 55.6%) patient global assessment (SSZ, 40.5% vs. placebo, DMARDs like SSZ and MTX is by TNF-α blockade. It could be that this 42.1%) morning stiffness (SSZ, 48.9% vs. placebo,44.4%) and back benefit is not transmitted to the level of axial and entheseal sites because pain (SSZ, 23.7% vs. placebo, 27.1%). Premature discontinuation rates of the fact that the inflammatory burden in AS is higher. In this setting, due to adverse events were 8% (11/131) and 5% (6/133) for SSZ and a higher dose of the conventional DMARDs may be effective, but this is placebo, respectively [6]. A major reanalysis of a series of randomized, double blind, placebo controlled, 36 week multicenter trials of SSZ (2 likely to be associated with significantly increased toxicity profile. The g/day) (including the above study) on the axial and peripheral articular other alternative available is the use of combination DMARD therapy. manifestations of AS (n=264), psoriatic arthritis (n=221), and reactive Combination DMARD therapy has been tried in rheumatoid arthritis (n=134) was recently reported of which 187 patients had arthritis and has been found to be better than monotherapy in halting only axial manifestations, while 432 patients had peripheral arthritis. the clinical and radiological progression of the disease process when The primary outcome measure was treatment response, determined given early in the disease [19]. A recent review of the toxicity profile on the basis of improvement in four outcome measures: patient and of these agents has proved them to be safe with withdrawal rates physician global assessments (all patients), morning stiffness and back due to toxicity being no higher than patients on monotherapy [20]. pain in patients with axial manifestations, and joint pain/tenderness Considering the effectiveness of combination DMARD therapy in RA, scores and joint swelling scores in patients with peripheral articular its potential as a safe and cheap alternative for inflammatory Chronic manifestations. Intention to treat analysis showed that SSZ provided Low Back Ache (CLBA) in SpA needs further investigation. significant improvement in patients with peripheral arthritis; response rates were 59.0% in patients treated with SSZ versus 42.7% in the Most of the studies evaluating the role of DMARDs in SpA, have included patients with advanced disease, in whom significant placebo group (p=0.0007). They did not find SSZ to be beneficial for Ankylosis has already occurred. Damage predominates over disease axial or entheseal disease [7]. However Braun et al. had demonstrated activity in this cohort and it is often very difficult to distinguish the efficacy of SSZ in inflammatory backache due to USpA and early whether symptoms are due to the former or latter. In addition the role AS, in patients without peripheral arthritis [8]. of combination therapy in inflammatory CLBA has not been evaluated The other major DMARD tried in AS is methotrexate (MTX). in well-designed randomized controlled trials. Though MTX monotherapy has not been found to be effective in axial In this prospective, double blind, placebo-controlled study, we symptoms of SpA in a number of studies, it has been reported to be compared the efficacy of SSZ monotherapy versus combination of useful in patients with peripheral arthritis [9-13]. Gonzalez-Lopez et DMARDs including SSZ, MTX and HCQ, for inflammatory CLBA al., reported significant improvement with MTX in physical well-being, in relatively early disease of AS/ USpA patients, refractory to NSAID BASDAI, BASFI, physician and patient global assessments, the HAQ, therapy. and spinal pain [14]. Haibel et al. studied the role of subcutaneous MTX at doses of 20 mg/week for 16 weeks in a NSAID refractory AS Materials and Methods patients with axial symptoms and found ASAS 20, 50 and 70 responses of 25%, 10% and none respectively, with no change in BASDAI [11]. In Patients who visited our SpA Clinic at Sanjay Gandhi Post- a recent Cochrane review, it was concluded that MTX may not improve Graduate Institute of Medical Sciences (Lucknow, India), and who overall disease activity, physical function, overall pain, tenderness or fulfilled criteria for the diagnosis of AS by the Modified New York swelling in the ligaments of the joints, movement of the spine, stiffness Criteria [21] or USpA by the Amor criteria [22], with disease duration ≤ 8 years, and with inflammatory CLBA of at least 6 months duration and overall well-being [15]. were included in the study, if they had a BASDAI ≥ 4 or early morning Leflunomide, the other major DMARD, has also fared poorly stiffness ≥ 1 hour despite taking maximum dose of at least one NSAID in a controlled trial in ankylosing spondylitis [16]. At present, there for 6 weeks duration. The study was carried out between Jan 2010 to is inadequate data regarding the efficacy of HCQ for inflammatory Dec 2012. backache. Apart from SSZ, there is no data available on the utility of Patients with renal or hepatic disease, severe uncorrected anemia DMARDS in USpA. (Hemoglobin <7 gm/dl), previous exposure to SSZ and/or MTX, The discovery of anti-TNF-α based biologics have been the major pregnant or lactating females, malignancy, chronic or on-going acute breakthrough in the management of SpA in recent times [17]. These infection, were excluded from the study. In addition patients who drugs, besides providing symptomatic improvement, also improve required and could afford biologicals and those receiving steroids in disease activity indices. However, as of now, they have not demonstrated the previous 3 months were also excluded.

