Dr. Jeffrey Curtis
ACR CONVERGENCE 2021—The ACR Convergence 2021 meeting reflected the continued advancement of science and practical research in the field of rheumatoid arthritis (RA). Among the most important topics this year in RA was the evolution of the risk-benefit profile of Janus kinase (JAK) inhibitors, for which new safety data emerged in a series of related abstracts.
JAK RESEARCH
Results from the recently completed, worldwide, randomized, head-to-head comparison of a JAK inhibitor therapy (tofacitinib) vs. tumor necrosis factor (TNF) inhibitor therapy, adalimumab or etanercept, were reported in a series of four important presentations.
Abstract 0831: Safety and efficacy of tofacitinib vs TNF inhibitors in RA patients aged 50 years or older with one or more cardiovascular risks: Results from a phase 3b/4 randomized safety trial Research by Ytterberg SR, et al.1
The comparative safety of JAK inhibitor therapy on the pre-specified outcomes of major adverse cardiac events (MACE) and malignancy from the Oral Surveillance trial were unveiled for the first time. This trial fulfilled a regulatory requirement and was designed to demonstrate the non-inferiority of tofacitinib compared with adalimumab (in North America) or etanercept (in the rest of the world) in 4,362 patients randomized to tofacitinib 10 mg twice daily, 5 mg twice daily, or TNF inhibitor therapy.
For both MACE and malignancy outcomes, tofacitinib failed to meet the pre-specified non-inferiority outcomes. The risk (hazard ratio) of MACE events was 1.33 (95% confidence interval [CI] 0.91, 1.94) in tofacitinib-treated patients, a non-significant result that failed to meet the non-inferiority margin of 1.8. For malignancies, the risk was 1.48 (95% CI 1.04, 2.00), consistent with a significantly increased risk. The number of patients needed to be treated with tofacitinib for one year to result in one extra MACE event or malignancy (i.e., the number needed to harm; NNH) was 567 for MACE and 276 for malignancy.
These unexpected results had important implications from both a regulatory and practical perspective, and led to a label change the first week of December 2021 in the prescribing indications for tofacitinib and upadacitinib. These and existing JAK inhibitor therapies (e.g., baricitinib) for RA are now indicated only for patients who have failed at least one TNF inhibitor. New and updated Boxed Warnings in the revised label relate to further information outlined in the related abstracts below.
Abstract 0958: Risk factors for major adverse cardiovascular events in patients aged ≥50 years with RA and ≥1 additional cardiovascular risk factor: Results from a phase 3b/4 randomized safety study of tofacitinib vs TNF inhibitors2 Research by Charles-Shoeman C, et al.
Additional information contextualizing the risk for MACE events was presented from the same trial. Of particular importance to clinicians is to consider the generalizability of the results. More specifically, should clinicians’ concerns for MACE associated with JAK inhibitors apply to their prescribing for all RA patients?
In additional subgroup analyses reported in this abstract, MACE risk with tofacitinib appeared largely confined to higher risk individuals (e.g., age ³65 or those who ever smoked). Event rates in such individuals receiving tofacitinib were 13.1 per 1,000 patient years of exposure, compared with 9.3 per 1,000 patient years, a non-significant 1.41-fold increase (95% CI 0.93, 2.15). In contrast, individuals aged 50–64 and who never smoked were at much lower risk (4.1 per 1,000 patient years), no different than TNF inhibitor-treated patients who had a nearly identical risk, 4.2 per 1,000 patient years, HR 0.98 (95% CI 0.42, 2.31).
These results highlight the importance of patient selection in prescribing JAK inhibitor therapy. Importantly, they suggest that for patients with RA at lower risk for cardiovascular disease (CVD) events, the safety concerns for MACE with JAK inhibitors (rather than TNF inhibitors) may be minimal.
Abstracts 1940 & 19413,4
1940: Malignancies in patients aged ≥50 years with RA and ≥ 1 additional cardiovascular risk factor: Results from a phase 3b/4 randomized safety study of tofacitinib vs TNF inhibitors Research by Curtis J, et al. (Author’s note: I am an author on this abstract.)
1941: The risk of venous thromboembolic events in patients with RA aged ≥ 50 years with ≥ 1 cardiovascular risk factor: Results from a phase 3b/4 randomized safety study of tofacitinib vs TNF inhibitors Research by Charles-Shoeman C, et al.
For cancer, a hazard ratio of 1.48 (95% CI 1.04, 2.09) for all malignancies, excluding non-melanoma skin cancer (NMSC), and 2.02 (95% CI 1.17, 3.50) for NMSC were observed for tofacitinib compared with TNF inhibitors. However, as with the MACE considerations, patient selection remains paramount.
