Title: Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE)-like Syndrome
after Immune Checkpoint Inhibition: a CanRIO Study

Authors: Azin Rouhi, Shahin Jamal, Marie Hudson, Janet Pope, Janet Roberts, Alexandra
Ladouceur, Sara Hewitt, Carrie Ye

Background:
Immune checkpoint inhibitors (ICI) have shown great promise in the treatment of different
malignancies. The use of ICIs has been associated with toxicities that are referred to as immune
related adverse events (irAE). Rheumatologic irAEs, such as inflammatory arthritis and
inflammatory myositis, have been described. Remitting seronegative symmetrical synovitis with
pitting edema (RS3PE) is a condition characterized by pitting edema in the distal extremities in
addition to findings of synovitis on exam with negative serology for RF. RS3PE has been
described as a paraneoplastic syndrome in association with solid organ tumors. To date, nine
case reports of RS3PE-like syndrome (RS3PE-LS) in association with ICI have been reported in
the literature. In one case, the patient received both ICI and a tyrosine kinase inhibitor, while in
another case, the patient received ICI and a poly (ADP-ribose) polymerase inhibitor. We present
a series of 10 patients, who developed RS3PE-LS after starting on ICI.

Methods:
The Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO) database, which
includes a large prospective cohort of oncology patients on ICI therapy across Canada, was
reviewed for all cases of RS3PE-like reactions. Data including the type of malignancy, ICI
therapy, clinical manifestations, time of onset and response to treatment were assessed.

Results:
Ten patients, who received ICI therapy for malignancy and presented with RS3PE-LS were
identified (Table 1). The mean age of the patients was 72.9 years and 6/10 were women. The
median time from start of ICI therapy to presentation with RS3PE-LS was 26 weeks, while the
median time from the diagnosis of malignancy to onset of RS3PE-LS was 63 weeks. None of the
patients had heart failure, liver cirrhosis or nephrotic syndrome. Seven out of 10 patients had
stable cancer on imaging prior to onset of RS3PE-LS, while 2 had partial response and 1 was in
complete remission. Pitting edema and synovitis was present in all patients. Symmetric
involvement of joints was observed in 8/10 patients. Nine patients had negative serology, while
1 patient had positive RF. Eight out of 10 patients received prednisone as first line therapy. The
remaining two were already on hydroxychloroquine (HCQ) for inflammatory arthritis prior to
RS3PE-LS, of which one was treated with prednisone after the development of pitting edema
and the other received intra-articular steroid injection into the ankles. Two patients were
started on a conventional synthetic DMARD (cs-DMARD) at the time of prednisone initiation
(1Methotrexate (MTX), 1 HCQ). Nine out of 10 patients required additional cs-DMARD for
management of their RS3PE-LS. Seven patients were continued on ICI or re-started on ICI after
it was held, of which 3 patients remained in remission on cs-DMARD, 3 flared on DMARD and
one flared off DMARD or prednisone therapy. Three patients had completed their course of ICI
therapy prior to onset of RS3PE-LS.

Conclusion:
RS3PE-like syndrome is a potential complication of ICI therapy. RS3PE-LS can flare after re-
initiation of ICI. Current management varies widely and optimal treatment remains to be
determined.