Page 3 of 6

Patients were initially given SSZ 1gm/day which was escalated to 2 Subject’s written consent was obtained according to the declaration g/day after 1 week, and continued until the completion of one month. of Helsinki, and study was approved by institutional ethics committee Patients not tolerating SSZ in the initial month were withdrawn from and it conforms to standards currently applied in India. Institutional the study. At the end of the first month, patients were randomized into ethics committee was responsible for data safety and monitoring. All two groups in a double blind fashion, either Combination DMARD the drugs and matching placebo were procured from IPCA Activa, group: MTX (10 mg escalated by 2.5 mg every week up to 20 mg/ Mumbai, India. week) and HCQS 200 mg/day (MTX + HCQS) or Monotherapy group: The primary end point of the study was proportion of patients placebo MTX and placebo HCQS. SSZ was continued in both the achieving ASAS 20 response [23] at the end of 6 months. Secondary groups for the next 5 months. Randomization sequence was generated end points included proportion of patients achieving ASAS 40, changes by using random digit table. MTX and HCQS and their respective identical looking (shape, color and smell) placebo tablets were first in the BASDAI [24], BASFI [25], BASMI [26], FACIT [27], patient pain packed in opaque yellow plastic envelops which were then packed VAS, patient global disease assessment VAS, physician global disease inside identical white opaque plastic boxes by another person, who was assessment VAS, quality of life measures including the SF-36 [28] and not a part of the study team. The boxes were coded as box 1xxxA or box the HAQ at the end of 6 months. 1xxxB and sealed. Box 1xxxA contained either MTX (2.5 mg tablets) or Statistical analysis placebo whereas box 1xxxB contained either HCQS or placebo. Both boxes (1xxxA and 1xxxB) provided to a particular patient, contained Intention to treat analysis was carried out. Patients who did not either only drugs or only placebo. The labeled boxes were distributed to completed the study; their last observation was carried forward the patients by one of the authors (VA). The key was sealed and stored for analysis. Paired T test was used to analyze the numerical data. beyond the reach of the investigators till the completion of the study Mann-Whitney U test and test of proportions was used to calculate and data entry, and was opened just before data analysis. the difference between the numbers of patients achieving ASAS20 responses in the combination DMARD vs. SSZ monotherapy group. Patients continued their current NSAIDs, and were advised to taper P value <0.05 was considered significant. All the statistical analysis was them in accordance with their symptom relief. Patients were required carried out on NCSS 2007 software. to follow up after completion of 1 month, 2 months, 4 months and 6 months after treatment initiation. Complete hemogram, renal and liver Results function tests monitored during every visit. Thirty three patients were enrolled in the study with a mean age Serum samples for analyzing MMP-3 and TIMP-1 were drawn at (24.9 years), M: F sex ratio (10:1), mean disease duration (39 months) baseline and at the end of the study and stored at -80°C till analysis. and mean BASDAI (6.0). Of these, 27 patients completed the study MMP-3 and TIMP-1 analysis was carried out by ELISA as per the with 16 being in the combination DMARD group and 11 in the SSZ manufacturer recommendations (R&D systems Inc., Minneapolis, monotherapy group. Three patients in each group dropped out of the MN, USA). study due to reasons mentioned in the Figure 1.

Screening for AS (Modified New York Criteria) / USpA (Amor Criteria) with following criteria • Inflammatory CLBA ≥ 6mon and • Either BASDAI ≥ 4 or EMS ≥ 1hour, despite full dose of at least one NSAID x 6 weeks

n = 33 SSZ 2g/d only for initial 4 weeks NSAIDs were continued

Combination DMARD SSZ Monotherapy Reasons for withdrawal Reasons for withdrawal SSZ + MTX + HCQS SSZ + Placebo Inadequate relief n = 19 n = 14 2 lost to follow up after 1st month visit Viral hepatitis Follow up One developed diarrhea nd Vomiting after 2 6 months which recovered on month withdrawal of drugs

Completed study Completed study n = 16 n = 11

Figure 1: Study design.