In the subgroup of lower risk individuals (i.e., aged 50 to <65, and never smoked), there was a low rate of malignancy (5.1 per 1,000 patient years) that did not differ from TNF inhibitors (HR 1.16, 95% CI 0.53, 2.55). Event rates for venous thromboembolism (VTE) were likewise low, particularly in those without a history of VTE: 3.1 per 1,000 in patients receiving 5 mg of tofacitinib twice daily. The NNH for VTE was 763 compared with TNF inhibitor therapy.
Taken together, this series of presentations highlights important safety concerns with JAK inhibitor therapy but should be interpreted in light of important considerations regarding generalizability. The trial intentionally recruited only patients with RA at high CVD risk; even in these higher risk individuals, it was only the patients at highest risk (e.g., those older than 65, current or former smokers, past VTE event) who experienced a risk that was greater than corresponding risks for TNF inhibitors. Despite the newly narrowed FDA indication and updated Boxed Warnings for JAK inhibitors, it is likely that many clinicians will still find JAK inhibitors to be an important option for many patients with RA, especially those without strong CV or VTE risk factors.
PREVENTION
Switching topics, the potential to prevent or delay progression to RA in at-risk but asymptomatic patients who may have subclinical disease is a topic of high interest. Rheumatologists and their patients likely would value treatment with demonstrable effectiveness for prevention.
Abstract 0957: Vitamin D and marine n-3 fatty acid supplementation and prevention of autoimmune disease in the VITAL randomized controlled trial5 Research by Hahn J, et al.
The association between vitamin D sufficiency and a reduced risk of incident autoimmune disease has been a long-observed phenomenon. However, past work supporting this association has suffered from non-interventional study designs, inadequately dosed vitamin D regimens (e.g., 400 IU/day) or concerns regarding the potential for substantial confounding.
The large-scale Vitamin D and Omega-3 Trial (VITAL), a U.S., double-blind, placebo-controlled trial, randomized men who were at least 50 years old and women who were at least 55 years old to vitamin D3 (2,000 IU/d) and/or n-3 fatty acids (1,000 mg/d) or placebo. This plenary presentation reported the effects of vitamin D3 and n-3 fatty acids upon the incidence of autoimmune disease. New-onset autoimmunity was reported by participants annually and then confirmed by medical record review by expert physicians for classification criteria.
During median follow-up of 5.3 years, confirmed autoimmune disease was diagnosed in 117 participants in the vitamin D3 group and 150 in the placebo group (HR 0.78, 95% CI 0.61–1.00, P=0.04). Confirmed autoimmune disease was diagnosed in 123 participants in the n-3 fatty acids group and 144 in the placebo group (HR 0.85, 95% CI 0.67–1.09). RA and polymyalgia rheumatic were among the more commonly occurring incident autoimmune conditions.
Results from this study provide new experimental evidence that sufficiently dosed vitamin D results in a lower risk for new-onset autoimmune conditions, and these findings likely represent an important public health message. This trial’s results may offer rheumatologists the opportunity to provide practical advice for those who may be concerned about developing autoimmune conditions in the future.
Abstract 0455: Abatacept reverses subclinical arthritis in patients with high-risk to develop rheumatoid arthritis—Results from the randomized, placebo-controlled ARIAA study in RA-at risk patients6 Research by Rech J, et al.
Given the potential for antibodies against citrullinated proteins (ACPA) to herald a sooner transition to manifest RA, the opportunity to abrogate or slow that progression may invite therapeutic intervention.
Patients who were ACPA positive with MRI signs of inflammation were randomized to receive subcutaneous abatacept for six months. Arthritis developed at a higher frequency of patients receiving placebo (34.7%) compared with those receiving abatacept (8.2%, P=0.0025).
Although some may argue that ACPA positivity and MRI-observed synovitis represent the forme fruste of RA, the potential benefit of abatacept to improve subclinical arthritis supports the concept that early intervention with abatacept may prevent, or at least delay, the development of RA.
COVID-19
COVID-19 continues to capture the attention of rheumatologists and patients alike. Although rituximab has been repeatedly recognized to be associated with a suboptimal response to COVID-19 vaccination, perhaps warranting a supplemental vaccine dose, the impact of other RA therapies on COVID-19 vaccination is less clear.
Abstract L02: COVID-19 vaccine in immunosuppressed adults with autoimmune diseases7 Research by Colmegna I, et al.
