ICI Arthritis Tied to Cancer Progression Save

Cancer patients treated with immune checkpoint inhibitors (ICI) who develop severe arthritis may be at risk for progression of the malignancy, a single-center study suggested.

Almost 90% of patients treated with ICI develop immune-related adverse events, which can include pulmonary, gastrointestinal, dermatologic, and rheumatic events. Arthritis has been reported in almost 4%, with the most common presentation being a rheumatoid arthritis (RA)-like phenotype characterized by small-joint involvement.

In a cohort of 42 patients with ICI arthritis whose baseline Clinical Disease Activity Index (CDAI) was 15 and who were followed for a median of 7.4 months, the median time to arthritis onset was 2.8 months, according to Karmela Kim Chan, MD, of the Hospital for Special Surgery in New York City, and colleagues.

In a multivariable analysis that adjusted for time to onset of arthritis after initiation of ICI therapy and for the use of disease-modifying antirheumatic drugs (DMARDs), each one-point increase in baseline CDAI was associated with a 9% increase in the likelihood of cancer progression (HR 1.09, 95% CI 1.00-1.19, P=0.05), the researchers reported online in ACR Open Rheumatology.

Immune checkpoint inhibitors are increasingly being used to treat various types of cancer, and have been shown to prolong survival, even in some patients with metastatic disease. "ICI target inhibitor molecules, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and/or programmed cell death-1 (PD-1) or its ligand, PD-L1, blocking pathways that normally serve to protect the body from excessive immune cell activation," they explained.

Patients being treated for cancer at Memorial Sloan Kettering Cancer Center or NewYork Presbyterian Hospital/Cornell who develop ICI-associated arthritis were fast-tracked to be seen at the Hospital for Special Surgery within a week, where a registry of these patients was established in 2018.

Among the 42 patients included in this analysis, mean age was 65, and slightly more than half were women. The most common types of cancer were melanoma, in 33%, non-small cell lung cancer in 17%, and renal cancer in 17%. Most were stage IV.

At baseline, median erythrocyte sedimentation rate was 29 mm/h, C-reactive protein was 1.1 mg/dL, and 27% were positive for rheumatoid factor or cyclic citrullinated peptide antibodies.

The arthritis was of the RA small-joint phenotype in 62%, primarily involved the large joints in 9%, was arthralgia without swelling in 17%, and a polymyalgia rheumatica-like pattern in 12%.

Baseline CDAI was highest in the small-joint subgroup, at 22.3, representing high disease activity, compared with 11 in the large-joint group, 6 in the arthralgia group, and 11.5 in the polymyalgia group, which were low to moderate scores for disease activity. Most patients with small-joint involvement received the PD-1 monotherapy, whereas most patients with large-joint involvement were given combination therapy with PD-1 plus CTLA-4.

In the first 60 days, median prednisone dose was 15 mg/day. Conventional DMARDs were given to 36% (most often hydroxychloroquine), biologics were given to 5%, usually tumor necrosis factor inhibitors, and both DMARDs and biologics were used by 14%. ICI treatment was discontinued by 48% of patients, in 5 because of joint pain and in 15 for other reasons including progression of the cancer. By 6 months, 69% of patients had persistent arthritis, as did 58% at 12 months.

Cancer outcomes included complete responses in 26%, partial responses in 12%, stable disease in 29%, and progression in 33%.

Comparison of patients who progressed with nonprogressors found no differences in age, sex, race, type of cancer, seropositivity, or arthritis phenotype. Progressors did, however, have a shorter time to the onset of arthritis, at a median of 2 months versus 4.1 months (P=0.05), and more often had received a DMARD (77% vs 42%, P=0.04). In a univariate analysis, patients who progressed had a higher baseline CDAI (OR 1.11, 95% CI 1.02-1.20), which remained statistically significant in the multivariate analysis.

The observation that most patients had the RA-like phenotype and had received PD-1/L1 inhibitors was "of interest," the researchers wrote. "There is evidence that PD-1 inhibition mimics the biology of RA," they wrote. In one study, "a nivolumab (anti-PD-1) gene signature was demonstrated in peripheral blood mononuclear cells from patients with active RA," and PD-1 expression is upregulated in the synovium with active RA, they noted.

Currently, treatment decisions are made in consultation with the patient, rheumatologist, and oncologist, with the choice to use a DMARD often being influenced by the necessity of tapering steroids, which can have an adverse impact on cancer outcomes. Hydroxychloroquine was the most commonly used DMARD in this cohort, because of its perceived safety and also its ability to limit autophagy.

Few data are available on choosing among biologics for patients with severe, persistent arthritis. Some studies have shown efficacy for infliximab (Remicade) for ICI-associated enterocolitis, but one report suggested that this medication had a negative impact on cancer survival in patients experiencing severe toxicities.

"Untangling the relationship between ICI-arthritis disease severity (e.g., CDAI), ICI-arthritis treatment (e.g., TNF inhibitors), and cancer survival will be critical to the development of safe treatment approaches," the researchers concluded.

A limitation of the study was its relatively small number of patients.

Source Reference: Chan K, et al "Higher checkpoint inhibitor arthritis disease activity may be associated with cancer progression: Results from an observational registry" ACR Open Rheum 2020; DOI: 10.1002/acr2.11181.