TNF inhibitor

It’s a TNF Inhibitor! It’s a Steroid! It’s Two (Potential) RA Drugs in One!

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Hints in mid-stage trial that novel conjugate will surpass adalimumab in efficacy

A computer rendering of antibodies approaching an inflamed joint

A novel drug conjugate combining steroidal and tumor necrosis factor (TNF) inhibitor activity appeared highly effective in a phase IIa trial as a treatment for rheumatoid arthritis (RA).

Patients with active RA assigned to the product, called ABBV-3373, showed responses after 12 weeks that were at least as good as seen with the leading approved TNF inhibitor, adalimumab (Humira), according to Frank Buttgereit, MD, of Charité University Medicine in Berlin, and colleagues.

With changes in the 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) as the primary outcome, scores declined 2.65 points among 31 patients receiving ABBV-3373, compared with a decrease of 2.13 points in a historical cohort of 242 adalimumab-treatment patients (P=0.02), the researchers reported in Arthritis & Rheumatologyopens in a new tab or window.

Another 17 patients in the trial were randomized to adalimumab, and this group showed a mean decline in DAS28-CRP of 2.51 points, which did not differ significantly from the ABBV-3373 group.

Buttgereit and colleagues estimated from these data that ABBV-3373 had a probability of superiority over adalimumab of 79.3%-99.5%.

The most notable safety finding with the novel intravenous agent was one case of anaphylactic shock. Following this incident, investigators increased the infusion duration from 3 minutes to 15-30 minutes, with no more anaphylaxis cases occurring.

Both ABBV-3373 and adalimumab are AbbVie products, and the latter serves as the new agent’s anti-TNF backbone. The steroidal activity comes from “a proprietary glucocorticoid receptor modulator,” Buttgereit and colleagues explained.

The idea, they added, is that the combined molecule will gravitate selectively to activated immune cells expressing TNF, “thus increasing overall efficacy, while minimizing systemic exposure to the [steroidal component].” It’s hoped that this mechanism will cut incidence of the adverse effects known to come with long-term steroid treatment, while improving on adalimumab’s efficacy; the phase IIa trial was conceived to prove the conceptopens in a new tab or window.

To be eligible, patients needed DAS28-CRP scores of at least 3.2 plus at least four swollen and at least four tender joints, indicating moderate-to-severe disease activity, despite taking maximal doses of methotrexate. Past use of biologic or other targeted RA drugs was an exclusion.

ABBV-3373 was given at 100 mg IV along with subcutaneous placebo every other week; the adalimumab control group received IV placebo plus 80 mg of the active drug by subcutaneous injection every other week. Methotrexate was continued in both groups. The historical adalimumab-treated cohort was drawn from three prior trials involving the same dosage and with DAS28-CRP scores available.

Outcome measures included other DAS28-based values, ACR50 response rates (50% decline in symptoms by American College of Rheumatology criteria), physician and patient global RA assessments, and overall health status. The trial also included a 12-week extension, during which the ABBV-3373 group was switched to placebo while those assigned to adalimumab continued with it.

Mean patient age was about 52, and three-quarters were women. DAS28-CRP values at baseline averaged 5.6 in the two randomized arms and 6.5 for the historical controls. Other indicators all confirmed that the patients had moderate to severe symptoms.

Although changes in DAS28-CRP showed rough equivalence and potential superiority for ABBV-3373 versus adalimumab, ACR50 responses did not. Some 65% of patients assigned to adalimumab reached this benchmark at week 12 compared with 52% of the ABBV-3373 group (P not reported). Other secondary outcomes, though, did indicate comparable efficacy with the two agents.

Efficacy was generally maintained in both groups during the extension period as evaluated with DAS28-CRP and most other outcome measures.

