A Year to Remember: Dr. Jinoos Yazdany Presents the 2020 Clinical Research Review

ACR Convergence 2020—2020 is a year that will not soon be forgotten—for many reasons. But even amidst a pandemic, notable advances in clinical rheumatology are a silver lining for the year. During the ACR Convergence 2020 Clinical Year in Review session, Jinoos Yazdany, MD, MPH, Alice Betts Endowed Professor and chief of rheumatology, Zuckerberg San Francisco General Hospital, University of California, San Francisco, discussed the highlights of these past 12 months and the ways in which numerous studies and discoveries will shape treatment changes in years to come.

Dr. Yazdany

TULIP-2 Results
With regard to systemic lupus erythematosus, Dr. Yazdany discussed a phase 3, randomized, controlled trial of anifrolumab, a human monoclonal antibody to type 1 interferon receptor, published this year.¹ As readers may recall, a prior study involving anifrolumab (the Treatment of Uncontrolled Lupus via the Interferon pathway [TULIP] 1 study) did not show a significant effect on the primary end point of the Systemic Lupus Erythematosus Responder Index (SRI) 4, which is a composite of changes in three scales.² This was disappointing because a phase 2 trial of this medication had shown promising results.³

However, in the TULIP 2 study, the authors used the British Isles Lupus Assessment Group (BILAG) based Composite Lupus Assessment (BICLA) as the primary endpoint to evaluate more than 360 patients with moderate or severe active lupus. Patients were randomized to receive anifrolumab or placebo, and those with severe renal or central nervous system involvement were excluded from the study. Whereas SRI-4 requires complete resolution within a particular item to register change and, therefore, does not capture partial improvements, the BICLA can register partial and complete improvement within an organ system, noted the authors.

The TULIP 2 study showed 48% of patients who received a monthly administration of anifrolumab had a BICLA response, compared with 31.5% in the placebo group.¹

Dr. Yazdany said these studies indicate that trial endpoints of lupus studies can make a big difference, and it remains challenging to identify which endpoints to use. Also, large trials with years of endpoint scrutiny and planning are needed to identify the optimal treatments for lupus patients.

Practically speaking, the TULIP trials also indicate that—if approved by the U.S. Food & Drug Administration—anifrolumab may become a treatment option for patients with active lupus who do not have severe renal or central nervous system disease.

Tapering Glucocorticoids
Next, Dr. Yazdany discussed the theme of optimizing glucocorticoid dosing and safety in the treatment of rheumatologic diseases.

In the Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS) study, patients in both the plasma exchange and no plasma exchange arms were further randomized to a standard glucocorticoid tapering regimen or a low-dose glucocorticoid regimen.⁴ The latter regimen ensured all patients were tapered to 10 mg/day or less of prednisone by week 14. The low-dose glucocorticoid regimen proved non-inferior to the standard-dose group with regards to the primary composite outcome of death from any cause or end-stage kidney disease. Additionally, patients in the low-dose group had fewer infections (27% vs. 33%) over one year of follow-up.

Similarly, a retrospective cohort study of more than 200,000 patients with rheumatoid arthritis receiving stable disease-modifying anti-rheumatic drugs (DMARDs) for more than six months showed the treatment of patients with glucocorticoids was associated with a dose-dependent increase in the risk for serious infection, with small but significant risks even at doses of 5 mg or less per day.⁵

Dr. Yazdany said these trials illustrate that it’s worthwhile to evaluate how quickly glucocorticoids can be tapered in the treatment of certain conditions without sacrificing efficacy. Additionally, even low doses of glucocorticoids can be associated with adverse events clinicians should seek to avoid.

Maintenance Therapy
Dr. Yazdany went on to discuss the emerging evidence for different maintenance therapies in two conditions: axial spondyloarthritis (axSpA) and vasculitis.

