Efficacy of HDAC inhibitors and epigenetic modulation in the amelioration of synovial inflammation, cellular invasion, and bone erosion in rheumatoid arthritis pathogenesis.

Rheumatoid arthritis (RA), an auto-immune disorder affected 1 % of the population around the globe. The pathophysiology of RA is highly concerted process including synovial hyperplasia, pannus formation, bone erosion, synovial cell infiltration in joints, and cartilage destruction. However, recent reports suggest that epigenetics play a pivotal role in the formation and organization of immune response in RA. Particularly, altered DNA methylation and impaired microRNA (miRNA) were detected in several immune cells of RA patients, such as T regulatory cells, fibroblast-like synoviocytes, and blood mononuclear cells. All these processes can be reversed by regulating the ubiquitous or tissue-based expression of histone deacetylases (HDACs) to counteract and terminate them. Hence, HDAC inhibitors (HDACi) could serve as highly potent anti-inflammatory regulators in the uniform amelioration of inflammation. Therefore, this review encompasses the information mainly focussing on the epigenetic modulation in RA pathogenesis and the efficacy of HDACi as an alternative therapeutic option for RA treatment. Overall, these studies have reported the targeting of HDAC1, 2 & 6 molecules would attenuate synoviocyte inflammation, cellular invasion, and bone erosion. Further, the inhibitors such as trichostatin A, suberoyl bis-hydroxamic acid, suberoyl anilide hydroxamic acid, and other compounds are found to attenuate synovial inflammatory immune response, clinical arthritis score, paw swelling, bone erosion, and cartilage destruction. Insight to view this, more clinical studies are required to determine the efficacy of HDACi in RA treatment and to unravel the underlying molecular mechanisms.

Occurrence and outcome of COVID-19 in AIRD patients on concomitant treatment with Tofacitinib- results from KRA COVID COHORT (KRACC) subset.

INTRODUCTION: We assessed the risk factors and outcome of COVID-19 in patients with autoimmune rheumatic diseases(AIRD) who contracted infection while on background treatment with tofacitinib. METHODS: This is a non-interventional, cross-sectional, questionnaire based telephonic study which included consecutive AIRD patients on tofacitinib co-treatment. Data related to the AIRD subset, disease modifying anti rheumatic drugs(DMARDs) including glucocorticoids and comorbidities, was collected from 7 rheumatology centers across Karnataka during the second wave of COVID-19 pandemic. The information about COVID-19 occurrence and COVID-19 vaccination was recorded. RESULTS: During the study period (Jun-July 2021), 335 AIRD patients (80.6% female) on treatment with tofacitinib were included. The mean duration of tofacitinib use was 3.4+/-3.1months. Thirty-six(10.75%) patients developed COVID-19. Diabetes mellitus (p = 0.04 (OR 2.60 (1.13-5.99)) was identified as a risk factor for COVID-19 in our cohort. Almost half of our cohort was COVID-19 vaccinated with at least one dose, with resultant decline in incidence of COVID-19(OR 0.15 (0.06-0.39) among the vaccinated. Recovery amongst COVID-19 infection group was 91.2%. CONCLUSIONS: The subset of AIRD patients who were on treatment with tofacitinib were found to have a higher rate of COVID-19 infection as compared to our KRACC cohort. Pre-existing comorbidity of diabetes mellitus was the significant risk factor in our cohort. This subset of the KRACC cohort shows RA patients had a lesser infection and PsA patients had a higher infection.

Risk factors associated with COVID-19 in systemic lupus erythematosus: Results from a longitudinal prospective cohort.

INTRODUCTION: Patients with SLE (systemic lupus erythematosus) have a higher risk of infection due to dysregulated immune system as well as long-term use of immunosuppressants (IS). This could influence the risk of COVID-19 and its outcome. METHODS: We conducted a longitudinal prospective study across 15 rheumatology centres during the first wave of the pandemic to understand the risk factors contributing to COVID-19 in SLE patients. During the 6 months follow-up, those who tested positive for COVID-19, their clinical course and outcome information were recorded. RESULTS: Through the study period (April-December 2020), 36/1379 lupus patients (2.9%) developed COVID-19. On analysing the COVID-19 positive versus negative cohort during the study period, male gender (adjusted RR 3.72, 95% C.I. 1.85,7.51) and diabetes (adjusted RR 2.94, 95% C.I. 1.28, 6.79) emerged as the strongest risk factors for COVID-19, in the adjusted analysis. There was no significant influence of organ involvement, hydroxychloroquine, glucocorticoid dosage (prednisolone< 7.5 mg or ≥ 7.5 mg/day) or IS on the risk of COVID-19. There was only one death (1/36) among the lupus patients due to COVID-19. CONCLUSION: Traditional risk factors rather than lupus disease process or IS influenced the risk of COVID-19 in our cohort.

