Shawn Yee, Mercer University College of Pharmacy
Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints. Disease-modifying antirheumatic drug (DMARD) therapy, such as methotrexate (MTX) is commonly used for the treatment of RA. However, for patients unresponsive or refractory to this therapy, a newer treatment with monoclonal antibodies (mAb) is being further studied. 
One of the proposed underlying mechanisms of RA includes the activity of interleukin-6 (IL-6) in the joints, where higher levels of IL-6 is associated with joint damage and inflammation. [1,2] Therefore, inhibiting the activity of IL-6 with drug therapy is thought to improve RA symptoms and overall disease progression.  Previous studies analyzing the effect IL-6 receptor antagonism with monoclonal antibodies such as tocilizumab and sarilumab found success with improving RA outcomes, and showed reduction in RA symptoms, improved physical function and reduced the rate of RA progression. [3,4,5,6]
In a previous phase II trial, sirukumab (selective IL-6 cytokine human mAb), showed efficacy in patients refractory to MTX therapy.  The phase III trial is summarized below. 
|Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study|
|Design||Global, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III trial; N= 1,670|
|Objective||Evaluate the efficacy and safety of sirukumab in rheumatoid arthritis (RA) patients who are refractory to disease-modifying antirheumatic drugs (DMARDs)|
|Methods||Patients from 18 countries were randomized in a 1:1:1 ratio into each treatment group. There was screening period for up to six weeks, a treatment period for 104 weeks, and safety follow-up for 16 weeks. The Sharp/van der Heijde score (SHS) was used to analyze radiographic data of joints to determine degree of damage, with higher scores indicating narrowing of joint space. The health assessment questionnaire disability index (HAQ-DI) scoring was calculated from patient answers to the questionnaire, and scores ranged from zero (no disability) to three (complete disability). Disease Activity Score 28 joints C-reactive protein (DAS28-CRP) calculator was used to evaluate RA disease severity. The disease improvement data was monitored with the American College of Rheumatology (ACR) response criteria, with ACR20 indicating 20% improvement.
|Duration||July 2012 to September 2015|
|Primary Outcome Measure||
|Adverse Events||Common Adverse Events (≥ 5% frequency with sirukumab treatment groups): elevated liver enzymes, upper respiratory tract infection, bronchitis, nasopharyngitis, injection site erythema and pruritus, leukopenia, neutropenia, headache, and hypertension|
|Serious Adverse Events:
Sirukumab 50 mg every four weeks: 11.0% total (7 deaths, serious infection 4.1%, gastrointestinal perforation in one patient)
Sirukumab 100 mg every two weeks: 9.8% total (3 deaths, serious infection 3.3%)
Placebo: 6.8% total (one death, serious infection 1.8%, one gastrointestinal perforation)
|Percentage that Discontinued due to Adverse Events:
Sirukumab 50 mg every four weeks: 8%
Sirukumab 100 mg every two weeks: 7.7%
|Study Author Conclusions||Both sirukumab treatment groups (100 mg every two weeks and 50 mg every four weeks) provided significant reduction in RA symptoms as well as RA progression for patients refractory to DMARD treatment. Both doses provided similar effectiveness and provided an improved quality of life with an acceptable safety profile.|
This study provides data for multiple outcomes on the use of sirukumab for RA treatment and affirms the conclusion from the previous phase II trial where patients experienced improvement in RA symptoms. Patients in the sirukumab treatment groups showed a decrease in RA progression as seen by radiographic data (SHS) and an improvement in overall RA symptoms (HAQ-DI, ACR criteria, and DAS28-CRP).  However long term efficacy as well as safety and tolerability remains to be seen with sirukumab injections. There were several common adverse events (≥ 5%) in this study such as elevated liver enzymes, upper respiratory infections, hypertension and bronchitis that are of concern. Also the rates of death and serious infections are higher in the sirukumab treatment groups, which should be taken into consideration.
Moderate to severe RA patients who are refractory to ≥ 1 DMARD treatment (azathioprine, MXT, sulfasalazine, etc.) were included in this study, and based on the data, this patient population may benefit from sirukumab treatment. However, the burden associated with cost and bi-weekly or monthly injections should be considered by patient and provider, as well as the uncertain long-term effects of sirukumab treatment.
 Takeuchi T, Thorne C, Karpouzas G, et al. Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study. Ann Rheum Dis. 2017;76(12):2001-2008.
 Flannery CR, Little CB, Hughes CE, et al. IL-6 and its soluble receptor augment aggrecanase-mediated proteoglycan catabolism in articular cartilage. Matrix Biol 2000;19:549–53.
 Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008;67:1516–23.
 Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010;69:88–96.
 Nishimoto N, Hashimoto J, Miyasaka N, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis 2007;66:1162–7.
 Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol 2015;67:1424–37.
 Smolen JS, Weinblatt ME, Sheng S, et al. Sirukumab, a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis 2014;73:1616–25.