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11 Articles in Volume 21, Issue #1
Advanced Practice Matters with Theresa & Jeremy: Mentorship
Ask the PharmD: What is a true opioid allergy?
Behavioral Medicine: How Clinicians Can Reduce the Stigma Attached to Chronic Pain
Chronic Headache: How to Conduct a Virtual Neurological Examination
COVID-19 Long Haulers: A Look at Cardiovascular Risk
How COVID Has Changed Pain Practice and Policies
How to Conduct a Pain Evaluation Using Telemedicine
Inside the Potential of Biologics for the Treatment of Rheumatoid Arthritis
Managing Pain in Parkinson’s Disease
Spinal Cord Stimulation Shown to Improve Pain and Movement in Parkinson’s Disease
TeleRheumatology Before and During the COVID-19 Pandemic

Inside the Potential of Biologics for the Treatment of Rheumatoid Arthritis

Olokizumab and otilimab could prove to be valuable treatment options for patients with moderate or high RA disease activity and who have been refractory to other approaches.

Pathophysiology and Presentation of RA

There is no known specific cause of rheumatoid arthritis (RA), which is believed to result from a mix of both genetic and non-genetic factors combined with a triggering event. Based on epidemiologic studies, genes in the human leukocyte antigen (HLA) system are thought to play a role as are genetics in general based on some familial studies. Environmental factors may also be associated with RA and include cigarette use, coffee consumption, obesity, and occupational hazards.1

Inflammatory pathway dysregulation is associated with RA, and multiple factors in this pathway contribute to its development. T cells present with a high allele expression of HLA and CD 27 in patients with RA, increasing affinity for lymphokines. When activated, T cells stimulate B cells, producing autoantibodies and osteoclasts that destroy bone.

It is known that macrophages triggered by the immune system can stimulate T cells and osteoclasts, thereby increasing inflammation. Fibroblasts may also appear, which promote downstream bone degradation and further production of proinflammatory cytokines. Through these mechanisms, activated T cells and macrophages release factors that lead to tissue destruction and increased blood flow, and result in invasion of cells into the synovial tissue and joint fluid causing inflammation.2-4

The presentation of rheumatoid arthritis varies in patients depending on the location of their inflammation. Joint involvement typically occurs in hands, wrists, ankles, and feet. Elbows, knees, shoulders, hips, cervical spine, and temporomandibular joints are affected less commonly. Patients generally report warmth and swelling, with or without pain, in the affected areas. Prolonged morning stiffness is common as well, as is decreased overall functionality. For instance, pain and swelling often affect grip strength and range of motion at the joint.

If left untreated, long-term inflammation can lead to deformities, subluxations, and bony erosions.5

Editor's Note: See also how anxiety and psychiatric disorders can affect people with rheumatoid arthritis.

ACR Guidelines

The most current American College of Rheumatology (ACR) guidelines recommend that treatment for RA be approached based on the patient’s disease activity and prior therapies. The ACR advises that patients typically begin pharmacological treatment with DMARD monotherapy, using agents such as hydroxychloroquine, methotrexate, and sulfasalazine. Based on disease activity, if there is a lack of response to initial therapy patients may then progress to DMARD combinations, TNF inhibitors, or non-TNF biologics, with or without methotrexate.6


Investigational Drugs

Investigational drugs for RA are currently targeting immune-mediated pathways. Two biologics – olokizumab and otilimab – are in Phase III trials in the United States. A third drug, secukinumab, was being studied but the research was terminated due to discontinuation of its development for this indication. Below is the latest data on the two biologics.


Olokizumab (R-Pharm)  works as a monoclonal antibody that blocks the IL-6 cytokine. Blocking the IL-6 cytokine may benefit patients as IL-6 is a mediator in inflammatory processes including T cell activation, B cell proliferation, and osteoclast differentiation. Ongoing Phase III trials are evaluating the use of olokizumab in patients taking either methotrexate or a TNF alpha inhibitor but are still having active disease.

Safety and efficacy tests in a Phase IIb study evaluated in 221 patients with inadequate response to TNF inhibitor therapy.7 The trial, conducted from 2010 to 2012, evaluated subcutaneous olokizumab in patients with moderate to severely active RA who had previously failed TNF inhibitor therapy and had an inadequate response to methotrexate. Patients were assigned to one of nine groups, two were placebo groups at various dosing frequencies, six were olokizumab at various doses and frequencies, with the last group receiving tocilizumab (Actemra, Genentech) 8 mg/kg every four weeks. Patients were required to be on a stable dose of methotrexate before the study and continued the drug throughout.