A prospective longitudinal study evaluating the influence of immunosuppressives and other factors on COVID-19 in autoimmune rheumatic diseases.

BACKGROUND: We conducted this study to identify the influence of prolonged use of hydroxychloroquine (HCQ), glucocorticoids and other immunosuppressants (IS) on occurrence and outcome of COVID-19 in patients with autoimmune rheumatic diseases (AIRDs). METHODS: This was a prospective, multicenter, non-interventional longitudinal study across 15 specialist rheumatology centers. Consecutive AIRD patients on treatment with immunosuppressants were recruited and followed up longitudinally to assess parameters contributing to development of COVID-19 and its outcome. RESULTS: COVID-19 occurred in 314 (3.45%) of 9212 AIRD patients during a median follow up of 177 (IQR 129, 219) days. Long term HCQ use had no major impact on the occurrence or the outcome of COVID-19. Glucocorticoids in moderate dose (7.5-20 mg/day) conferred higher risk (RR = 1.72) of infection. Among the IS, Mycophenolate mofetil (MMF), Cyclophosphamide (CYC) and Rituximab (RTX) use was higher in patients with COVID 19. However, the conventional risk factors such as male sex (RR = 1.51), coexistent diabetes mellitus (RR = 1.64), pre-existing lung disease (RR = 2.01) and smoking (RR = 3.32) were the major contributing risk factors for COVID-19. Thirteen patients (4.14%) died, the strongest risk factor being pre-existing lung disease (RR = 6.36, p = 0.01). Incidence (17.5 vs 5.3 per 1 lakh (Karnataka) and 25.3 vs 7.9 per 1 lakh (Kerala)) and case fatality (4.1% vs 1.3% (Karnataka) and 4.3% vs 0.4% (Kerala)) rate of COVID-19 was significantly higher (p < 0.001) compared to the general population of the corresponding geographic region. CONCLUSIONS: Immunosuppressants have a differential impact on the risk of COVID-19 occurrence in AIRD patients. Older age, males, smokers, hypertensive, diabetic and underlying lung disease contributed to higher risk. The incidence rate and the case fatality rate in AIRD patients is much higher than that in the general population.

Is butyrate a natural alternative to dexamethasone in the management of CoVID-19?

Coronavirus disease 2019 (CoVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 has affected more than 100 million lives. Severe CoVID-19 infection may lead to acute respiratory distress syndrome and death of the patient, and is associated with hyperinflammation and cytokine storm. The broad spectrum immunosuppressant corticosteroid, dexamethasone, is being used to manage the cytokine storm and hyperinflammation in CoVID-19 patients. However, the extensive use of corticosteroids leads to serious adverse events and disruption of the gut-lung axis. Various micronutrients and probiotic supplementations are known to aid in the reduction of hyperinflammation and restoration of gut microbiota. The attenuation of the deleterious immune response and hyperinflammation could be mediated by short chain fatty acids produced by the gut microbiota. Butyric acid, the most extensively studied short chain fatty acid, is known for its anti-inflammatory properties. Additionally, butyric acid has been shown to ameliorate hyperinflammation and reduce oxidative stress in various pathologies, including respiratory viral infections. In this review, the potential anti-inflammatory effects of butyric acid that aid in cytokine storm depletion, and its usefulness in effective management of critical illness related to CoVID-19 have been discussed.

Maternal and fetal outcomes of lupus pregnancies: A collective effort by Karnataka Rheumatologists.

