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1 Author s Accepted Manuscript Rheumatologic symptoms in oncologic patients on PD-1 inhibitors Wilson F. Kuswanto, Lindsey A. MacFarlane, Lydia Gedmintas, Alexandra Mulloy, Toni K. Choueiri, Bonnie Bermas PII: DOI: Reference: S (17) YSARH51264 To appear in: Seminars in Arthritis and Rheumatism Cite this article as: Wilson F. Kuswanto, Lindsey A. MacFarlane, Lydia Gedmintas, Alexandra Mulloy, Toni K. Choueiri and Bonnie Bermas, Rheumatologic symptoms in oncologic patients on PD-1 inhibitors, Seminars in Arthritis and Rheumatism, This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Rheumatologic symptoms in oncologic patients on PD-1 inhibitors Wilson F. Kuswanto M.D. PhD 1, Lindsey A. MacFarlane M.D. M.P.H. 2, Lydia Gedmintas M.D. M.P.H. 2, Alexandra Mulloy N.P. 3, Toni K. Choueiri M.D. 1,3, Bonnie Bermas M.D Harvard Medical School, Boston, MA. 2. Division of Rheumatology, Immunology and Allergy, Brigham and Women s Hospital, Boston, MA. 3. Dana Farber Cancer Institute, Boston, MA. Corresponding author: Lindsey A. MacFarlane M.D. M.P.H. Division of Rheumatology, Brigham and Women s Hospital 60 Fenwood Road, Boston, MA Telephone: Fax: This work did not receive financial support or other benefits. Dr. Bermas receives royalties from Up-to-Date and has consulted for UCB Dr. Choueiri has consulted for AstraZeneca, BMS, Exelixis, Genentech, GSK, Merck, Novartis, Peloton, Pfizer, Roche, Tracon, and Eisai. The remainder of the authors have no disclosures to report. Abstract Objective: Immune check-point inhibitors are effective cancer therapies that have been associated with immune related adverse events (iraes). Recent reports of iraes describe symptoms resembling classic rheumatologic syndromes, most notably associated with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor blockade. There are limited reports of rheumatologic disease associated with programmed cell death protein-1 (PD-1) inhibitors. Here, we describe a case series of four patients presenting to the Brigham and Women s Hospital 1

3 (BWH) Arthritis Center with de novo polymyalgia rheumatica (PMR)-type conditions and/or peripheral synovitis after treatment with PD-1/PD-Ligand 1 (PD-L1) pathway inhibitors. Methods: Patients with metastatic renal cell carcinoma (RCC) who were treated with PD-1/PD- L1 pathway inhibitors and subsequently developed complaints of new joint pain were referred to the BWH Arthritis Center as part of routine care and identified retrospectively. The electronic medical record was reviewed for cancer history and treatment, rheumatologic symptoms, physical exam, laboratory testing and clinical course. Results: All four female patients subsequently developed iraes consistent with a PMR-type syndrome and/or peripheral synovitis. Symptoms persisted despite discontinuation of the PD- 1/PD-L1 pathway inhibitors; however, three of the patients responded well to oral glucocorticoids alone while one patient required the addition of oral methotrexate. All patients had an eventual decline in inflammatory markers. Conclusion: These cases highlight the need for both oncologists and rheumatologists to recognize the possible development of rheumatologic disease during treatment with immune checkpoint blockade. Further investigation is needed to optimize the course and management of iraes, particularly in light of increasing use of checkpoint inhibitors to treat malignancies. Significance and Innovations Our case series identifies four patients who present with a polymyalgia rheumatica (PMR)-type disorder and/or peripheral arthritis after therapy with PD-1/PD-L1 inhibitors. Three out of four patients responded to prednisone and a fourth patient required methotrexate in addition to glucocorticoids. While others have reported on adverse immune responses in patients treated with these medications, our series is the first to report on the clustering of PMR symptoms. 2

4 Given the increased use of these medications we believe that this case series adds to the growing literature in this field and provides important information to practicing rheumatology clinicians. Introduction Emerging cancer therapies that augment the endogenous immune system offer new treatment options for malignancies previously refractory to therapy. The immune checkpoint inhibitors programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) essentially release the breaks to potentiate the immune system which can target malignant cells and in the process disrupt immune homeostasis [1]. To date, four immune checkpoint inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of an ever expanding list of malignancies: Ipilimumab, a monoclonal antibody specific for CTLA-4, Pembrolizumab and Nivolumab, both monoclonal antibodies specific for PD-1, and finally atezolizumab, a monoclonal antibody targeting the ligand to PD-1, programmed deathligand 1 (PD-L1) [2, 3]. While disinhibiting the immune system may be effective for cancer therapy, immune checkpoint blockade may also provoke autoimmunity. Early reports of patients on combination or single checkpoint inhibitor therapy have been associated with an increased incidence of immune related adverse events (iraes) with worse toxicity associated with combination blockade (CTLA-4/PD- 1) [4, 5]. The most frequent iraes reported involve dermatologic, gastrointestinal, hepatic and endocrine organs. Increasingly, there are reports of iraes resembling classic rheumatologic syndromes associated with CLTA-4 blockade. Goldstein et al described the development of 3