Results from this prospective, open label trial at two centers in Quebec of patients with seropositive RA on stable treatment for at least three months found that on average, patients with RA did not have significant side effects or disease worsening (i.e., flare) after vaccination. As observed previously, immunogenicity, measured by anti-spike antibodies and antibodies against its receptor binding domain, was poor in rituximab-treated patients (Note: Only 17.6% of patients responded after the second dose) and was numerically lower (i.e., 88%) in JAK inhibitor-treated patients. Biologic-treated patients had a robust immunogenicity in this study, although the response to specific biologic agents was not reported.
This study adds to growing evidence that COVID-19 vaccination is safe and generally well tolerated in patients with RA or other autoimmune diseases, albeit with some small risk for adverse events or flare. It also raises some concerns that other immunomodulators, such as JAK inhibitors, may attenuate COVID-19 vaccine response.
Abstract L18: Humoral and cellular immune responses to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: A cohort study8 Research by Mahil SK, et al.
Because immunomodulatory agents have potentially important implications on vaccine response for patients for RA or other disease indications (e.g., psoriasis, psoriatic arthritis), new data were presented on the influence of methotrexate (MTX). Patients with psoriasis (n=82) receiving MTX (n=14) or TNF inhibitors (n=19) all were shown to have seroconverted after the second vaccine dose. However, detectable T cell responses were lower in MTX-treated patients (62%, 95%CI 32–86) or targeted biologic users (74%, 95% CI 60–85%) compared with healthy controls (100%, P=0.022).
Although not an RA study, this study suggests that MTX and perhaps even some biologics may result in a suboptimal vaccine response. Although humoral responses (e.g., anti-spike antibody) appeared sufficient, measuring T cell response is likely important to assure that patients are adequately protected against SARS-CoV-2.
Abstract L17: Additional heterologous versus homologous booster vaccination in immunosuppressed patients without SARS-CoV-2 antibody seroconversion after primary mRNA vaccination: A randomized controlled trial9 Research by Bonelli M, et al.
Building on the theme of how to best manage patients who may have had a poor response to vaccination, this late-breaking abstract reported results on patients receiving rituximab who did not seroconvert following the second mRNA vaccination with either Pfizer or Moderna. These individuals were randomized to receive a supplemental dose with the same mRNA or a vector vaccine (ChAdOx1 nCoV-19, Oxford-AstraZeneca). Seroconversion rates at week 4 were numerically, albeit not a statistically significant amount, lower between those receiving a supplemental dose with the vector (6/27 patients, 22%) vs. the mRNA (9/28, 32%) vaccine (P=0.6). Overall, only 27% of patients seroconverted.
This study suggests that in rituximab-treated patients, an additional (supplemental) dose is warranted, although not all patients will respond to even a third dose. Although the study was too small to detect significant differences between which type of supplemental dose may be preferred, the 10% numeric difference between vaccine types suggests the mRNA vaccine may be preferable over a vector vaccine among those who mount a suboptimal primary response.
These results provide supportive evidence for the current guidance from the ACR COVID-19 Vaccine Task Force, which favors use of an mRNA vaccine over an adenoviral vector for supplemental vaccine dosing.
OTHER RESEARCH OF NOTE
Abstract L10: A randomized, double-blinded, placebo-controlled phase 2 study of the safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis interstitial lung disease10 Research by Solomon J, et al.
Managing the extra-articular manifestations of RA continues to challenge clinicians. Currently approved RA treatments sometimes, but not always, address the non-musculoskeletal manifestations of RA, such as interstitial lung disease (ILD).
The TRAIL1 trial recruited and randomized 123 patients with RA-ILD at 33 sites in 4 countries who had at least 10% fibrosis on high resolution CT (HRCT). The incidence of the composite in the decline of forced vital capacity or death was lower in pirfenidone-treated patients, 11 vs. 15%, odds ratio 0.57, (95% CI 0.22, 2.03). Annual change in FVC was lower in pirfenidone treated patients (–66 vs. –146 mL, P=0.0082). The findings were even more profound for those with the usual interstitial pneumonia (UIP) pattern seen on high-resolution computed tomography.
Although the trial was underpowered because recruitment was halted prematurely, with the COVID-19 pandemic offered as a partial explanation, it nevertheless offers hope that non-traditional RA therapies may confer benefit to slow or even halt the devastating manifestations of ILD that affect many RA patients.
Abstract 0982: B cells repertoire repartition predicts response to methotrexate at 6 and 12 months in naïve RA: A machine learning driven approach11 Research by Najm A, et al.
Enthusiasm abounds to use automated, data-driven approaches to predict treatment response coupled with advances in precision medicine. However, in RA, many datasets are too small for machine learning or artificial intelligence to be effectively used, or are conducted with minimal attention to replication and validation—an essential feature of any machine learning-based approach.
