|Ahead of print publication
A prospective, randomized, single-center, two-arm, open-label study to evaluate the efficacy of biotherapi®, a two-strain bacillus probiotic blend, as an adjunctive therapy in the treatment of rheumatoid arthritis
Arindam Nandy Roy, Yarram Ashok Kumar, Syeda Sana Fatima
Department of Rheumatology, Yashoda Hospitals, Secunderabad, Telangana, India
|Date of Submission||06-Oct-2020|
|Date of Acceptance||15-Oct-2020|
Arindam Nandy Roy,
Department of Rheumatology, Yashoda Hospitals, Behind Hari Hara Kala Bhavan, S. D. Road, Secunderabad - 500 003, Telangana
Source of Support: None, Conflict of Interest: None
Objective: Probiotics have been shown to alleviate the symptoms of rheumatoid arthritis (RA) by normalizing the composition of gut microbiota. The objective of this study was to evaluate the effect of twice-daily Biotherapi® (Sanzyme Private Limited, India) as an adjunct to standard of care on disease activity and functional ability of patients with RA.
Methods: In this prospective, randomized, single-center, two-arm, open-label study, patients were randomized (1:1) to receive twice-daily adjunctive Biotherapi® (n = 125) or standard of care alone (n = 125) for 12 weeks. The primary endpoint was the change from baseline to days 45 and 90 in the Disease Activity Score-28-erythrocyte sedimentation rate (DAS-28-ESR).
Results: Standard of care alone and adjunctive Biotherapi® significantly reduced the mean DAS-28-ESR at days 45 and 90 (P < 0.05). However, the reduction from baseline was greater in patients receiving adjunctive Biotherapi® compared to standard of care alone at day 45 (–0.67 ± 0.77 vs. −0.15 ± 0.84, P < 0.0001) and day 90 (–1.21 ± 0.99 vs. –0.48 ± 0.69, P < 0.0001). Consequently, compared to standard of care, more patients achieved remission (4.3% vs. 23.6%) and showed good (6.52% vs. 35.45%) and moderate (31.5% vs. 41.81%) European League Against Rheumatism response at 90-day Biotherapi®. A similar pattern of improvement in the scores including Health Assessment Questionnaire was observed. No clinically significant changes in the laboratory parameters were reported during the study.
Conclusion: Twice-daily supplementation with Biotherapi® probiotic blend as an adjunct to standard-of-care treatment for RA is beneficial for alleviation of severity and symptoms of the disease and results in improvement in patients' quality of life.
Keywords: Autoimmune diseases, microbiome, probiotics, rheumatoid arthritis, standard of care
|How to cite this URL:|
Roy AN, Kumar YA, Fatima SS. A prospective, randomized, single-center, two-arm, open-label study to evaluate the efficacy of biotherapi®, a two-strain bacillus probiotic blend, as an adjunctive therapy in the treatment of rheumatoid arthritis. Indian J Rheumatol [Epub ahead of print] [cited 2021 Jul 25]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=321200
| Introduction|| |
A systemic autoimmune disease, rheumatoid arthritis (RA), is characterized by chronic inflammatory responses leading to significant articular pain, progressive cartilage, joint and bone degradation and destruction, and functional disability., Approximately 20 million people suffer from RA, globally positioning it as a major public health challenge. Although many pharmacological agents are effective in managing the symptoms of RA, they are associated with various adverse events (AEs). Hence, safer therapies that can effectively target the underlying causes of the disease are currently under development.
Interestingly, evidence from human studies suggests alteration in the composition and population of the gut microbiota (dysbiosis) and impaired immune response of the intestinal mucosal cells may lead to the etiology and pathogenesis of RA.,, In patients demonstrating clinical improvement following treatment with disease-modifying antirheumatic drugs (DMARDs), the altered microbiome was seen to partially restore to normal.