Safety findings couldn’t be definitive with only 48 participants in the study. Other than the anaphylactic reaction, however, no major safety issues emerged in the trial. Overall adverse events were less common with ABBV-3373 than with adalimumab (37% of patients vs 75% through week 24) and only one very mild case of liver enzyme elevation (alkaline phosphatase more than 1.5 times the upper limit of normal) was seen with the novel agent. Two serious infections were observed in the ABBV-3373 group, with none in the adalimumab arm. One patient in each group quit the study because of adverse events.

Despite the favorable results, this is probably the end of the line for ABBV-3373 because, as Buttgereit and colleagues noted, AbbVie has since developed a “slightly modified” version called ABBV-154 that is suitable for subcutaneous injection. Phase II studies with this improved product are now underway in RAopens in a new tab or window, polymyalgia rheumaticaopens in a new tab or window, and Crohn’s diseaseopens in a new tab or window. Results could begin to appear as soon as next year.

TNF inhibitor use in juvenile idiopathic arthritis triples risk for psoriasis

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Exposure to TNF inhibitors nearly triples the risk for psoriasis among children with juvenile idiopathic arthritis, according to data published in the Annals of the Rheumatic Diseases.

“Previous studies have reported the increased risk for new-onset of psoriasis in children with JIA, inflammatory bowel disease and non-bacterial osteomyelitis (CNO) from a single Children’s Hospital, as well as a prevalence of nearly 3% in these children from another tertiary children’s hospital,” Yongdong Zhao, MD, PhD, RhMSUS, of the Seattle Children’s Research Institute, told Healio.

RH0222Zhao_Graphic_01
Exposure to TNF inhibitors nearly triples the risk for psoriasis among children with JIA, according to data derived from Zhao Y, et al. Ann Rheum Dis. 2022;doi:10.1136/annrheumdis-2021-221694.

“However, the association between TNF inhibitors and subsequent psoriasis in JIA has not been systematically assessed using a large prospective clinic-based registry, such as the Childhood Arthritis and Rheumatology Research Alliance (CARRA),” he added. “This large-scale dataset offers the advantage of safety surveillance for pediatric rheumatic medications such as TNF inhibitors.”

To analyze the association between TNF inhibitors and new-onset psoriasis in children with JIA, Zhao and colleagues studied data from the CARRA Registry. According to Zhao, the CARRA Registry features data from more than 10,000 children with rheumatic disease, including more than 9,000 with JIA, across more than 70 sites in North America. The researchers included patients with JIA and follow-up data who were enrolled from June 30, 2015, to Jan. 1, 2020. Those with documented IBD or psoriasis on or before their JIA diagnosis, or with incomplete data, were excluded.

Zhao_Yongdong_2022

Yongdong Zhao

In all, the researchers included 8,225 patients, with a median follow-up of 3.9 years, in their analysis. Among these, 4,437 received TNF inhibitors. Exposure to TNF inhibitors was characterized as either “ever use,” recorded from first use until psoriasis outcome or more recent visit date irrespective of ongoing use or discontinuation; “current use,” recorded from first use and continued for as long as the patient received the drug; or “first use only,” recorded from first use and continues until first use ended.

The researchers determined adjusted HRs between exposed and unexposed groups, adjusting for methotrexate use, sex, race, family history of psoriasis and initial JIA category.

According to the researchers, the adjusted HR for new-onset psoriasis following ever exposure to TNF inhibitors was 2.93 (95% CI, 2.15-3.98). The psoriasis incidence rate was the highest among children who ever received, and were actively receiving, adalimumab (Humira, AbbVie). Meanwhile, ever concurrent MTX use (HR = 0.45; 95% CI, 0.29-0.69) was associated with lower risk for psoriasis.

“We observed a three-fold increased risk for psoriasis in children with JIA after TNF-inhibitor exposure and an adjusted HR of 5.6 in the non-psoriatic arthritis subset,” Zhao said. “There was no association between family history or race/ethnicity and psoriasis development.