Page 4 of 6

Baseline assessments Parameter Combination DMARD (n=19) SSZ monotherapy (n=14) At Baseline p-value Baseline At 6months p-value The baseline characteristics were comparable in both groups 6months (Table 1). The mean age (± S.D) of the patients was 25.4 (± 5.5) and 6.1 ± 1.3 1.8 ± 1.8 5.9 ± 1.5 2.4 ± 1.9 BASDAI* <0.0001 <0.0001 24.3 (± 4.3) years in the combination DMARD (SSZ+MTX+HCQS) (4.0 – 9.16) (0 – 5.78) (4.8 – 8.72) (0 – 6.4) and SSZ monotherapy groups respectively, while the mean duration BASDAI ≥ 4.0 19 (100%) 5 (26.3%) 14 (100%) 5 (35.7%) of disease was 3.1 (± 2.2) and 3.7 (± 1.9) years, respectively. There was n (%) one female in each group, with the ratio of patients of AS/USpA being BASDAI 9/7 (n=16) and 6/5 (n=11) in the combination DMARD group and SSZ 50% 11 (58%) 7 (50%) 0.65 monotherapy groups respectively. reduction n (%) Baseline mean BASDAI was 6.1 ± 1.3 (4.0–9.16) and 5.9 ± 1.5 *Results expressed as mean ± SD (range). Comparison between baseline and (4.8–8.72) in the combination DMARD and SSZ monotherapy groups, 6 month follow up done using paired Student’s t-test. BASDAI 50% reduction respectively. analyzed by Chi Square test. Table 2: BASDAI assessments between the combination DMARD and SSZ Therapy response at the end of 6 months monotherapy groups. The primary end point, ASAS 20 response, was achieved in 68.4% Parameter Combination DMARD (n = 19) SSZ monotherapy (n=14) (13/19) and 50% (7/14) in the combination DMARD group and the SSZ Baseline 6 months p-value Baseline 6 months p-value monotherapy groups (p=0.47, Fisher’s exact test), respectively. BASDAI BASDAI 6.1 ± 1.3 1.8 ± 1.8 <0.001 5.9 ± 1.5 2.4 ± 1.9 <0.001 scores (Table 2) decreased significantly in both the combination BASFI 4.7 ± 2.6 1.3 ± 1.3 <0.001 5.1 ± 1.8 2.0 ± 1.7 0.001 DMARD and SSZ monotherapy groups (6.1 ± 1.3[4.0–9.16] to 1.8 ± BASMI 10 2.5 ± 1.7 1.9 ± 2.1 <0.009 2.5 ± 1.5 2.2 ± 1.7 0.291 1.8[0–5.78] p <0.001; 5.9 ± 1.5[4.8–8.72] to 2.4 ± 1.9[0 – 6.4] p <0.001, point FACIT (0- respectively). At the completion of 6 months of therapy, BASDAI ≥ 4 23.2 ± 9.4 15.1 ± 11.4 0.045 28 ± 10.4 18.2 ± 11.9 0.067 was present only in 14.8% (2/16 and 2/11) patients in the combination 52) Patient DMARD and SSZ monotherapy groups, respectively. Other secondary Pain VAS 59.9 ± 21.5 19.9 ± 21.6 <0.001 67.2 ± 27.2 23.7 ± 18.3 0.018 end points (Table 3), including BASFI, patient pain VAS, patient (0-100) global disease VAS, HAQ, and MCS of SF-36 significantly improved in PGD VAS 59.0 ± 25.1 19.3 ± 21.0 <0.001 64.1 ± 28.1 27.5 ± 22.2 0.044 both the groups, while the 10 point BASMI, FACIT and PCS of SF-36 (0-100) improved significantly in the combination DMARD group only. Phy GD VAS (0- 70.2 ± 17.3 14.5 ± 11.8 <0.001 67.1 ± 9.3 22.3 ± 19.1 <0.001 The levels of MMP-3 were significantly increased and the levels 100) of TIMP-1 were