According to the Food and Agriculture Organization of the United Nations and the World Health Organization, probiotics are defined as live microorganisms, which, upon adequate administration, are beneficial for the health of the host. As gut microbiota have been seen to modulate immune responses, the use of probiotic bacteria as a therapeutic intervention for RA has been explored in a limited number of animal and human studies.,,,,, Although initial clinical studies investigating different probiotic strains have reported functional improvement or overall subject well-being without any change in disease activity and inflammatory biomarkers, recent trials have shown improvement in disease activity in addition to the profile of inflammatory cytokines.,,
Bacillus coagulans (SNZ 1969) and Bacillus subtilis have been generally recognized as safe, consistent with Section 201(s) of the Federal Food, Drug, and Cosmetic Act. B. coagulans (SNZ 1969) and B. subtilis have been demonstrated to promote gastrointestinal (GI) health and are considered an effective probiotic., These spore-forming Bacillus species are highly stable in extremely acidic environments and at high temperatures and are thus preferred over nonspore-forming bacteria (Lactobacillus species) in probiotic blends. However, the combination of spore-forming Bacillus species has been hardly evaluated clinically compared to nonspore-forming bacteria,,,,, for the treatment of RA. Moreover, these studies are limited by small sample size, and none of them evaluated probiotics for the Indian population.
Given the unmet need for novel therapies in the treatment of RA, the demonstrated treatment potential of probiotic supplements in previous studies, this study evaluated the effects of the combination of B. subtilis (SNZ 1972) and B. coagulans (SNZ 1969) (Biotherapi®, Sanzyme Private Limited, Hyderabad, Telangana, India) on disease activity and functional ability of patients with RA as an adjunctive treatment with pharmacological antirheumatic medications.
| Methods|| |
Study design and patient population
This was an investigator-initiated, prospective, randomized, two-arm, open-label, single-center study conducted from March 5, 2018, to April 21, 2019. Patients were between 18 and 75 years of age and were recruited from the Department of Rheumatology, Yashoda Hospital, Secunderabad, India. All patients were clinically diagnosed with RA according to the American College of Rheumatology (ACR) 2010 criteria, had active disease defined by the Disease Activity Score-28-with erythrocyte sedimentation rate (DAS-28-ESR) >2.6, were on treatment for RA for >3 months, and were expected to stay on a stable dose of medication throughout the study.
Patients with chronic renal failure or renal tubular acidosis, pancreatitis, inflammatory bowel disease or leaky gut, or any illness impairing the ability to comply with the study protocol were excluded from the study. In addition, patients consuming probiotics with a refusal of a 2-week washout period or allergic to the study product or planning to commence treatment with biological agents or a surgery during the study period were excluded. Furthermore, patients exposed to >10 mg/day of prednisolone and pregnant and lactating women were also excluded.
Before participating in the study, all patients were provided with information regarding the study protocol, and written informed consent was obtained. This study was approved (RP/02/2017) by the Institutional Ethics Committee of Yashoda Academy of Medical Education and Research for Yashoda Group of Hospital, Secunderabad, India, and was conducted in accordance with the Declaration of Helsinki, International Conference on Harmonization (E6[R2]) “Guidance on Good Clinical Practice.” The study is retrospectively registered at ISRCTN, study ID: ISRCTN79856269.
Patients with RA (n = 250) were randomized 1:1 into two groups. Patients in the intervention group (n = 125) received adjunctive probiotic supplement (capsules) for RA, and patients in the nonintervention group (n = 125) received only the standard-of-care treatment. Randomization was performed such that every alternate patient received adjunctive probiotic as per protocol. Each probiotic capsule contained not less than (NLT) 5 billion colony-forming units (CFUs) of B. subtilis (SNZ 1972) and B. coagulans (SNZ 1969). The standard-of-care treatment consisted of methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, and methylprednisolone. One capsule of the probiotic supplement was self-administered by the patient twice daily for a period of 90 days (3 months). Ongoing medication and/or additional therapy such as physiotherapy were allowed. Because this was an open-label study, neither the investigators nor the patients were blinded to product assignment. Patients were observed at two follow-up visits after randomization over the course of 90 days on days 45 and 90.