“However, concurrent use of methotrexate was significantly associated with a lower risk for psoriasis in those without psoriatic subtype of JIA,” he added. “Clinicians should educate patients and families about potential unwanted side effects while taking medications and inquire about symptoms during regular visits. Concurrent methotrexate use can be considered to lower the risk.”

Making Rational Treatment Decisions in Rheumatoid Arthritis When Methotrexate Fails.

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Advances in the treatment of rheumatoid arthritis in recent years have profoundly muted the destructive potential of this disease. The safety profile of methotrexate has made earlier treatment possible, and biologic therapies have opened the door to combination rather than sequential therapy, with the result that treatment recommendations now aim for disease remission.1,2 However, the evidence base guiding the treatment that should be given after a patient has an inadequate response to methotrexate monotherapy is weak, despite the armamentarium of efficacious agents.

O’Dell et al. now report in the Journal the results of their randomized clinical trial evaluating the safety and efficacy of adding sulfasalazine and hydroxychloroquine to methotrexate (triple therapy) as compared with adding etanercept (a tumor-necrosis-factor [TNF] receptor) to methotrexate in patients with rheumatoid arthritis who have active disease.3 If the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating greater disease activity) had not decreased by at least 1.2 units at 24 weeks, patients were switched in a blinded fashion to the alternative regimen. The primary outcome — the difference between the two groups in the change in the DAS28 at 48 weeks — showed the noninferiority of triple therapy to etanercept–methotrexate. The progression of radiographic joint damage (as assessed with the use of the van der Heijde modification of the Sharp score, which ranges from 0 to 380, with higher scores indicating more extensive disease) over 48 weeks also did not differ significantly between the groups (an increase of 0.54 Sharp score units in the triple-therapy group and 0.29 Sharp score units in the etanercept–methotrexate group, P=0.43). These results are certainly encouraging, but several caveats must be considered.

The noninferiority margin chosen by O’Dell et al. (0.6) is half the minimum clinically meaningful improvement of 1.2 in the DAS28, but justification that this margin is acceptable to clinicians and patients is not provided. This may be a moot concern, since improvement with triple therapy as compared with improvement with etanercept–methotrexate was much closer than 0.6. Furthermore, Table S2 in the Supplementary Appendix of the article (available with the full text of the article at NEJM.org) shows each component of the DAS28 improving similarly in the two regimens, suggesting equivalent efficacy across the DAS28 domains. Figure S2 in the Supplementary Appendix of the article indicates that the proportions of patients who continued with the originally assigned regimen and of patients who switched to the alternative regimen were similar in the two groups, as were the proportions of patients who withdrew or were lost to follow-up and of patients who completed the study — further reducing concerns that missing data or poor implementation biased the results toward a finding of noninferiority. Since a noninferiority margin was not specified for the secondary outcomes, the reader cannot determine whether P values for these outcomes, such as radiographic progression, identify triple therapy as noninferior to etanercept–methotrexate.

The study by O’Dell et al. is not the first to compare these treatment regimens. In the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study, patients were randomly assigned to methotrexate monotherapy, triple therapy, or methotrexate plus etanercept.4 No significant difference in the primary outcome (the change in DAS28 scores from week 48 to week 102) was observed between the two combination-treatment groups — similar to the results in the study by O’Dell et al.; however, the Sharp scores for radiographic progression increased more in the triple-therapy group than in the methotrexate–etanercept group (1.69 vs. 0.64, P=0.046). In the Swedish Pharmacotherapy (Swefot) study, in which patients who had not had an adequate response to methotrexate were randomly assigned to triple therapy or to infliximab (an anti-TNF antibody) plus methotrexate, the superiority of infliximab–methotrexate with respect to a good response according to European League against Rheumatism (EULAR) criteria was observed at 12 months but not at 18 or 24 months.5,6 The Sharp scores for radiographic progression increased more in the triple-therapy group than in the infliximab–methotrexate group (7.23 vs. 4.00, P=0.009) — a finding consistent with that in the TEAR study.