5 polymyalgia rheumatic (PMR)/giant cell arteritis (GCA) in two patients with metastatic melanoma and receiving ipilimumab [6]. Monotherapy with PD-1/PD-L1 blockade has also resulted in autoimmune manifestations including arthritis, uveitis, and Sicca syndrome [7-9]. Given the increasing use of checkpoint inhibitors to treat malignancies, oncologists and rheumatologists need to be aware of the potential risk for the development of autoimmune conditions with patients treated with checkpoint inhibitors, especially rheumatologic conditions as these may have an insidious presentation. Here, we present a case series of four patients presenting to the Brigham and Women s Hospital (BWH) Arthritis Center with de novo PMRtype conditions and/or peripheral synovitis after treatment with PD-1 or PD-L1 inhibitors for the treatment of renal cell carcinoma. Case Reports Patient 1 The patient is a 68-year-old woman who was initially treated with a pembrolizumab-based combination (PD-1 blocker) every 3 weeks for metastatic renal cell carcinoma. Three months following the initial pembrolizumab dose, she developed morning stiffness, and arthalgias, most predominantly in the neck and shoulders with elevation in ESR (34 mm/hr) and CRP (37.4 mg/l) (Fig. 1). Pembrolizumab was discontinued and she was placed on 50 mg prednisone daily with taper to 10 mg over 10 days by her oncologist. The patient responded well to initial prednisone treatment with improvement in morning stiffness and arthralgias, however symptoms recrudesced with taper, and she was maintained on mg of prednisone daily. Two months later, she was seen in the BWH Arthritis Center while on 20 mg of prednisone daily. At that time, she reported bilateral hand, shoulder and knee arthralgias with morning stiffness. She denied any headaches, visual symptoms or jaw claudication. Exam revealed no obvious synovitis, ESR was 4

6 17 mm/hr and CRP to 8.7 mg/l. The diagnosis was a PMR-like presentation and a gradual prednisone taper was planned given that her symptoms were stable. Three months into taper (12 mg/day of prednisone), she had worsening achiness and stiffness most notably in the pelvic girdle with an increase in ESR to 20 mm/hr and CRP to 91.6 mg/l. Increase in prednisone to 15 mg per day resolved the PMR-like symptoms and a prolonged taper was recommended. One year after initial presentation while on prednisone 4 mg daily, she reported bilateral wrist and finger pain and was noted to have decreased grip strength, tender proximal interphalangeal joints and bilateral wrist synovitis. Her symptom evolution at this point was felt to be more consistent with an inflammatory arthritis. The patient was started on methotrexate and the dose was titrated up to 20 mg per week. Despite ongoing methotrexate therapy, the patient has residual morning stiffness and wrist synovitis and a tumor necrosis factor (TNF)-alpha inhibitor is being considered. Pembrolizumab was not restarted and she continues to be in remission from renal cell carcinoma off treatment. Patient 2 The patient is a 65-year-old woman who was started on nivolumab (3 mg/kg) (PD-1 blocker) every 2 weeks for metastatic renal carcinoma that progressed while on pazopanib (tyrosine kinase inhibitor). Sixteen months after starting nivolumab therapy, she developed proximal myalgias in her thighs and arms, and weakness described as difficulty combing her hair or rising from a chair. ESR was elevated at 72 mm/hr and CRP at 39.3 mg/l (Fig. 1). Creatinine kinase at this time was normal. Her oncologist started 30 mg of prednisone daily and nivolumab was discontinued. Her ESR decreased to 28 mm/hr, and the prednisone was tapered but she developed pelvic girdle pain once the prednisone dose was lowered to 10 mg daily. Two months after the development of symptoms the patient was evaluated by rheumatology for persistent 5

