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5 Articles in this Series
ACR Releases Updated Draft Guidelines for Juvenile Idiopathic Arthritis (JIA)
Debate: When Methotrexate Fails – The Use of JAK or TNF Inhibitors
Pharmacotherapy & Rheumatic Disease in Older Adults
Rheumatoid Disease Therapy and Immunological Complications
When Rheumatoid Arthritis Treatment Gets Difficult: 3 Cases Offer Potential Solutions

Rheumatoid Disease Therapy and Immunological Complications

An ACR Convergence 2020 Meeting Highlight with Anne Sofie Sorensen, Tiphaine Lenfant, MD, and Valentin S. Schafer, MD


Immunological complications of rheumatoid arthritis therapy can make clinical decisions around treatment more difficult. In an ACR 2020 Convergence panel, experts reviewed inflammatory arthritis in the context of immune checkpoint inhibitors, including a look at the safety of the recombinant zoster (shingles) vaccine and cancer tumor response in patients with rheumatic disease.

Clues to Inflammatory Arthritis & Checkpoint Inhibitors

Immune checkpoint inhibitors (CPIs) are a class of drugs that have been shown to effectively manage many cancers by disrupting the signaling pathways that inhibit immunity against cancer, but these promising therapies can also cause immune-related adverse events. For example, their use can not only unmask the presence of rheumatoid arthritis (RA) but may also cause flares, said Anne Sofie Sorensen, a medical student at Aarhus University in Denmark.

The immunological mechanisms are not fully understood, she said. Her team developed an in vitro model to characterize inflammatory arthritis associated with checkpoint inhibitors. Specifically, they studied monocyte activation (MCP-1 production) and differentiation after treatment with pembrolizumab (Keytruda). They investigated whether tumor necrosis factor (TNF) inhibitors and interleukin (IL)-6 inhibitors can inhibit pembrolizumab-induced inflammation, hypothesizing that monocytes are important in the development of immune-related adverse events. (See our TNF primer.)

Sorensen’s team used the MCP-1 as a marker of inflammatory response. They found that use of pembrolizumab increased MCP-1 production in intermediate but not classical monocytes. The pembrolizumab induced the expression of TNF but not IL-6. “Taken together,” she said, “these findings could imply that TNF but not IL-6 is important in pembrolizumab-induced inflammation.”

Is the Shingles Vaccine Safe In Individuals with Rheumatoid Arthritis?         

Patients with immune-mediated inflammatory diseases (IMID) are known to have a higher risk of developing herpes zoster as are those on immunosuppressants. So, questioned Tiphaine Lenfant, MD, a clinical research fellow at Cleveland Clinic, are patients with rheumatic disease at higher risk of flare after receiving a recombinant zoster (shingles) vaccine (RZV)?

She and a team of researchers at the Clinic evaluated 622 rheumatology patients to find out. Their retrospective, single-center study utilized EMR data. All patients in the sample had at least one dose of RZV during the period of February 2018 to May 2020. The median age of the sample was 67 and 67% were female; 77% had both doses of RZV. The median follow-up was 36 weeks.

The team examined the patients’ outcome regarding any reported flares after vaccination. Of the 359 IMID subjects, they had diagnoses of:

Among the total sample, 16% (59) flared after receiving the RSV; most flares occurred after the first dose with a median time to flare of 31 days. Patients with RA had a higher rate of flare, with 1 in 4 reporting outbreaks. To manage flares, half were given glucocorticoids, a quarter  change in immunosuppressant therapy.

On further evaluation of the EMRs, only glucocorticoid use at the time of vaccination remained significantly associated with flares (OR=2.31, P=0.004), Dr. Lenfant said.  Her conclusion: “Use of RZV appears safe in IMID patients,” as only mild flares were common in the first 12 weeks after the vaccine. Of note, if a patient had a flare after the first dose, it seemed to boost their risk of having a flare after the second dose as well.

Immune Checkpoint Inhibitors & Adverse Events

In a related presentation, Valentin S. Schafer, MD, head of rheumatology at University Hospital, Bonn, Germany, presented results of a retrospective study of 437 cancer patients, treated with immune checkpoint inhibitors including:

  • ipilimumab (Yervoy) – anti-CTLA-4 blocking antibody
  • nivolumab (Opdivo) – a PD-1 inhibitor
  • pembrolizumab – a PD-1 inhibitor
  • a combination of ipilimumab and nivolumab

Patients were observed from 2014 to 2019. Median age was 66 overall, with nearly 60% male. Researchers evaluated rheumatic immune-related adverse events, non-rheumatic immune-related adverse events (AEs), and cancer tumor response.

Nineteen (19) of the 437 patient sample developed at least one rheumatic immune-related adverse event. This included 5.3% on nivolumab, 5% on pembrolizumab, 2.6% on ipilimumab, and none on the combination of ipilimumab and nivolumab. Three of the 19 had pre-existing rheumatological diseases. Of these, the median onset of the adverse event was 109 days and the events included arthralgia only, arthritis, myositis, and myalgia.

Six of the 19 discontinued the immune checkpoint inhibitor therapy due to the adverse events.

In addition, 153 of the 437 had at least one non-rheumatic immune-related adverse event, including rash, colitis, hepatitis, vitiligo, and other issues. 

As for tumor response, 94.4% of those with rheumatic immune response AEs responded to the therapy, while lower percentages of those with non-rheumatic immune-related AEs (62.4%) and those without immune-related AEs (31.2%) did. Rheumatic immune-related AEs were associated with a significantly improved tumor response, Dr. Schafer said. As to why that was found protective, he cannot say. Research is ongoing.


In a recent report on the management of rheumatic complications of immune checkpoint inhibitors in oncology patients, Steven and Fisher wrote that oncologists and rheumatologists must work together. They concluded, “Treatment should be offered on balance of risk and benefit, including whether to continue CPI treatment and recognizing the uncertainty over whether glucocorticoids and DMARDS might compromise cancer control.”


Disclosures: Dr. Schafer reported a role on the speakers’ bureau for Novartis, AbbVie, Lilly, Pfizer and others; is an advisor for Novartis, AbbVie, Sanofi, Lilly, and others.



Calabrese, LH. Rheumatic immune-related adverse events from cancer immunotherapy. National Rev Rheum, 2018;14(10):569-579.

Brahmer JR, Lacchetti C, Schneider B. Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714-1768.

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