INTRODUCTION: Identifying factors predicting adverse pregnancy outcomes involving systemic lupus erythematosus (SLE) is a research priority. The aims of this study were to investigate (a) the maternal and fetal outcomes of pregnant lupus patients and the factors associated with adverse pregnancy outcomes, and (b) the effect of pregnancy on lupus disease activity of these patients. METHODS: This was an ambi-directional study collecting information from five multi-specialist referral centres across the state of Karnataka, India over 5 years (2013-2018). Clinical details of pregnancies and outcomes that were temporally associated with lupus disease were recorded using a structured pro forma. The Safety of Estrogen in SLE National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) was used to assess lupus activity during the 6 months prior to pregnancy and the intra- and post-partum periods. Modifications suggested in the SLE Pregnancy Disease Activity Index were considered while scoring. RESULTS: A total of 121 pregnancies in 80 SLE patients with a mean age of 27.1 (±4.5) years and with a mean disease duration of 4.6 (±4.1) years were reviewed. Largely patients were in clinical remission (109/121; 90.1%). Antiphospholipid antibody positivity was seen in 45/121 (37.2%) patients. A history of lupus nephritis was noted in 29/121 (24%) patients. Maternal complications (32%) were mainly due to hypertensive disorders of pregnancy (HDP; 19/121; 15.7%). Adverse fetal outcomes (58%) were mainly in the form of spontaneous first-trimester abortions (21/121; 16%), stillbirth (14/121; 11.6%) and prematurity (24/121; 20%). HDP is strongly associated with stillbirth and prematurity and is independent of active lupus. Disease activity was associated with a three-fold increased risk of adverse fetal outcome in univariate analysis. The risk of major flare during pregnancy is low (4.1%) when conception occurs during stable disease. Hydroxychloroquine (HCQ) use was associated with reduced risk of flare (p = 0.001) in patients in remission at the time of conception. CONCLUSIONS: The risk of major flare during pregnancy is low when conception happens during stable disease. HCQ use was associated with reduced risk of flare in patients in remission at the time of conception. HDP was strongly associated with stillbirth and prematurity and are independent of active lupus in our cohort.

Pharmacokinetic Similarity and Comparative Pharmacodynamics, Safety, Efficacy, and Immunogenicity of DRL_RI Versus Reference Rituximab in Biologics-Naïve Patients with Moderate-to-Severe Rheumatoid Arthritis: A Double-Blind, Randomized, Three-Arm Study.

OBJECTIVES: The aims were to demonstrate pharmacokinetic (PK) similarity between DRL_RI, a proposed rituximab biosimilar, and two reference innovator products (Rituxan® [RTX-US] and MabThera® [RTX-EU]) and compare their pharmacodynamics (PD), efficacy, safety, and immunogenicity in rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX)-based therapy and no prior biologic administration. METHODS: In this randomized, double-blind, parallel-group study, 276 patients with moderate-to-severe active RA were randomized to receive DRL_RI, RTX-US, or RTX-EU on days 1 and 15. The primary PK end points included area under the concentration-time curve from time 0 to 336 h after first infusion (AUC0-14 days, first infusion), AUC from day 1 through week 16 (AUC0-∞, entire course), and AUC from time 0 to time of last quantifiable concentration after the second dose (AUC0-t, second infusion). Secondary end points included other PK parameters, such as maximum concentration (Cmax), time to Cmax after each infusion, terminal half-life, systemic clearance, and volume of distribution after the second infusion; PD parameters and efficacy until week 24; safety and immunogenicity at week 24 and 52; and B cell recovery until week 52. AUC from time 0 to time of last quantifiable concentration after the first dose and over the entire course from day 1 through week 16 (AUC0-t, entire course) was analyzed as an exploratory end point. RESULTS: The 91% confidence intervals (CIs) of the geometric mean ratios (GMRs) for the primary end point of AUC0-∞, entire course were within the bioequivalence limits of 80-125% for all comparisons: DRL_RI versus RTX-US 100.37% (92.30-109.14), DRL_RI versus RTX-EU 93.58% (85.98-101.85), and RTX-US versus RTX-EU 93.24% (85.62-101.54). PD outcomes (peripheral blood B-cell depletion and mean change in Disease Activity Score [28 joints]-C-reactive protein), efficacy, safety, and immunogenicity were also comparable between DRL_RI and the reference products. CONCLUSION: DRL_RI, a proposed biosimilar, demonstrated three-way PK similarity with RTX-EU and RTX-US, the reference innovator products, with comparable efficacy, PD, safety, and immunogenicity. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02296775.

Influence of disease duration and socioeconomic factors on the prevalence of infection and hospitalization in rheumatoid arthritis: KRAC study.