In the C-OPTiMise trial, more than 300 patients with early axial axSpA who had achieved sustained remission with certolizumab after a 48-week run-in period were randomized to receive either 200 mg of certolizumab every two weeks or tapered to 200 mg of certolizumab every four weeks vs. placebo. This study found patients were able to safely reduce their treatment from every two weeks to every four weeks without a statistically significant increase in the number of disease flares. Meanwhile, stopping treatment did lead to a significantly increased risk of flare.⁶

For vasculitis, the MAINRITSAN clinical trials have yielded helpful insights into sustaining remission in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides. MAINRITSAN 1 showed patients receiving maintenance therapy with rituximab were more likely to have sustained remission compared with those maintained on azathioprine.⁷ MAINRITSAN 2 showed relapse rates did not differ significantly between patients receiving a fixed-schedule rituximab regimen for maintenance therapy (500 mg on days 0 and 14, followed by 500 mg at months 6, 12 and 18 after the first infusion) and those receiving an individually tailored regimen of rituximab (500 mg at randomization, followed by reinfusion only when CD19+B lymphocytes or ANCA had reappeared or ANCA titer rose markedly based on trimestrial testing until month 18).⁸ 

MAINRITSAN 3 was published in 2020. In the study, 68 patients with granulomatosis with polyangiitis and 29 patients with microscopic polyangiitis in remission were randomized to receive rituximab every six months or placebo. At 28 months of follow-up, flare-free survival was 96% in the rituximab arm and 74% in the placebo arm, with flares more common in patients with antibodies to proteinase 3.⁹

Dr. Yazdany explained that trials like these will continue to be important, guiding clinicians on when to consider tapering treatment for their patients and what to expect when doing so.

COVID-19
Given the COVID-19 pandemic, Dr. Yazdany spent time highlighting research on rheumatic medications that have been in the spotlight as possible treatment for this disease.

In summarizing the substantial body of emerging literature on this topic, Dr. Yazdany noted dexamethasone is the only commonly used rheumatologic medication, thus far, that has shown a survival benefit for COVID-19 patients. She said hydroxychloroquine has failed to demonstrate efficacy for treatment of hospitalized COVID-19 patients and those in outpatient settings. Additionally, it has not proved to be an effective prophylactic treatment for the disease. Finally, it remains to be seen if Janus kinase inhibitors (Jakinibs) and anti-interleukin 6 receptor treatments improve outcomes in COVID-19 patients when these immunomodulating agents are combined with steroids.

Jason Liebowitz, MD, completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his medical degree. He is currently in practice with Skylands Medical Group, N.J.

References

1. Morand EF, Furie R, Tanaka Y, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020 Jan 16;382(3):211–221.
2. Furie RA, Morand EF, Bruce IN, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): A randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019 Dec 1;1(4):e208–e219.
3. Furie R, Khamashta M, Merrill JT, et al. Anifrolumab, an anti-interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376–386.
4. Walsh M, Merkel PA, Peh CA, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med. 2020 Feb 13;382(7):622–631.
5. George MD, Baker JF, Winthrop K, et al. Risk for serious infection with low-dose glucocorticoids in patients with rheumatoid arthritis: A cohort study. Ann Intern Med. 2020 Dec 1;173(11):870–878.
6. Landewé RB, van der Heijde D, Dougados M, et al. Maintenance of clinical remission in early axial spondyloarthritis following certolizumab pegol dose reduction. Ann Rheum Dis. 2020 Jul;79(7):920–928.
7. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014 Nov 6;371(19):1771–1780.
8. Charles P, Terrier B, Perrodeau É, et al. Comparison of individually tailored vs. fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: Results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann Rheum Dis. 2018 Aug;77(8):1143–1149.
9. Charles P, Perrodeau É, Samson M, et al. Long-term rituximab use to maintain remission of antineutrophil cytoplasmic antibody-associated vasculitis: A randomized trial. Ann Intern Med. 2020 Aug 4;173(3):179–187.