Assessments and endpoints
Change from baseline to days 45 and 90 in the DAS-28-ESR was the primary endpoint of the study. The secondary endpoints included change in Clinical Disease Activity Index (CDAI), tender joint count (TJC), swollen joint count (SJC), patient general assessment score, physician global assessment of DAS, and Health Assessment Questionnaire (HAQ) score at days 45 and 90. The changes in proportion of patients with different disease activity levels (remission, low, moderate, and high) for all these scores were also compared between the treatment groups. Improvement in disease activity level (good, moderate, and none) was compared between the treatment groups using European League Against Rheumatism (EULAR) response criteria, which was calculated from difference in DAS-28 value at days 45 and 90 from the baseline. All joint assessments were performed by a trained medical officer, and DAS-28-ESR, CDAI, and HAQ were assessed by a single investigator. Safety endpoints included changes in hemoglobin, red blood cell count, leukocyte count (white blood cells), platelet count, alanine transaminase, aspartate aminotransferase, serum creatinine, and estimated glomerular filtration rate and were measured at all visits. During the study, all patients completed several questionnaires, each targeting a different symptom. The scores were calculated by the formula and stratified by the cutoffs reported in previous literature.,,,
At the screening visit, all patients were evaluated for recruitment. Patients underwent a physical examination at all visits. On days 45 and 90, the physician reviewed any new medications that were prescribed to the patients since the previous visit and any AEs that the patient might have experienced. Treatment compliance was assessed on days 45 and 90 based on the number of capsules consumed by the patient per container. In addition, a follow-up telephonic interaction was performed 30 days after the reported withdrawal of patients to assess any AE.
Continuous data were presented as mean ± standard deviation (SD) and categorical data as number (%). Continuous data were compared using the independent samples Student's t-test and categorical data using the Chi-square test. The Wilcoxon signed-rank test was used to assess within-group changes, and the Mann–Whitney U-test was used to assess between-group differences throughout the study. The baseline characteristics were analyzed using the randomized set which consisted of all randomized patients who were treated with at least one dose of study drug. Primary efficacy analyses were conducted based on an intent-to-treat (ITT) principle using the full analysis set, which was defined as all randomized patients who were treated with at least one dose of study drug and had a baseline and at least one postbaseline primary endpoint assessment for treatment. Missing values were treated based on the last-observation-carried-forward method. The endpoints were also analyzed in per-protocol (PP) population, which included all patients in the full analysis set who successfully completed the study without any major protocol deviation. All statistical tests were two-tailed, and the level of significance (α) was set at P ≤ 0.05. All analyses were performed using SAS® version 9.4, SAS Institute Inc., Cary, North Carolina, US.
The study required to enroll at least 226 patients to provide 80% power to obtain a significant change of 0.28 in DAS-28-ESR score with an SD of 0.7, an alpha 0.05%, and a dropout rate of 15%.
| Results|| |
Of the total (n = 250) patients who were randomized, 96 patients in the adjunctive probiotic (Biotherapi®) and 85 patients in the standard-of-care alone group completed the study (lost to follow-up at days 45, n [%]: adjunctive Biotherapi®, 11 [8.8]; standard of care alone, 33 [26.4]; lost to follow-up at days 90, n [%]: adjunctive Biotherapi®, 12 [9.6]; standard of care alone, 7 [5.6]; due to AEs, n [%]: adjunctive Biotherapi®, 6 [4.8]) [Figure 1]. In the adjunctive Biotherapi® and in the standard of care alone, n = 110 and n = 92 patients, respectively, were analyzed in the ITT population.
The baseline and demographic characteristics of the patients who participated in the study are described in [Table 1]. The mean age of the patients in the adjunctive Biotherapi® and standard-of-care alone groups was 48.48 ± 10.38 and 48.01 ± 11.59 years, respectively. Most patients in both the groups were female, n (%): adjunctive Biotherapi®, 105 (84.0); standard of care alone, 113 (90.4). All patients were of Asian-Indian origin. Although all comorbidities were comparable between the groups, diabetes was more common among patients in the standard-of-care alone group; however, the difference was not significant. The duration of disease was significantly higher (P = 0.031) among patients receiving standard of care alone. The standard-of-care medications prescribed to patients were methotrexate, hydroxychloroquine, sulfasalazine, methylprednisolone, and leflunomide [Table 1]. The proportion of patients receiving these medications were similar between the treatment groups with the exception of hydroxychloroquine that was prescribed more in the standard of care alone compared to the adjunctive Biotherapi® group (72.8% vs. 60.0%, P < 0.05). The mean dose of these drugs was similar between the groups (P > 0.05). The proportion of patients receiving DMARD-monotherapy was 24.8% and 12.0% in the adjunctive Biotherapi® and standard-of-care groups, respectively, and the difference was significant (P = 0.009) [Table 1]. The DMARD-triple-drug combinations were prescribed more to patients in the standard-of-care alone group compared to patients in the adjunctive Biotherapi® group (42.4% vs. 29.6%, P = 0.035) [Table 1]. The baseline ESR was 37.56 ± 17.91 in the adjunctive Biotherapi® and 30.08 ± 15.63 in the standard-of-care group (P = 0.001).