There are considerable methodologic differences across the studies. The study by O’Dell et al. and the TEAR study were double-blind studies that included observed data without imputation of missing data and used etanercept as the biologic therapy, whereas the Swefot study was not a blinded study, included persons who, for any reason, did not have a measurable response, and used infliximab as the alternative therapy to triple therapy. The Swefot and TEAR studies targeted early disease, whereas O’Dell et al. targeted established disease. The inclusion and exclusion criteria also varied among the studies. Even so, the results were remarkably consistent. The efficacy rates at the extended time points, as well as the frequencies of total and serious adverse events, were relatively similar with the two treatment regimens in all the studies. The TNF inhibitor–methotrexate regimen showed modest superiority over triple therapy in slowing radiographic progression, although the trend in the study by O’Dell et al. was not significant.

We have to consider, however, whether these findings have arrived too late to influence modern practice, in which arguably a TNF inhibitor is the preferred next step when methotrexate alone is inadequate.7,8 Whether third-party payers who currently require failure of methotrexate monotherapy before prescription of expensive biologic therapy will change this policy to require failure of the cheaper nonbiologic combination is an interesting question. The development of more affordable biosimilar agents may change the treatment choices yet again,9 potentially rendering the studies with nonbiologic agents cited above irrelevant. We hope that with the ever-increasing number of effective treatments for rheumatoid arthritis, future recommendations for treatment will be guided by additional comparative-effectiveness studies such as the study by O’Dell et al. In addition, future identification of biomarkers to identify the patients who are most likely to have a response to, or are least likely to have side effects with, specific therapies will be the next great leap in the treatment of rheumatoid arthritis.

 

Source: Editorial, NEJM

Long-Term Benefits and Risks of Methotrexate in Crohn Disease.

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In patients previously treated with thiopurine, risk for adverse reaction was low with methotrexate monotherapy, but so was the rate of sustained response.

In treating patients with Crohn disease, clinicians typically use anti–tumor necrosis factor (anti-TNF) agents and the immunomodulatory agents azathioprine and 6-mercaptopurine before methotrexate. Gastroenterologists tend to be concerned about the long-term risks of methotrexate, including liver fibrosis, although recent studies suggest that the risk for cirrhosis is considerably lower than previously thought. Now, investigators have retrospectively assessed the long-term response and safety of methotrexate for Crohn disease.

The study cohort of 174 patients (mean age, 35 years; median disease duration, 4 years) received intramuscular methotrexate monotherapy following thiopurine therapy, with 23% also having received but not responded to anti-TNF therapy. Patients received 25 mg of methotrexate weekly, eventually tapering to 15 mg. The most common indication was intolerance of a thiopurine (55%), followed by clinical failure of thiopurines (24%), failure of anti-TNF monotherapy (9%), and failure of combination anti-TNF agents and thiopurines (12%). A sustained clinical benefit was defined as ongoing use of methotrexate or intentional discontinuation of successful therapy (e.g., in anticipation of pregnancy) prior to the end of study.

Patients intolerant of thiopurine were more often intolerant of methotrexate than were patients in whom methotrexate was initiated for thiopurine failure (22 vs. 6). The rate of sustained clinical benefit of monotherapy methotrexate was 86% at 6 months; 63% at 12 months; 47% at 24 months; and 20% at 60 months. The most common reasons for discontinuation were adverse reaction (56%; most frequently GI complaints and general malaise, including fatigue, fever, dizziness, and headache); loss of response (38%); and primary nonresponse (5%). No liver biopsies were taken, and only 6% of discontinuations were for asymptomatic increases in liver enzymes.

Comment: This study indicates that when used in patients with thiopurine failure in Crohn disease, methotrexate has a low risk for adverse reactions, but also a relatively low long-term sustained response rate.

 

Source: Journal Watch Gastroenterology