significantly reduced in the AS/UspA patients as PCS 33.4 ± 6.6 44.3 ± 8.8 <0.001 34.8 ± 5.4 41.1 ± 6.8 0.065 compared to healthy controls at baseline (Table 4). In the Combination MCS 33.8 ± 9.4 43.4 ± 11.2 0.003 34.9 ± 9.6 44.1 ± 10.7 0.028 HAQ (0-3) 1.2 ± 0.6 0.4 ± 0.5 0.001 1.5 ± 0.5 0.5 ± 0.4 <0.001 DMARD group, the levels of MMP-3 decreased significantly following therapy as compared to the SSZ monotherapy group (Table 5). All values refer to the mean ± SD. Comparison between baseline and 6 month follow up in each group done using the paired Student’s t-test. PGD; Patient global However, the levels of TIMP-1 remained unchanged in both the groups disease, Phy GD; Physician global disease, PCS: Physical component score, as compared to baseline. MCS: Mental component score, HAQ: Health assessment questionnaire. Table 3: Secondary end points data in the combination DMARD and SSZ SSZ Combination monotherapy groups. Parameter Monotherapy p value DMARD (n = 19) (n = 14) AS Patients Healthy Control P value Age (years) 25.4 ± 5.5 24.3 ± 4.3 0.55 (n =22) (n= 20) Gender M:F 18:1 13:1 NS MMP 3 48.29 ± 14.92 13.34 ± 5.48 <0.001 Duration of CLBA (years) 3.2 ± 2.3 3.7 ± 1.9 0.65 TIMP-1 132.76 ± 32.58 181.05 ± 19.10 <0.001 No. of AS patients n (%) 9 (47.3) 6 (43) NS Results expressed in ng/ml No. of USpA patients n (%) 10 (53.7) 8 (57) NS 5.9 ± 1.5 (4.8 – Table 4: Serum levels of MMP3 and TIMP-1 in AS patients and healthy controls. Baseline BASDAI 6.1 ± 1.3 (4.0 – 9.2) 0.47 8.7) Baseline BASFI 4.7 ± 2.6 5.1 ± 1.8 0.81 Toxicity profile Baseline BASMI (10 point) 2.5 ± 1.7 2.5 ± 1.5 0.86 Almost all patients tolerated the drugs except for one patient in the PGD VAS (0-100) 59.0 ± 25.1 64.1 ± 28.1 0.75 SSZ monotherapy group who withdrew due to drug induced diarrhea, Patient Pain VAS (0-100) 59.9 ± 21.5 67.2 ± 27.1 0.49 which recovered after stopping the drug, and one patient in the Phy GD VAS (0-100) 70.2 ± 17.3 67.0 ± 9.25 0.44 combination DMARD group who developed drug associated vomiting HAQ (0-3) 1.2 ± 0.6 1.5 ± 0.5 0.21 after which he withdrew at the end of 2 months. One patient developed FACIT (0-52) 23.2 ± 9.4 28.0 ± 10.4 0.36 transient transamniitis which required discontinuation of medications SF-36 PCS 33.5 ± 6.6 34.8 ± 5.4 0.45 for 4 weeks but patient completed the study without recurrence. SF-36 MCS 33.8 ± 9.4 34.9 ± 9.6 0.70 *values indicate mean ± SD unless otherwise indicated. Comparison at baseline Discussion was done with the Mann-Whitney U test. PGD; Patient global disease, Phy GD; Physician Global Disease In this prospective, double-blind, placebo-controlled study, we have Table 1: Demographic and baseline disease characteristics of the combination assessed the efficacy of combination DMARDs (SSZ+MTX+HCQS) DMARD and SSZ monotherapy groups. versus that of SSZ monotherapy in NSAID refractory inflammatory