Peripheral blood leucocytes from early RA patients in the SERA cohort had their B cell repertoire measured as a predictive marker to response to MTX. Baseline levels of circulating IgD+ B cells clones were more frequent in responders compared with non-responders (P=0.004), whereas IgA1+ and IgA2+ clones tended to be more frequently represented in non-responders (P=0.069 and P=0.001 respectively). A gradient boosting statistical model showed the response to MTX could be predicted with a sensitivity of 78%, specificity of 79% and an area under the curve of 0.88, consistent with good discrimination.
Although further replication is warranted, this study is one of the first immunology-based prediction model for MTX and suggests that advanced machine learning methods may be useful to support precision medicine in RA. Those predicted to be non-responders to MTX may be targeted to start combination therapy, rather than MTX monotherapy, when RA therapies are first prescribed.
Jeffrey Curtis, MD, MS, MPH, is a professor of medicine and holds the Marguerite Jones Harbert—Gene Ball Endowed Professorship in Rheumatology and Immunology, in the Division of Clinical Immunology & Rheumatology at the University of Alabama at Birmingham (UAB). He is board certified in both rheumatology and clinical informatics. He is the co-director of the UAB Pharmacoepidemiology and Pharmacoeconomics Research (PEER) Unit.
In 2012, he was awarded the Henry Kunkel Young Investigator Award by the ACR) and was accepted into the American Society for Clinical Investigation (ASCI) in 2016. The evaluation of the efficacy, comparative effectiveness, and safety of the medications used to treat RA and spondyloarthritis are among Dr. Curtis’s research interests.
He served on the Core Expert Panel for the ACR’s 2008, 2012 and 2015 Recommendations for the Use of Nonbiologic and Biologic Disease Modifying Antirheumatic Drugs in RA. He was the deputy director for a collaborative project between the U.S. Food & Drug Administration (FDA), the Agency for Healthcare Research and Quality (AHRQ) and a number of academic centers studying the safety of biologic agents using multiple, pooled national data sources.
References
- Ytterberg S, Bhatt D, Mikuls T, et al. Safety and efficacy of tofacitinib vs TNF inhibitors in RA patients aged 50 years or older with one or more cardiovascular risks: Results from a Phase 3b/4 randomized safety trial [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
- Charles-Schoeman C, Buch M, Dougados M, et al. Risk factors for major adverse cardiovascular events in patients aged ≥50 years with RA and ≥1 additional cardiovascular risk factor: Results from a phase 3b/4 randomized safety study of tofacitinib vs TNF inhibitors [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
- Curtis J, Yamaoka K, Chen Y, et al. Malignancies in patients aged ≥50 years with RA and ≥1 additional cardiovascular risk factor: Results from a phase 3b/4 randomized safety study of tofacitinib vs TNF inhibitors [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
- Charles-Schoeman C, Fleischmann R, Mysler E, et al. The risk of venous thromboembolic events in patients with RA aged ≥ 50 years with ≥ 1 cardiovascular risk factor: Results from a phase 3b/4 randomized safety study of tofacitinib vs TNF inhibitors Arthritis Rheumatol. 2021;73(suppl 10).
- Hahn J, Cook N, Alexander A, et al. Vitamin D and marine n-3 fatty acid supplementation and prevention of autoimmune disease in the VITAL randomized controlled trial Arthritis Rheumatol. 2021;73(suppl 10).
- Rech J, Ostergaard M, Tascilar K, et al. Abatacept reverses subclinical arthritis in patients with high-risk to develop rheumatoid arthritis—Results from the randomized, placebo-controlled ARIAA study in RA-at risk patients Arthritis Rheumatol. 2021;73(suppl 10).
- Colmegna I, Useche M, Rampakakis E, et al. COVID-19 vaccine in immunosuppressed adults with autoimmune diseases [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
- Mahil S, Bechman K, Raharja A, et al. Humoral and cellular immune responses to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: A cohort study [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
- Bonelli M, Mrak D, Tobudic S, et al. Additional heterologous versus homologous booster vaccination in immunosuppressed patients without SARS-CoV-2 antibody seroconversion after primary mRNA vaccination: A randomized controlled trial [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
- Solomon J, Woodhead F, Danoff S, et al. A randomized, double-blinded, placebo-controlled, phase 2 study of safety, tolerability and efficacy of pirfenidone in patients with rheumatoid arthritis interstitial lung disease [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
- Najm A, Sarda S, Toro M, et al. B cells repertoire repartition predicts response to methotrexate at 6 and 12 months in naïve RA: A machine learning driven approach [abstract]. Arthritis Rheumatol. 2021;73(suppl 10).