In the ITT analysis, at baseline, the mean DAS-28-ESR was 4.49 ± 0.82 and 4.46 ± 0.76 in the adjunctive Biotherapi® and standard-of-care alone groups, respectively, and the scores were comparable (P = 0.853). The standard of care alone and adjunctive Biotherapi® significantly reduced the mean DAS-28-ESR at days 45 and 90. However, the improvement in terms of reduction from baseline in DAS-28-ESR was greater in patients receiving adjunctive Biotherapi® compared to standard of care alone at day 45 (–0.67 ± 0.77 vs. −0.15 ± 0.84, P < 0.0001) and day 90 (–1.21 ± 0.99 vs. –0.48 ± 0.69, P < 0.0001). A similar pattern of improvement in the CDAI score was also observed with greater reduction with adjunctive Biotherapi® compared to standard of care alone at day 45 (−4.12 ± 5.61 vs. −2.13 ± 5.74, P = 0.014) and day 90 (–7.84 ± 6.27 vs. –5.04 ± 6.16, P = 0.003), as shown in [Table 2]. The TJC, SJC, patient global assessment, physician global assessment, and HAQ scores also improved in both the treatment groups. Reduction in the scores was greater with the adjunctive Biotherapi® compared to standard of care alone at 45 days and at the end of treatment at 90 days [Table 2]. However, it should be noted that the minimum clinically important difference (MCID) of 0.22 was not attained except at day 90 in adjunctive Biotherapi®, where it approached MCID. The PP results corroborated the findings of the ITT analysis [Table 2].
|Table 2: Changes in rheumatoid disease activity indices at days 45 and 90 in the intent-to-treat and per-protocol populations|
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[Table 3] shows the proportion of patients with symptoms of RA as determined by various scores following treatment with or without adjunctive Biotherapi® in the ITT population. At baseline, the majority of the patients had moderate disease activity (DAS-28-ESR >3.2 − ≤5.1), with 72.7% in adjunctive Biotherapi® and 72.8% in standard of care alone, and the proportion was similar between the treatment groups. When compared to standard of care alone, treatment with adjunctive Biotherapi® led to better improvement in the DAS-28-ESR which was reflected as more patients achieving remission (4.3% vs. 23.6%) and showed good (6.52% vs. 35.45%) and moderate (31.5% vs. 41.81%) EULAR response at the end of treatment. After 45 days, 16.36% of the patients in the adjunctive Biotherapi® group showed “;good” and 34.54% of the patients showed “moderate” response in the EULAR criteria compared to those (3.26% and 17.39%, respectively) in the standard-of-care alone group [Table 3]. A similar trend of improvements in SJC, TJC, and CDAI was also observed at the end of treatment (P = 0.001).
|Table 3: Rheumatoid arthritis activity score levels in intent-to-treat population|
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No clinically significant changes in the laboratory parameters were reported during the study. Overall, six AEs were reported at the end of the study in the adjunctive Biotherapi® group (giddiness, n = 2; swelling of legs, n = 2; constipation, n = 1; and stomach bloating, n = 1).