Page 5 of 6

Drug (n = 15) Placebo (n = 7) disease activity, and hence partially obviating the influence of damage Parameter Baseline Follow-up p value Baseline Follow-up p value in assessment of disease activity. In the present study we have observed MMP 3 45.0 ± 15.3 30.4 ± 17.6 0.001 55.4 ± 12.0 53.8 ± 9.2 0.756 that both combination DMARDs and SSZ monotherapy are associated 121.7 ± with good response to treatment in SpA patient with NSAID refractory TIMP-1 137.1 ± 37.2 131.4 ± 30.1 0.271 123.5 ± 18.5 0.809 34.4 inflammatory CLBA. Though superiority (as far as ASAS20 response is (Results are expressed in ng/ml). considered) of combination of MTX, HCQS and SSZ was not observed however, combination DMARD group has significant improvement in Table 5: Effect of combination DMARD vs. SSZ monotherapy on serum levels of MMP 3 and TIMP-1. physical component score of SF-36, BASMI and fatigue as compared to SSZ monotherapy group. Moreover, more number of patients CLBA in patients with AS/ USpA of relatively short duration (≤ 8 reported ASAS 20 responses in the combination DMARD group. May years). The disease duration chosen was based on an Indian study be due to small number of patients in both the groups the study was which showed that the average delay from the onset of initial symptoms not sufficiently powered to demonstrate superiority of combination to diagnosis was 8 years [29]. DMARD therapy as compared to SSZ monotherapy group. In the present study we observed that both combination DMARD MMP-3 has been reported to reflect degree of inflammation as well as SSZ monotherapy are effective in the treatment of NSAID [32] and correlate with disease activity in AS [33] and radiographic refractory inflammatory CLBA in SpA of short disease duration. We progression [34]. MMP-3 is involved in degradation of extracellular found that combination of MTX, HCQS and SSZ, did not provide matrix proteins and is involved in degradation of cartilage and bone of additional efficacy over that provided by SSZ monotherapy, as inflamed joints [35]. We observed significant decrease in MMP-3 levels evidenced by the ASAS 20 responses of 68% (13/19) and 50% (7/14) in the combination DMARD group as compared to SSZ monotherapy in the two groups respectively. BASDAI improved significantly in both group. Thus combination DMARD therapy has potential to minimize the groups compared to baseline, and at the end of 6 months all but joint damage by reducing the levels of MMP-3. 4 (14.8%) patients had a BASDAI <4. Both the therapies were well tolerated. The limitations of our study include the small sample size due to single center and rigid inclusion criteria and absence of a control arm DMARDs for axial symptomatology in SpA, have been evaluated in with only NSAIDs, due to its perceived unethicality in a cohort which a very limited number of studies. Although SSZ is the most well evaluated is already in discomfort due to NSAID refractoriness. of these, its efficacy is mostly limited to peripheral arthritis associated Hence we conclude that, in a small cohort of patients SSZ with SpA [6]. The ASCEND trial, which compared Etanercept 50 mg monotherapy is efficacious in a significant proportion of patients with once weekly with SSZ 3g/d for 16 weeks, in active AS with both axial and NSAID refractory, inflammatory CLBA associated with AS/ USpA peripheral symptoms, reported that ASAS 20 responses were achieved in relatively early disease, and would help probably delay or may be in almost 52.9% on SSZ, which is a significant number, though it was totally avoid the use of expensive anti-TNF biologics and its associated inferior to Etanercept (75.9%; p<0.0001). The mean disease duration in complications in this subset, especially in the under developed world. the study was 7.6 years [30]. The study by Braun et al., evaluating SSZ Moreover, we have found that the triple combination of SSZ, MTX and vs. placebo in inflammatory CLBA associated with AS/ USpA, included HCQS is not superior to SSZ monotherapy. However, a larger study 230 patients, with 47% also having peripheral arthritis. At the end of 6 with sufficient sample size and power is necessary to make a definite months, there was no significant difference in the reduction in BASDAI recommendation. and most other secondary outcome variables between the two groups, though in the group without peripheral arthritis, there was significant Acknowledgement benefit with SSZ in reduction in BASDAI, spinal pain and morning Authors acknowledge the support of IPCA Activa, Mumbai, India for their stiffness compared to placebo [8]. In a re-analysis of three randomized, generous support in supplying the study drugs as well as placebo. placebo controlled trials of SSZ 2g/day vs. placebo in AS, PsA and ReA References by the Department of Veterans Affairs Cooperative Study group, SSZ 1. Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH (2008) was found to be effective in peripheral articular manifestations, but not Rheumatology 4th Edition, Elsevier publishers, USA. in axial disease [7]. 2. Boonen A, Chorus A, Miedema H, van der Heijde D, Landewé R, et al. (2001) In a retrospective study on the efficacy of combination DMARDs Withdrawal from labour force due to work disability in patients with ankylosing spondylitis. Ann Rheum Dis 60: 1033-1039. (SSZ + MTX) versus SSZ monotherapy in NSAID refractory AS, Can et al. had reported a significant improvement in BASDAI scores in 3. Dagfinrud H, Mengshoel AM, Hagen KB, Loge JH, Kvien TK (2004) Health status of patients with ankylosing spondylitis: a comparison with the general both the groups at 6 months, which consequently lead to a reduction population. Ann Rheum Dis 63: 1605-1610. in the requirement of biological therapy by 21-24% if BASDAI was the 4. Amor B, Santos RS, Nahal R, Listrat V, Dougados M (1994) Predictive factors decisive factor. BASDAI was >4 in 32.8% (20/61) of patients in the SSZ for the longterm outcome of spondyloarthropathies. J Rheumatol 21: 1883- monotherapy and in 44% (11/26) in the combination arm at the end of 1887.