AIM: The use of healthcare resources by rheumatoid arthritis (RA) patients can be related to the presence of disease, comorbid conditions, use of steroids, and the combined use of immunosuppressants. This study evaluated the risk factors associated with infection and hospitalization in RA. METHODS: This multicenter, cross-sectional study enrolled 3247 RA subjects fulfilling the 2010 American College of Rheumatology/European League Against Rheumatism criteria to examine the prevalence of hospitalization and episodes of documentable non-tubercular infections as a part of the "Karnataka rheumatoid arthritis comorbidity" study (KRAC). The study included 2081 subjects and 1166 were excluded due to incomplete data. Demographic, clinical and treatment variables were collected, and the events related to infections and hospitalization were extracted from the medical records. Comparative analysis and multivariate logistic regression were performed. RESULTS: Around 22% of the subjects had hospitalizations and 2.9% had infections. Infections were pertaining to dental (1.3%), urinary tract (1.6%) and candidiasis (0.2%). Skin- and soft tissue-related infections were found in 1.8% and 0.3% of patients, respectively. Increased need of hospitalization in RA patients was associated with advanced age (≥60 years), lower education, family income, and longer duration of RA. Presence of comorbidity, usage of three or more disease-modifying anti-rheumatic drugs (DMARDs) and family income influenced the likelihood of infection. Dental infections were less likely in working subjects and more likely in patients with increased disease duration, higher family income, comorbidities and those between the age group 40-59 years. Urinary tract infection was associated with DMARD usage. CONCLUSION: Patient-specific risk factors should be considered to improve treatment strategies and to reduce the risk of infection and hospitalization in RA patients.

Reciprocal regulation of pro-inflammatory Annexin A2 and anti-inflammatory Annexin A1 in the pathogenesis of rheumatoid arthritis.

Annexin A2 has been implicated in several immune modulated diseases including Rheumatoid arthritis (RA) pannus formation. The most relied treatment option for RA pathogenesis is glucocorticoids. Glucocorticoids regulate the synthesis, phosphorylation and cellular deposition of Annexin A1. This annexin mediates the anti-inflammatory actions of glucocorticoids. These two first characterized members of annexin superfamily proteins acts reciprocally, one as an anti-inflammatory and the other proinflammatory in nature. The possibility of these molecules as soluble biomarkers and as an upstream regulator of major cytokine devastation at RA microenvironment has not been previously explored. Current study elucidates the reciprocal regulation of these two annexins in RA pathogenesis. These Annexin A2/A1 and downstream cytokines in RA serum were analysed by ELISA. Western blot, Immunocytochemistry, immunoprecipitation and Immunohistochemistry were adapted to analyse these molecules in tissue and synovial fibroblasts and also in different experimental conditions. Significant increase in the level of Annexin A2 was noticed in naïve RA patients compared to controls (14.582 ± 1.766 ng/ml vs. 7.37 ± 1.450 ng/ml; p ≤ 0.001). In remission cases significant low levels was detected. On the contrary, significant decrease in the level of Annexin A1 was noticed in naïve RA patients compared to healthy controls (12.322 ± 2.91 vs. 16.998 ± 4.298 ng/ml; p ≤ 0.001), wherein remission cases serum Annexin A1 was significantly high. The knockdown of proinflammatory Annexin A2 by siRNA/antibody treatment could mimic the glucocorticoid treatment as which induced cellular Annexin A1 and membrane translocation resulting in the terminal action. Current data elucidating the regulatory interplay between Annexin A2 and Annexin A1 in RA pathogenesis.

Prevalence and Clinical Use of Anti-Thyroid Antibodies in RA Patients: A Prospective Case-Control Study.

Aim: To evaluate the prevalence of anti-thyroid antibodies in a cohort of rheumatoid arthritis (RA) patients from south India and their clinical use. Methods: A cross-sectional epidemiological study was conducted including 1217 patients aged more than 14 years with fever and thrombocytopenia admitted in the medical wards from October 2013 to September 2014. Detailed clinical examination and routine investigations were done; specific investigations like blood culture, widal test, antigen test for malaria, IgM ELISA leptospira, IgM ELISA dengue, bone marrow aspiration/biopsy etc. were done as and when indicated. The data are presented as percentage and numbers. Rates and ratios are computedThe prospective case-control study, conducted for 3 consecutive months in a tertiary care hospital based in India, evaluated 103 RA patients (active group) and 36 age-matched healthy controls without the disease. Both the control and active groups were compared for thyroid autoantibodies, and the clinical evaluation included assessment of swollen joint counts (SJC), tender joint counts (TJC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), pain scale, disease activity score (DAS), rheumatoid factor (RF), anti-nuclear antibody (ANA) and anti-cyclic citrullinated peptide (anti-CCP). The active group subjects were further subdivided into RA patients with and without hypothyroidism, and were compared for normal and abnormal levels of thyroid autoantibodies and the variations were statistically analysed. Results: The corresponding mean age of the subjects belonging to the active and control groups were 47.09±11.29 and 41.03±11, with a female to male ratio of 1:0.12 and 1:0.29 respectively. Among the various thyroid autoantibodies compared between the active and control groups, a significant correlation (P=0.00936) was observed for anti-TTG antibodies. Also, the study has noted a significantly elevated level of anti-TPO antibodies in RA patients with hypothyroidism compared to the group without hypothyroidism (P=0.0074). Conclusion: A significantly increased level of anti-TPO antibodies was noted in RA patients with hypothyroidism.