The primary efficacy endpoint was the change in C-reactive protein levels at week 12 with secondary endpoints evaluating ACR20/50/70 at week 12 between olokizumab and placebo. The study found across all groups treatment with olokizumab resulted in a greater improvement in C-reactive protein mean change from baseline to week 12 compared to placebo. The greatest improvement was in the olokizumab 240 mg every 2 weeks group with a -2.01 mean change compared to placebo change of -0.78, P < 0.0001. This was similar to the change in C-reactive protein the tocilizumab group experienced.

This study was not powered to detect significant differences in ACR20/50/70 response rates; however, the number of responses were higher for ACR20 and ACR50 than placebo at 12 weeks. At 12 weeks 5.0% to 33.3% of participants in the placebo group had an ACR20 response, while 33.3% to 75.0% of the olokizumab group did, with ACR20 highest in the 60 mg every 4 weeks group. When comparing ACR50 response at 12 weeks, 0% to 4.8% of patients in the placebo groups had an ACR50 response, while the olokizumab groups had an ACR50 response ranging from 14.3% to 37.5% with the highest response in the 60 mg every 4 weeks group. Overall results showed improvement in the efficacy variables when compared to placebo in patients with moderate-to-severe RA, and the results support further studies to assess its use.7

The number of treatment-emergent adverse events ranged from 63.6% to 87.0% in the olokizumab group, with similar numbers in the placebo and tocilizumab groups. Common side effects in the olokizumab group included diarrhea, headache, and injection site reactions, occurring in 17.4% to 47.8% of participants, compared with 20.9% in the tocilizumab group, and 18.2% in the placebo group. Infections including upper respiratory tract infections, urinary tract infections, and nasopharyngitis occurred in the olokizumab and placebo groups at 25.0% to 36.4% and 31.8% to 50.0% respectively.

Due to the fact that adverse events were only measured for 12 weeks, the long-term adverse effects of olokizumab are not known.7Longer clinical trials in a larger group of patients may show long-term adverse effects and whether the benefits of olokizumab outweigh its risks.


Otilimab works by binding to GM-CSF, which becomes neutralized and prevents binding to its targeted inflammatory cells, preventing proliferation and activation. This mechanism prevents inflammation through mechanisms such as TNF-alpha, IL-1, and IL-6. Current Phase III trials are evaluating both long-term safety and efficacy of otilimab, as well as the use of otilimab versus placebo and sarilumab in patients with active RA who have an inadequate response to DMARDs or JAK inhibitors. Final published results from a Phase IIb study conducted in patients with active RA are unavailable but exploratory analyses have been presented.8

The trial, conducted from 2015 to 2017, evaluated the safety and efficacy of otilimab plus methotrexate in patients with active moderate to severe RA who previously failed methotrexate therapy. Participants were assigned to one of six treatment groups, one being placebo plus methotrexate, and the other five being various dosing strengths of otilimab administered subcutaneously plus methotrexate.

Treatment was administered once weekly for 5 weeks, then every other week until Week 12. Participants' baseline pain was assessed using the visual analog scale (VAS) on a spectrum from 1 to 100. Participants had a mean VAS score of 67 at baseline, and the pain was assessed at each visit until week 12. At Week 12, it was found that that otilimab 90 mg had the largest difference in change from VAS baseline compared to placebo at -7.07 vs. -25.25 (95% CI -28.35 to -8.01).

Results were also assessed using the minimal clinically important difference (MCID). Participants in otilimab groups had a larger MCID compared to placebo at Weeks 4 and 8, with the greatest difference at Week 8. The percent difference to placebo at Week 8 ranged from 15% to 40% with the largest difference in the otilimab 135-mg group. Results showed a significant reduction in mean VAS score in the otilimab group when compared to placebo, supporting further studies to assess its use in this population.8 A drawback of this exploratory analysis is that safety was not assessed. Without safety, it is not possible to assess the utility, as adverse events may outweigh the clinical benefits of the drug. Final results will need to be published from this study, including safety analyses, before clinical value in patients suffering from active RA symptoms can be assessed.



While trials of olokizumab and otilimab are recruiting participants and will be ongoing, their possible place in future clinical practice is important. Olokizumab represents a medication that could become another treatment option for patients who have failed TNF inhibitor therapies, which is extremely beneficial in patients typically presenting with moderate or high disease activity. Otilimab may be a treatment option for those with moderate to high disease activity and represents a medication with a novel mechanism. This medication could be used instead of other non-TNF biologics currently recommended, including abatacept, rituximab, or tocilizumab.

While too early to decide their therapeutic role for rheumatoid arthritis, the potential for new treatment options in patients with moderate or high disease activity is valuable as patients with prior treatment failures may benefit. Data from Phase III trials will hopefully shed light as to how well these drugs work in larger populations while assessing any major safety concerns patients may experience during use.

Last updated on: May 11, 2021
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