7 myalgias, pelvic girdle stiffness and achiness and proximal muscle weakness while on 25 mg of prednisone daily. Exam revealed no evidence of weakness or synovitis. Repeat ESR was 38 mm/hr and CRP was 12.7 mg/l. The patient was diagnosed with PMR and a slow prednisone taper was initiated. Over fifteen months she was tapered to 5 mg of prednisone a day and her PMR-like symptoms have resolved. Nivolumab has not been re-started and follow-up imaging revealed no interval change of her renal cell cancer. Patient 3 The patient is a 63-year-old woman who was started on nivolumab (3 mg/kg) every 2 weeks for metastatic renal carcinoma following no tumor-response with high-dose interleukin-2 therapy. The patient had minimal side effects from nivolumab until nine months into treatment at which time she presented to her primary care physician with new right shoulder pain that was refractory to an intra-articular steroid injection. Nivolumab was held and the patient presented to the BWH Arthritis Center three weeks later with persistent right shoulder pain and onset of right knee, neck, and bilateral hip arthralgias with morning stiffness. The patient also reported proximal upper extremity weakness manifesting as difficulty in putting on clothes and in blow drying her hair. Exam demonstrated a 5-degree fixed elbow flexion deformity with synovitis and a knee effusion. The knee was aspirated which revealed 9,819 leukocytes and no evidence of urate or calcium crystals. ESR was elevated at 70 mm/hr and CRP at mg/l (Fig. 1). She was started on 10 mg prednisone daily. On follow-up examination two weeks later, the patient noted significant improvement in both her polyarticular arthralgias and range of motion at the knee and elbow. Her ESR declined to 24 mm/hr and CRP to 12.6 mg/l. Nivolumab was restarted and prednisone tapered from 10 to 5 mg daily with durable resolution of arthralgias, elbow flexion deformity and morning stiffness. Her ESR and CRP normalized to 13 mm/hr and 8.0 mg/l, 6

8 respectively. Patient was successfully tapered to 1 mg daily of prednisone. Nivolumab was resumed due to recent interval imaging scan revealing tumor progression. Patient 4 The patient is a 62-year-old-woman with metastatic collecting duct carcinoma who was started on an atezolizumab-based combination (1200 mg) (PD-L1 inhibitor) every 3 weeks. The patient tolerated atezolizumab well for 2 months after which she developed severe bilateral stiffness and arthralgias of the knees, hands and shoulders and requiring the use of a wheelchair. Magnetic resonance imaging of the right knee demonstrated Bakers cyst, effusion and synovitis. ESR at the time of presentation was 97 mm/hr and CRP at mg/l (Fig. 1). The patient was referred for rheumatologic evaluation. On exam, patient had decreased grip strength and range of motion in her shoulders and bilateral knee effusions, right greater than left. Synovial fluid of the right knee had insufficient quantity to assess for cell count but crystal analysis was negative. Atezolizumzb and bevacizumab were held and she was started on 15 mg of prednisone daily with improvement of arthralgias and stiffness. At her follow-up visit, the patient was ambulating without assistive device, although she had ongoing mild knee pain. There was improved shoulder range of motion and grip and minimal knee effusions. CRP declined to 4.9 mg/l and the patient is currently maintained on 10 mg of prednisone daily. She had sustained a partial tumor-response to atezolizumzb and bevacizumab and after discussion with her oncologist has opted to restart treatment. Discussion We present four patients with metastatic renal cell carcinoma who were all treated with antibodies targeting the PD-1/PD-L1 pathway and in whom subsequently developed rheumatologic disease consistent with PMR-like syndrome (Cases 1, 2 and 3) or an inflammatory 7

9 arthritis (Cases 1, 3 and 4). While symptoms persisted despite discontinuation of the PD-1/PD- L1 inhibitors, three of the patients responded well to glucocorticoids alone while one patient (Case 1) required the addition of methotrexate. All patients had an eventual decline in inflammatory markers (Fig. 1). CTLA-4 monotherapy appears to result in an increased incidence of iraes compared to PD-1 blockade [5]. Additionally, the development of irae is increased with combination CTLA-4/PD- 1 blockade versus CTLA-4 monotherapy, including two cases of fatal myocarditis [4, 10]. There are more limited data on iraes with isolated PD-1/PD-L1 checkpoint inhibition. Ping-Man et al describe a patient with advanced lung cancer who developed psoriasis and psoriatic arthritis while on nivolumab [11]. develasco et al report on a patient with renal cell carcinoma on nivolumab who developed autoimmune uveitis and Jaccoud s arthropathy [7]. Additionally, there are reports of patients developing either Sicca syndrome, an inflammatory arthritis, and/or tenosynovitis while on anti-pd-1 monotherapy [8, 9]. Our four cases add to this existing literature and suggest that symptoms may cluster so that presentations are consistent with known rheumatologic processes such as PMR, PMR with peripheral joint involvement and inflammatory arthritis. What was encouraging is that three out of four of the cases presented here had stable oncologic disease or were in remission, further studies are needed to determine whether the development of their rheumatologic process may portend a better prognosis for their underlying malignancy. Given the temporal relationship between initiation of checkpoint inhibitor therapy and onset of rheumatologic symptoms, these immune events are thought to be triggered by these medications. Early characterization of PD-1 in a mouse-model of chronic viral infection, classically described PD-1 as a marker of dysfunctional or exhausted T cells [12]. Further inquiry revealed the 8