Factors influencing remission in rheumatoid arthritis patients: results from Karnataka rheumatoid arthritis comorbidity (KRAC) study.

AIM: To study the prevalence of remission in rheumatoid arthritis (RA) patients and the influence of different factors like literacy, socioeconomic status, presence of comorbidity and treatment strategy in achieving remission. METHODS: The study involved 1990 RA patients who were recruited for the Karnataka Rheumatoid arthritis comorbidity (KRAC) study. Based on the factors evaluated, the study participants were classified as follows: age, < 30 years, 30-39 years, 40-49 years, 50-59 years and ≥ 60 years; educational status, illiterate/no formal education, high school or less, graduate, post-graduate and doctorate; family income (₹ per annum), < 50 000, 50-100 000, 100-500 000, and > 500 000; duration of illness prior (DOIP): ≤ 6 months, 6-24 months, 24-120 months and > 120 months. Joint counts were performed by a rheumatologist or trained joint assessor. To assess the treatment outcome, the disease activity score was calculated using the Disease activity Score of 28 joints - erythrocyte sedimentation rate (DAS 28-3 ESR). RESULTS: As per the DAS 28-3 ESR score, around 20% (n = 397) of the study subjects achieved remission. The corresponding mean ± SD of DAS 28-3 ESR noted for remission and non-remission groups were 2.13 ± 0.42 and 4.32 ± 1.28. The majority of the patients were treated with double disease-modifying anti-rheumatic drugs (DMARDs) (60.7%). The likelihood of remission was found to be more in patients who reported DOIP ≤ 6 months. Furthermore, the chances of remission reduced with increase in patient's age and the highest remission rate was noted for 30-39 years age group (59%), followed by 40-49 years (35.4%) and 50-59 years (19.7%). CONCLUSION: The prevalence of remission noted was around 20%. Early treatment, escalating dose of DMARDs, and patient counseling are important contributing factors for attaining remission.

Granulomatosis with Polyangiitis (GPA) Mimicking Tuberculosis.

Granulomatosis with Polyangiitis (GPA) is a rare disease with varied clinical manifestations. We present a case of GPA which manifested initially with symptoms suggestive of meningeal tuberculosis. High index of suspicion and collective review of all clinical features helped in the correct diagnosis. Treatment of this case with rituximab provided significant symptomatic relief.

Annexin A2 and its downstream IL-6 and HB-EGF as secretory biomarkers in the differential diagnosis of Her-2 negative breast cancer.

Background AnnexinA2 (AnxA2) membrane deposition has a critical role in HB-EGF shedding as well as IL-6 secretion in breast cancer cells. This autocrine cycle has a major role in cancer cell proliferation, migration and metastasis. The objective of the study is to demonstrate annexinA2-mediated autocrine regulation via HB-EGF and IL-6 in Her-2 negative breast cancer progression. Methods Secretory annexinA2, HB-EGF and IL-6 were analysed in the peripheral blood sample of Her-2 negative ( n = 20) and positive breast cancer patients ( n = 16). Simultaneously, tissue expression was analysed by immunohistochemistry. The membrane deposition of these secretory ligands and their autocrine regulation was demonstrated using triple-negative breast cancer cell line model. Results Annexina2 and HB-EGF expression are inversely correlated with Her-2, whereas IL-6 expression is seen in both Her-2 negative and positive breast cancer cells. RNA interference studies and upregulation of annexinA2 proved that annexinA2 is the upstream of this autocrine pathway. Abundant soluble serum annexinA2 is secreted in Her-2 negative breast cancer (359.28 ± 63.73 ng/mL) compared with normal (286.10 ± 70.04 ng/mL, P < 0.01) and Her-2 positive cases (217.75 ± 60.59 ng/mL, P < 0.0001). In Her-2 negative cases, the HB-EGF concentrations (179.16 ± 118.81 pg/mL) were highly significant compared with normal (14.92 ± 17.33 pg/mL, P < 0.001). IL-6 concentrations were increased significantly in both the breast cancer phenotypes as compared with normal ( P < 0.001). Conclusion The specific expression pattern of annexinA2 and HB-EGF in triple-negative breast cancer tissues, increased secretion compared with normal cells, and their major role in the regulation of EGFR downstream signalling makes these molecules as a potential tissue and serum biomarker and an excellent therapeutic target in Her-2 negative breast cancer.