| Discussion|| |
In the present study, the effects of adjunctive multi-species probiotic supplement (B. subtilis and B. coagulans) combined with standard treatment for RA were evaluated using TJC, SJC, DAS-28-ESR, EULAR, CDAI, HAQ, patient global assessment, and physician global assessment scores. The majority of the patients had moderate disease activity. Consumption of this probiotic supplement twice daily for 12 weeks resulted in significant improvement in all RA activity scores, suggesting an improvement in the severity and symptoms of RA compared with standard antirheumatic medications alone. Hence, these multi-species strains could survive and colonize the GI tract despite the extreme conditions and were biologically active and stable. Among previously reported studies evaluating probiotics, five studies evaluated Lactobacillus-based probiotics,,,, and one evaluated B. coagulans. However, our study investigated the anti-RA potential of a two-strain Bacillus probiotic blend. Most of these studies reported improvement in inflammatory markers and disease activity indices compared to placebo. Apart from the mean scores, our study also reported the proportion of patients achieving remission or low disease activity levels that were higher in the adjunctive Biotherapi® group. Our results are consistent with those reported by previous studies evaluating probiotics.,,, The results of the study by Zamani et al. indicated favorable effects for probiotic supplements on DAS-28 among RA patients after 8 weeks. Alipour et al. found a significant difference in EULAR response between the groups indicating the efficacy of the probiotic group. The disease activity and inflammation in patients with RA improved significantly following probiotic adjunct therapy in the study by Vaghef-Mehrabany et al. Mandel et al. demonstrated the effectiveness of probiotic adjunctive treatment for the relief of symptoms of RA. In contrast to our results, the clinical trial by Pineda et al. and Hatakka et al. showed no significant difference within groups and between the two groups for ACR response and for the measured cytokines, respectively., The comparison of our results with the previously reported studies is presented in [Table 4].,,,,,
|Table 4: Comparison of the results of the present study with those of previously reported studies|
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Antigenic mimicry, activation of antigen-presenting cells through toll-like receptors and nucleotide oligomerization domain-like receptors, promotion of T-cell differentiation, and increase of T-helper type 17-mediated mucosal inflammation are some of the proposed mechanisms by which gut microbiota are thought to contribute to the etiology of RA.
Although the exact mechanism of action of probiotics in the amelioration of RA symptoms is unknown, they are observed to balance the composition of the gut microbiota by favoring healthy bacteria, conferring antimicrobial benefits, increasing the integrity of the mucosal barrier, and reducing gut permeability.,
Following treatment with probiotics, a decrease in inflammatory cytokines (interleukin [IL]-1γ, IL-2, IL-6, IL-12, IL-17, interferon-γ, and tumor necrosis factor [TNF]-α) and an upregulation in the immunoregulatory IL-10 and TGF-γ levels have been observed.,,,
Probiotics have been shown to be safe in RA patients in previous studies.,, Similarly, only six AEs were observed among the group of patients who received the adjunctive probiotic supplement; these were neither serious nor life-threatening and nonstatistically significant compared to the majority of the patients in whom no AEs were reported. Hence, the probiotic supplement containing B. subtilis (SNZ 1972) and B. coagulans (SNZ 1969) was well-tolerated and is safe for human consumption.
Although highly efficacious biological drugs have transformed the management of RA, many patients cannot afford biologic medications, especially in low-income countries like India. The biological therapies for RA are costly and still sometimes fail to attain desirable significant clinical response. Probiotics are dietary supplements and have shown a promising therapeutic potential to prevent or treat RA.,,, Moreover, clinically relevant AEs for probiotics are none or very less. Patients who have active disease despite an optimum dosage of triple DMARDs or those who have contraindications to bDMARDs or tsDMARDs or developed side effects to biologic medications can be suitable candidates for probiotic therapy. Hence, probiotic supplement therapy may offer more benefits than their cost for the long-term treatment of patients with RA.
However, due to the small sample size of this study and the short duration of the intervention, future studies involving a larger sample size and a longer duration of intervention are needed to validate the findings. Nevertheless, patients enrolled in our studies are far more than those in the previous studies.,,,,, The other limitation was that the effects on pro-inflammatory cytokines and inflammatory factors, including serum levels of TNF-α and IL-6, could not be determined.
| Conclusion|| |
Based on the results of our study, twice-daily supplementation with a capsule containing NLT 5 billion CFUs of B. subtilis (SNZ 1972) and B. coagulans (SNZ 1969) as an adjunct to standard of care for RA is beneficial for the alleviation of the severity and symptoms of the disease and for improvement in patients' quality of life.
The authors acknowledge CBCC Global Research for data management, statistical analysis, and medical writing assistance in the development of this manuscript.
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]