6 month follow up [31]. This being a retrospective study is obviously 5. Braun J, McHugh N, Singh A, Wajdula JS, Sato R (2007) Improvement in biased by the physicians’ subjectivity in disease assessment and their patient-reported outcomes for patients with ankylosing spondylitis treated personal choices with regards to therapy. with etanercept 50 mg once-weekly and 25 mg twice-weekly. Rheumatology (Oxford) 46: 999-1004. To the best of our knowledge, this is the first placebo controlled 6. Dougados M, vam der Linden S, Leirisalo-Repo M, Huitfeldt B, Juhlin R, et double blind study, to evaluate the efficacy of combination DMARDs, al. (1995) Sulfasalazine in the treatment of spondylarthropathy. A randomized, which includes the combination of SSZ + MTX + HCQ, for inflammatory multicenter, double-blind, placebo-controlled study. Arthritis Rheum 38: 618- CLBA in AS/USpA. In addition we have included patients with relatively 627. shorter disease duration, which ensures a more precise assessment of 7. Clegg DO, Reda DJ, Abdellatif M (1999) Comparison of sulfasalazine and

Page 6 of 6

placebo for the treatment of axial and peripheral articular manifestations of criteria for ankylosing spondylitis. A proposal for modification of the New York the seronegative spondylarthropathies: a Department of Veterans Affairs criteria. Arthritis Rheum 27: 361-368. cooperative study. Arthritis Rheum 42: 2325–2329. 22. Harris ED, Budd RC, Genovese MC, Firestein GS, Sargent JS, et al. 8. Braun J, Alten R, Burmester G, Ebner W, Gomor B, et al. (2006) Efficacy Parameters in Amor criteria for diagnosing spondylarthropathy: Kelleys Text of sulfasalazine in undifferentiated spondyloarthritis and early ankylosing book of Rheumatology. Elsevier Saunders:17th edition, USA. spondylitis: a multicenter randomized controlled trial. Ann Rheum Dis 65: 1147- 1153. 23. Anderson JJ, Baron G, van der Heijde D, Felson DT, Dougados M (2001) Ankylosing spondylitis Assessment Group Preliminary definition of short term 9. Sampaio-Barros PD, Costallat LT, Bertolo MB, Neto JF, Samara AM (2000) improvement in Ankylosing Spondylitis. Arthritis Rheum 44: 1876-1886. Methotrexate in the treatment of ankylosing spondylitis. Scand J Rheumatol 29: 160-162. 24. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, et al. (1994) A new approach to defining disease status in ankylosing spondylitis: the Bath 10. Biasi D, Carletto A, Caramaschi P, Pacor ML, Maleknia T, et al. (2000) Efficacy Ankylosing Spondylitis Disease Activity Index. J Rheumatol 21: 2286-2291. of methotrexate in the treatment of ankylosing spondylitis: a three-year open study. Clin Rheumatol 19: 114-117. 25. Calin A, Garrett S, Whitelock H, Kennedy LG, O’Hea J, et al. (1994) A new approach to defining functional ability in ankylosing spondylitis: the development 11. Haibel H, Brandt HC, Song IH, Brandt A, Listing J, et al. (2007) No efficacy of of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol 21: 2281- subcutaneous methotrexate in active ankylosing spondylitis: a 16-week open- 2285. label trial. Ann Rheum Dis 66: 419-421. 26. Jenkinson TR, Mallorie PA, Whitelock HC, Kennedy LG, Garrett SL, et al. 12. Roychowdhury B, Bintley-Bagot S, Bulgen DY, Thompson RN, Tunn EJ, et (1994) Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS al. (2002) Is methotrexate effective in ankylosing spondylitis? Rheumatology Metrology Index. J Rheumatol 21: 1694-1698. (Oxford) 41: 1330-1332. 27. Webster K, Cella D, Yost K (2003) The Functional Assessment of Chronic 13. Altan L, Bingöl U, Karakoç Y, Aydiner S, Yurtkuran M, et al. (2001) Clinical Illness Therapy (FACIT) Measurement System: Properties, applications, and investigation of methotrexate in the treatment of ankylosing spondylitis. Scand interpretation. Health and Quality of Life Outcomes 1: 79. J Rheumatol 30: 255-259. 28. Ware JE Jr, Sherbourne CD (1992) The MOS 36-item short-form health survey 14. Gonzalez-Lopez L, Garcia-Gonzalez A, Vazquez-Del-Mercado M, Munoz-Valle (SF-36). I. Conceptual framework and item selection. Med Care 30: 473-483. J, Gamez-Nava J (2004) Efficacy of methotrexate in ankylosing spondylitis: a randomized, double blind, placebo controlled trial. J Rheumatol 31: 1568–1574. 29. Aggarwal R, Malaviya AN (2009) Clinical characteristics of patients with ankylosing spondylitis in India. Clin Rheumatol 28: 1199-1205. 15. Chen J, Veras MM, Liu C, Lin J (2013) Methotrexate for ankylosing spondylitis. Cochrane Database Syst Review 2: CD004524. 30. Braun J, van der Horst-Bruinsma IE, Huang F, Burgos-Vargas R, Vlahos B et al. (2011)Clinical efficacy and safety of etanercept versus sulfasalazine in 16. van Denderen JC, van der Paardt M, Nurmohamed MT, de Ryck YM, Dijkmans ankylosing spondylitis patients: a randomized, double-blind study (ASCEND BA, et al. (2005) Double blind, randomised, placebo controlled study of Trial). Arthritis Rheum 63: 1543–1551. leflunomide in the treatment of active ankylosing spondylitis. Ann Rheum Dis 64: 1761-1764. 31. Can M, Aydin SZ, Nigdelioglu A, Atagunduz P, Direskenelli H (2012) Conventional DMARD therapy (methotrexate-sulphasalazine) may decrease 17. Gorman JD, Sack KE, Davis JC Jr (2002) Treatment of ankylosing spondylitis the requirement of biologics in routine practice of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 346: 1349-1356. patients: A real-life experience. Int J Rheum Dis 15: 526–530.