Reduced incidence of extra-articular manifestations of RA through effective disease control: Karnataka Rheumatoid Arthritis Comorbidity (KRAC) study.

AIM: To estimate the prevalence of extra-articular manifestations (EAM) in rheumatoid arthritis (RA) patients and the impact of demographic, clinical and treatment factors. METHOD: The study was carried out as a part of 'Karnataka Rheumatoid arthritis comorbidity (KRAC) study' conducted at 14 centers across Karnataka, India between September 2014 and July 2015. The data were collected by trained clinical research associates using a structured pro forma, under the supervision of the consulting rheumatologists. Based on the factors evaluated, the study participants were classified as follows: age, < 30 years, 30-39 years, 40-49 years, 50-59 years and ≥ 60 years; and duration of illness prior to visiting rheumatologist (DOIP), ≤ 6 months, > 6 months-2 years, 2-10 years and > 10 years. The Disease Activity Score of 28 joints-3 (erythrocyte sedimentation rate) score was calculated for each patient by three variable methods. RESULTS: The total number of patients considered for the study after exclusion was 1716. The subjects had a mean (SD) age of 48.1 (12.71) years, the male-to-female ratio was 1 : 5, and median (range) of duration of RA was 48 (0.5-484) months. The prevalence of EAM noted was around 13%. EAM were more likely during the first 2 years of the disease (odds ratio [OR]: 1.465; P = 0.047) and increased with longer DOIP. The incidence was less in patients with low disease activity (OR: 0.657) and worse with the presence of deformities (OR: 2.1). CONCLUSION: The study corroborates the current concept of effective disease control to reduce the incidence/likelihood of EAM in RA patients.

A prospective, randomized, double-blind, multicentre, parallel-group, active controlled study to compare efficacy and safety of biosimilar adalimumab (Exemptia; ZRC-3197) and adalimumab (Humira) in patients with rheumatoid arthritis.

AIM: In this study, efficacy, tolerability and safety of biosimilar adalimumab (Exemptia; Zydus Cadila) was compared with reference adalimumab (Humira; AbbVie) in patients with moderate to severe rheumatoid arthritis (RA). METHOD: In this multicentre, prospective, randomized, double-blind, active controlled parallel arm study, 120 patients with moderate to severe RA were given 40 mg of either test adalimumab (Exemptia) or reference adalimumab (Humira) by subcutaneous route every other week for 12 weeks. The primary endpoint was proportion of responders in two tretament groups by American College of Rheumatology 20 (ACR20) at week 12. The secondary endpoints were change in Disease Activity Score of 28 joints - C-reactive protein (DAS28-CRP) and proportion of patients with an ACR50 and ACR70 response in two treatment groups at week 12. Safety outcomes were also assessed. RESULTS: After 12 weeks, patients treated every other week with test adalimumab (Zydus Cadila) had statistically similar response rates as compared to reference adalimumab (AbbVie): ACR20 (82% vs. 79.2%; P > 0.7); ACR50 (46%, vs. 43.4%; P > 0.7); ACR70 (14% vs. 15.1%; P > 0.8). The change in DAS28-CRP score was -2.1 ± 1.09 and -2.1 ± 1.21, in test and reference products, respectively. It was statistically significant compared to baseline, but not significantly different between the two products. Three serious adverse events and no death was reported during the study. Both adalimumab preparations were safe and well tolerated in this study. CONCLUSION: The results demonstrated biosimilarity with respect to efficacy, tolerability and safety of test adalimumab (Exemptia) and reference adalimumab (Humira) in patients with moderate to severe RA.