How Much Prednisone Is Too Much in Treating Rheum Effects From Cancer Therapies?

Overall survival is significantly shortened for cancer patients receiving more than 20 mg of prednisone (or the equivalent) at any point to treat arthritic side effects from immune checkpoint inhibitors (ICIs), a researcher said here.

Records from 103 such patients treated during 2015-2024 at a major French hospital showed more than doubled overall mortality risk (HR 2.35, 95% CI 1.18-4.69) with a peak daily prednisone-equivalent dose >20 mg, compared with patients never receiving that much, according to Eleonore Mourre, MD, of Hôpital Bicêtre in Paris. Moreover, patients receiving high doses didn't see any better control of their arthritic symptoms.

Cumulative doses, however, did not significantly affect survival, and progression-free survival was not markedly shortened either by peak doses >20 mg nor large cumulative doses, Mourre told attendees at the European Alliance of Associations for Rheumatology's (EULAR) annual meeting.

Immune-related adverse effects (irAEs) from ICIs are a major headache in oncology. The products have come as close to wonder drugs in oncology than could have been imagined 20 years ago, at least for those tumor types that respond to them. ICIs work by essentially removing the blindfolds on immune cells that tumor cells are able to put on them, allowing them to go after cancers that have avoided attack. Dramatically lengthened survival, both overall and progression-free, has been documented. The problem is that the newly unleashed immune cells don't always limit their attack to the tumors. Autoimmune syndromes are common -- often mild, though not always, and usually requiring treatment. And inflammatory arthritis is one such irAE.

For the current study, Mourre and colleagues identified patients treated with corticosteroids for ICI-related arthritic symptoms at Hôpital Bicêtre and its affiliated cancer center over a 10-year period after ICI therapy became available. Patients suspected of having mechanical joint problems or flares of underlying, previous autoimmune arthritis were excluded. Steroid doses given during the first 6 months after symptom onset were analyzed along with patients' overall and progression-free survival. Steroids' effectiveness in relieving the symptoms was examined as well.

Median patient age was 65 and 40% were female. Some 41% of patients had melanoma and 22% non-small cell lung cancer; oropharyngeal, kidney, and bladder cancer accounted for 11%; and the rest had "other" tumor types. Two-thirds of the patients received a so-called PD-1 inhibitor such as pembrolizumab (Keytruda), while most of the rest had been treated with a combination of anti-PD-1 and anti-PD-1-ligand drugs.

Half of the arthritic conditions resembled polymyalgia rheumatica. Another 30% showed polyarthritis. Inflammation affecting one or a few joints was diagnosed in the remainder. One-third of cases were grade 1, 48% grade 2, and 19% grade 3.

The median peak steroid dose was right at 20 mg (interquartile range 15-40), and the median aggregate dose over 6 months was 1,361 mg (IQR 683-1,950). Some 45% eventually had a disease-modifying anti-rheumatic drug added, usually methotrexate, less often tocilizumab (Actemra). The median time to start steroid dosing was 35 days from symptom onset.

One-year mortality was markedly higher for those patients receiving a peak dose above 20 mg during that 6-month period: about 50%, versus less than 15% for those not getting that much. After the 1-year mark, Kaplan-Meier survival curves declined in parallel for another year, then began to converge; at 4 years, the gap was only about 10 percentage points, with 14 patients still alive.

Kaplan-Meier curves for cumulative dosing, comparing patients above versus below the median of 1,360 mg, also showed a numeric mortality disadvantage for those with higher doses -- a maximum of about 25 percentage points at year 3 -- but it did not reach statistical significance (P=0.13).

Curves for peak doses >20 mg versus less showed almost no difference in progression-free survival: numerically lower by a few percentage points with high peak doses but not even close to statistical significance.

Meanwhile, Mourre emphasized, giving patients doses above 20 mg didn't improve their chances of arthritis remission. Their analysis showed a hazard ratio of 0.84 (P=0.28) for achieving remission among patients getting peak doses >20 mg.