10 critical role of PD-1 and its ligands, PD-L1 and PD-L2, in the maintenance of immune homeostasis via the direct negative inhibitory signals that limit T cell activation and the promotion of a population of dominant immune suppressive cells known as regulatory T cells [12]. Imbalance of the PD-1/PD-L1 pathway in animal models prone to autoimmune disease results in exacerbation of disease [12]. Recent studies in humans with rheumatologic disease have characterized PD-1+ T cells with an inflammatory rather than an exhausted or dysfunctional phenotype. In a human study of GCA, there was an accumulation of PD-1+ T cells and low tissue expression of PD-L1 [13]. Furthermore, PD-1 blockade in explanted human artery-mouse chimeras resulted in the accumulation of inflammatory PD-1+ T cells with intimal layer hyperplasia [13]. Similarly, in a study of seropositive patients with rheumatoid arthritis, there was an accumulation of activated PD-1+ T cells in the inflamed synovium and peripheral blood that were capable of providing B cell help [14]. Thus, a potential mechanism for de novo autoimmunity in patients treated with immune checkpoint blockade may include disruption of tolerance mechanisms involving inflammatory PD-1+ T cells. Given the identification of activated PD-1+ T cells in several human autoimmune diseases, alternative therapies modulating the PD-1/PD-L1 pathway may prove to be effective, e.g. PD-L1 agonists. Treatment guidelines have been established by oncologists for the management of a subset of iraes [5]. Immune suppression with corticosteroids for iraes such as colitis, hepatitis and pneumonitis is relatively effective, and based on limited studies did not affect overall survival [5, 15]. In another report of inflammatory arthritis after PD-1 monotherapy, the patient responded well to 10 mg prednisone daily with tapering to 7.5 mg daily after three months [8]. In our series, three out of the four patients had improvement in their symptoms with initial prednisone doses 9

11 ranging from 10 to 30 mg daily and tolerated prednisone taper. One patient, however, ultimately required methotrexate therapy. Continued monitoring of patients will determine durability of response if and when prednisone is stopped. Finally, punctual modulation of immune homeostasis via immune checkpoint inhibitors provide a unique opportunity to study human immune responses in vivo and we hope these cases contribute to the growing knowledge and management of this unique and expanding patient population. References: 1. Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, (4): p Martin-Liberal, J., et al., The expanding role of immunotherapy. Cancer Treat Rev, : p Choueiri, T.K. and R.J. Motzer, Systemic Therapy for Metastatic Renal-Cell Carcinoma. N Engl J Med, (4): p Postow, M.A., et al., Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med, (21): p Friedman, C.F., T.A. Proverbs-Singh, and M.A. Postow, Treatment of the Immune- Related Adverse Effects of Immune Checkpoint Inhibitors: A Review. JAMA Oncol, (10): p Goldstein, B.L., L. Gedmintas, and D.J. Todd, Drug-associated polymyalgia rheumatica/giant cell arteritis occurring in two patients after treatment with ipilimumab, an antagonist of ctla-4. Arthritis Rheumatol, (3): p de Velasco, G., B. Bermas, and T.K. Choueiri, Autoimmune Arthropathy and Uveitis as Complications of Programmed Death 1 Inhibitor Treatment. Arthritis Rheumatol, (2): p Cappelli, L.C., et al., Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis, (1): p Chan, M.M., et al., Arthritis and tenosynovitis associated with the anti-pd1 antibody pembrolizumab in metastatic melanoma. J Immunother, (1): p Johnson, D.B., et al., Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med, (18): p Law-Ping-Man, S., et al., Psoriasis and psoriatic arthritis induced by nivolumab in a patient with advanced lung cancer. Rheumatology (Oxford), (11): p Francisco, L.M., P.T. Sage, and A.H. Sharpe, The PD-1 pathway in tolerance and autoimmunity. Immunol Rev, : p Zhang, H., et al., Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc Natl Acad Sci U S A, (6): p. E970-E Rao, D.A., et al., Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature, (7639): p

12 CRP (mg/l) ESR (mm/hr) 15. Horvat, T.Z., et al., Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol, (28): p Figure 1: Inflammatory marker dynamics following initiation of checkpoint inhibitor therapy. A 100 Erythrocyte Sedimentation Rate Patient 1 Patient 2 Patient 3 Patient Post-Initiation of Checkpoint Inhibitor (months) B C-Reactive Protein Patient 1 Patient 2 Patient 3 Patient Post Initiation of Checkpoint Inhibitor (months) Patients 1-4 were started on checkpoint inhibitor blockade which was withheld following development of rheumatic symptoms. Patients were then started on corticosteroid therapy and Erythrocyte Sedimentation Rate (A) and C-Reactive Protein (B) were followed over time from peripheral blood. 11

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