Nivolumab induced remitting seronegative symmetrical synovitis with pitting edema in a patient with melanoma: a case report

Abstract

Background: Novel immune checkpoint inhibitors have been often utilized for different types of malignancies as salvage therapy with varying success. One obstacle to immune checkpoint inhibitor use is the higher incidence of immune-mediated side effects that can prompt discontinuation of therapy. Remitting seronegative symmetrical synovitis with pitting edema has been described with immune checkpoint inhibitors only once previously. We report a case of a patient who developed remitting seronegative symmetrical synovitis with pitting edema related to immune checkpoint inhibitor therapy and stress that these symptoms can be managed without cessation of immune checkpoint inhibitor therapy. Case presentation: We present a 70-year-old white man who presented with 4 months of progressive inflammatory arthritis with pitting edema. He had been started on nivolumab therapy for his metastatic melanoma with excellent response prior to symptom onset. The symptoms started in his knees and subsequently involved both hands and feet. On evaluation, he was wheelchair bound and completely dependent for all activities of daily living. Evaluation revealed negative serological testing and plain film imaging. Ultrasound demonstrated diffuse flexor tenosynovitis and soft tissue swelling, and a diagnosis of remitting seronegative symmetrical synovitis with pitting edema was made. He was treated with orally administered corticosteroids (0.5 mg/kg per day) which improved his symptoms significantly and allowed him to regain prior independent functioning. His corticosteroids were tapered (0.15 mg/kg per day) but not discontinued and his nivolumab treatment was not interrupted. In follow up he continued to have stable control of his melanoma as well as his remitting seronegative symmetrical synovitis with pitting edema. Conclusions: In conclusion we present the first case of nivolumab-induced remitting seronegative symmetrical synovitis with pitting edema that is controlled by maintenance low-dose orally administered corticosteroids allowing for continuation of nivolumab therapy. Clinicians who encounter mild-to-moderate immune checkpoint inhibitor immune-mediated adverse effects can consider maintaining immune checkpoint inhibitor therapy with concomitant low-dose corticosteroids rather than abrupt cessation of the immune checkpoint inhibitor.

Rheumatic Manifestations in Patients Treated with Immune Checkpoint Inhibitors

“…Besides the criteria-fulfilling RA patients, who tested all positive for rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (CCP) antibodies, the other cases were mostly seronegative. Case reports of remitting seronegative symmetrical polyarthritis with pitting edema (RS3PE) [16][17][18][19] and patients with a reactive arthritis (ReA)-like syndrome with concurrent urethritis and conjunctivitis [20] extend the spectrum of clinical phenotypes. A study by Cappelli et al [21] provides interesting data linking combination ICI therapy with a more severe disease course and distinct clinical features compared to anti-PD1/PDL1 monotherapy.…”

RS3PE Following Treatment With Combination of Hormonal Therapies Plus Ipilimumab in a Patient With Metastatic Prostate Cancer

“…Symptoms developed 1 week to 18 months after the initiation of ICI therapy, and RS3PE responded well to steroids. ICIs were either continued [14,16,17] or withheld, [13,15,18] and in two of the three cases in which ICIs were withheld, RS3PE did not recur after resumption of ICIs. [13,17] Our case has distinct clinical features when compared with the cases reported so far.…”

“…To the best of our knowledge, six cases of RS3PE have been reported so far [13][14][15][16][17][18] (Table 1). Patients were receiving either a PD-1/PD-L1 inhibitor (n ¼ 4) or Table 1.-Previous cases of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) reported in the literature (extended on the next page).…”

“…Ngo et al [14] Metastatic melanoma Nivolumab and ipilimumab for 6 weeks followed by nivolumab monotherapy…”

Management of immune checkpoint inhibitor‐related adverse events: A review of case reports

“…Most patients required discontinuation of therapy completely for a short period of time as well as immunosuppressant treatment. (32) Vitiligo (1), granuloma annulare (2), bullous pemphigoid (3), psoriasis (22), erythema multiforme (1), lichenoid reaction (2), Grover's disease (1) Endocrinologic (52) Type 1 diabetes mellitus (38), hypophysitis (9), isolated adrenal insufficiency (1), thyroid storm (2), hypothyroidism (2) Gastrointestinal (47) Acute liver failure (1), hepatitis (8), bile duct obstruction (1), cholangitis (1), pancreatitis (1), hemorrhagic gastritis (1), ileitis (1), colitis (32), intestinal obstruction (1) Pulmonary (11) Organizing pneumonia (5), sarcoidosis (2), pneumonitis (4) Neurologic (20) Myasthenia gravis (5), Guillain-Barre syndrome (3), cerebral edema (1), necrotizing encephalopathy (1), encephalitis (2), mononeuropathy multiplex with rhabdomyolysis (1), necrotic myelopathy (1), Bell's palsy (1), inflammation enteric neuropathy (1), brachial plexus neuritis (2), peripheral neuropathy (2) Cardiac (7) Myocarditis (2), cardiomyopathy (1), coronary spasm (1), pericardial effusion (3) Rheumatologic (28) Remitting seronegative symmetrical synovitis with pitting edema (1), arthritis (12), dermatomyositis/myositis (4), Goodpasture's disease (1), scleroderma (2), polymyalgia rheumatic (3), sicca syndrome (5) Nephrotic (7) Cystitis (1), renal failure (1), nephrotic syndrome (4), acute glomerulonephritis (1) Hematologic (16) Pancytopenia (2), neutropenia (6), aplastic anemia (2), pure red cell aplasia (1), thrombocytopenia (3), acute thrombosis (1), hemophagocytic lymphohistiocytosis (1) Ophthalmologic (17) Uveitis (7), Vogt-Koyanagi-Harada disease-like uveitis (2), orbital inflammation (3), dry eye (2), ulcerative keratitis (1), ocular myositis (2) Otorhinolaryngologic (2) Sinusitis…”