18. Baraliakos X, Davis J, Tsuji W, Braun J (2005) Magnetic resonance imaging 32. Zhu J, Yu DT (2006) Matrix metalloproteinase expression in the examinations of the spine in patients with ankylosing spondylitis before and spondyloarthropathies. Curr Opin Rheumatol 18: 364-368. after therapy with the tumor necrosis factor alpha receptor fusion protein etanercept. Arthritis Rheum 52: 1216–1223. 33. Chen CH, Lin KC, Yu DTY, Yang C, Huang F, et al. (2006) Serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in ankylosing 19. Möttönen T, Hannonen P, Leirisalo-Repo M, Nissilä M, Kautiainen H, et al. spondylitis: MMP-3 is a reproducibly sensitive and specific biomarker of (1999) Comparison of combination therapy with single-drug therapy in early disease activity. Rheumatology (Oxford) 45: 414-420. rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet 353: 1568-1573. 34. Maksymowych WP, Landewé R, Conner-Spady B, Dougados M, Mielants H, et al. (2007) Serum matrix metalloproteinase 3 is an independent predictor of 20. Donahue KE, Gartlehner G, Jonas DE, Lux LJ, Thieda P, et al. (2008) structural damage progression in patients with ankylosing spondylitis. Arthritis Systematic review: comparative effectiveness and harms of disease-modifying Rheum 56: 1846-1853. medications for rheumatoid arthritis. Ann Intern Med 148: 124-134. 35. Murphy G, Knäuper V, Atkinson S, Butler G, English W, et al. (2002) Matrix 21. van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of diagnostic metalloproteinases in arthritic disease. Arthritis Res 4 Suppl 3: S39-49.

This article was originally published in a special issue, Arthritis & Pain handled by Editor(s). Dr. Rostyslav V Bubnov, Clinical Hospital Pheophania

J Arthritis Arthritis & Pain ISSN: 2167-7921 JAHS, an open access journal