Mourre acknowledged the single-center design and small sample size were limitations to the analysis. Data were also lacking on reasons for giving high steroid doses, although she said it was clear that steroids were meant to treat the irAEs, not the cancers.

 

 

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Risk of new heart problems jumps after Covid; mRNA shot side effects no different for cancer patients

The following is a summary of some recent studies on Covid-19. They include research that warrants further study to corroborate the findings and that has yet to be certified by peer review.

Risk of new heart problems much higher after Covid recovery

Long after recovery from Covid-19, people face significantly higher risks for new heart problems, a large study has found.

Researchers at the US Department of Veterans Affairs compared rates of new cardiovascular problems in 153,760 individuals infected with the coronavirus before vaccines were available, 5.6 million people who did not catch the virus, and another 5.9 million people whose data was collected before the pandemic. An average of one year after their recovery from the acute phase of the infection, the Covid-19 survivors had a 63% higher risk for heart attack, a 69% higher risk for problematic irregular heart rhythm, a 52% higher risk of stroke, a 72% higher risk of heart failure, and a nearly three times higher risk of a potentially fatal blood clot in the lungs compared with the other two groups, according to a report published on Monday in Nature Medicine. The elevated risks among former Covid-19 patients were evident in young and old, Blacks and whites, males and females, people with and without diabetes and with and without kidney disease, as well as smokers and nonsmokers, said Ziyad Al-Aly of the VA St. Louis Health Care System and Washington University in St. Louis.

The risks were high even in people who had mild Covid-19 and did not need to be hospitalized for it, he noted in a Twitter thread. "It really spared no one," Al-Aly told Reuters. "People with Covid-19 should pay attention to their health and seek medical care if they experience symptoms like chest pain, chest pressure, palpitation, swelling in the legs, etc."

mRNA vaccine side effects no worse in cancer patients

Covid-19 vaccines using mRNA technology do not produce any extra short-term side effects in cancer patients, a new study suggests.

Researchers surveyed 1,753 recipients of two doses of the Pfizer (PFE.N)/BioNTech vaccine, about two-thirds of whom had a history of cancer and about 12% of whom were receiving chemotherapy, immunotherapy, radiation therapy or surgery for their disease. More than 90% of the cancers involved solid tumors. The Pfizer vaccine has been shown to work well in such cases. People with and without cancer reported similar rates of pain at the injection site, muscle pain, joint pain, fever, chills, headache, nausea, and fatigue, the research team reported in the Journal of the National Comprehensive Cancer Network. Overall, post-vaccination symptoms were reported by roughly 73% of patients regardless of whether they had cancer, with pain at the injection site being the most common adverse event.

Earlier studies have found vaccine hesitancy among cancer patients, the researchers noted. The harms of Covid-19 are "compounded for patients with cancer who have refused vaccination," they said. "Our data, in combination with those from other sources, show that the mRNA Covid-19 vaccine is well tolerated by patients with a history of cancer, including those receiving active treatment."

Omicron's route into cells helps explain symptom profile

The Omicron variant's method of infecting cells is different from the mechanism most often used by earlier SARS-CoV-2 variants, which could help explain Omicron's milder symptom profile, a study published in Nature suggests.

Earlier variants use the ACE2 protein on cell surfaces and an enzyme called TMPRSS2 to fuse themselves to the cell membrane and inject their genetic material inside. Omicron prefers to enter cells by creating tiny sacs in the cell membrane called endosomes that cells use to transport materials internally, researchers found. Omicron still attaches itself to ACE2 proteins, but it does not need help from TMPRSS2. In fact, Omicron multiplies most readily in tissues where TMPRSS2 is scarce, such as the nose. In the lungs, where TMPRSS2 is plentiful, Omicron has spread less effectively and caused less damage than earlier variants.

The findings help explain "why the disease is less severe and causes less pneumonia" with Omicron, said Dr. Ravindra Gupta of the Cambridge Institute of Therapeutic Immunology and Infectious Diseases in the UK. Gupta also noted that drugs targeting TMPRSS2, such as camostat mesylate, a pancreatitis treatment that has shown some benefit in Covid-19 patients, may be less useful with Omicron.

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