Jean Tayar

Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series

Background Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with numerous cancers. However, these therapies are associated with immune-related adverse events (irAEs), which are inflammatory side effects potentially affecting any organ. Cases of ICI-induced inflammatory arthritis have also been reported. In general, mild irAEs are treated with corticosteroids, while tumour necrosis factor-α (TNFα) inhibitors are reserved for refractory cases. However, prolonged use of TNFα inhibitor (TNFαi) can induce widespread, significant immunosuppression, which can negatively impact the antitumour efficacy of ICI therapy. Therefore, in clinical scenarios where patients develop severe immunotherapy-induced irAEs, an unmet need exists for alternative therapeutic strategies that are effective and without immune dampening effects. Case reports The anti-interleukin (IL)−6 receptor antibody, tocilizumab, is a biological agent Food and Drug Administration approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Here, we report on three patients who developed severe polyarthritis while receiving ICI therapy and were treated with tocilizumab. All three patients demonstrated significant clinical improvement; one patient maintained a durable antitumour response derived from checkpoint inhibition. Conclusions These three cases suggest that anti-IL-6 receptor antibody may be an effective alternative to corticosteroids or TNFαi for the treatment of arthritis irAEs.

Adjuvant and salvage therapy with leflunomide for recalcitrant cytomegalovirus infections in hematopoietic cell transplantation recipients: A case series

Cytomegalovirus (CMV) reactivation is a clinically significant complication in hematopoietic stem cell transplant (HCT) recipients. Alternative therapy for multidrug-resistant CMV is limited and often fails. Leflunomide has been used to treat resistant CMV infections, however, data on efficacy, safety, and guidance for therapeutic drug level monitoring are lacking. In this report, we describe 3 HCT recipients with multi-drug resistant CMV infections who received leflunomide as adjuvant and salvage therapy. The therapeutic effect of leflunomide as an anti-CMV agent based on virologic responses and therapeutic drug monitoring were evaluated.

Outcome of acute limb ischemia in cancer patients

The optimal management strategy for acute limb ischemia (ALI) in patients with a concomitant malignancy is not well established. A very high mortality rate (83–100%) at 1 year has been reported in those who are treated surgically. Accordingly, a conservative management approach has been suggested as the main therapeutic modality. Our aim was to evaluate the survival outcomes of cancer patients treated for ALI at our cancer center. Cancer patients treated for ALI at the MD Anderson Cancer Center from 2001 to 2011 were included in this study. Overall survival and amputation-free survival rates were calculated. A total of 74 cancer patients with concomitant ALI were included in the study. Surgery was the most common therapy (36 patients; 49%). Percutaneous catheter-based interventions were used in 21 patients (28%). Eighteen patients (24%) received anticoagulation therapy only, and six patients (8%) received no therapy. The 30-day, 6-month, and 1-year overall survival rates were 80% (95% confidence interval [CI], 69% to 87%), 59% (95% CI, 47% to 69%), and 48% (95% CI, 36% to 59%), respectively. Eight patients (11%) underwent amputation. The 1-year amputation-free survival rate was 47% (95% CI, 35% to 58%). In conclusion, we did not find an invasive approach for the treatment of ALI in cancer patients to be associated with the very high mortality rates previously reported. In our opinion, the indications for surgery or catheter-based intervention in these patients should not differ from patients without cancer.

SAT0177 Baricitinib for Rheumatoid Arthritis: A Systematic Review and Meta-Analysis

Background Baricitinib is a small molecule inhibitor of the Janus kinase (JAK) pathways that reduce and modulate the production of inflammatory mediators and cytokines. Objectives We conducted a systematic review to evaluate the efficacy and safety of baricitinib for the treatment of patients with rheumatoid arthritis. Methods A comprehensive search of the literature was conducted in the following electronic databases: Cochrane Library, MEDLINE, EMBASE and Web of Science. Also, we searched clinicaltrials.gov and hand searched conference proceedings through December 2015. Any randomized controlled trial (RCT) comparing baricitinib alone or in combination with any DMARD versus placebo or other traditional or biologic DMARDs for the treatment of patients with rheumatoid arthritis were included. Two independent reviewers performed study selection, data collection and risk of bias assessment using Covidence.org. Our primary outcome was the percent of patients achieving an American College of Rheumatology (ACR) 50% response. Secondary outcomes included: clinical remission (Disease Activity Score (DAS <2.6)), minimum clinical important difference (MCID) ≥0.22 in the Health Assessment Questionnaire (HAQ), total withdrawals and serious adverse events (SAEs). Results Out of 146 citations, 7 RCTs met our inclusion criteria. Most studies were published in abstract format and risk of bias assessment was judged unclear in most domains. Five studies compared more than two doses of baricitinib, however, we only report here results for the dose of 4 mg once daily. Four comparisons were included: i) baricitinib plus methotrexate (MTX) vs MTX, ii) baricitinib alone vs MTX, iii) baricitinib plus MTX vs adalimumab (ADA) plus MTX, and iv) baricitinib plus MTX vs baricitinib alone. For the combination of baricitinib plus MTX, more patients in the baricitinib group achieved an ACR 50 response and clinical remission compared to patients in the MTX group at 12 and 24 weeks (at 12 weeks patients in the control group were re-assigned to baricitinib). The combination group reported lower withdrawal rates at 24 weeks (RR 0.61, (95% CI 0.47–0.81) and similar SAEs at 24 weeks compared to control. For baricitinib alone vs MTX, improvement rates were higher in the baricitinib group at 12 weeks (RR 1.7, 95% CI 1.3–2.1; 1.8, 95% CI 1.2–2.6; 1.3, 95% CI 1.2–1.4; for ACR50, clinical remission, and MCID HAQ rates, respectively). No differences were found in total withdrawals or SAEs. When baricitinib was compared to ADA, greater rates of ACR50 response were observed in the baricitinib group at 12 weeks (RR 1.3; 95% CI 1.1, 1.5); but also higher rates of SAEs compared to the ADA group at 24 weeks were reported (RR 2.5; 95% CI 1.0, 6.1). No significant differences were observed between baricitinib plus MTX compared with baricitinib alone. Conclusions Baricitinib alone or combined with MTX had better efficacy responses compared to MTX alone at 12–24 weeks. Total withdrawal rates were lower in the baricitinib combined group when compared to MTX. Baricitinib had similar effects compared to adalimumab, but higher rates of SAEs. Baricitinib can be considered an additional therapeutic option to treat patients with moderate to severe disease who have an inadequate response to other treatment agents. Disclosure of Interest N. Zamora: None declared, J. Tayar: None declared, M. Lopez-Olivo Grant/research support from: Dr. Lopez-Olivo is recipient of a career award from the Rheumatology Research Foundation and has received consulting fee from Complete HEOR Solutions outside the scope of the submitted work, R. Christensen Consultant for: Dr. Christensens unit has received consulting fees, honoraria, research or institutional support, educational grants, equipment, services or expenses from the following companies: Abbott, Astellas Pharma, Axellus, Bristol-Myers Squibb, Cambridge Nutritional Foods, Centocor, DSM Nutritional Products, HypoSafe, MSD, MundiPharma, NorPharma, Pharmavie, Pfi zer, Roche, Sanofi -Aventis, and Scandinavian Clinical Nutrition., M. Suarez-Almazor Grant/research support from: Dr. Suarez-Almazor is the recipient of a K24 career award from the National Institute for Musculoskeletal and Skin Disorders. She has received grant support from the Rheumatology Research Foundation and Pfizer.

Myositis as an adverse event of immune checkpoint blockade for cancer therapy

OBJECTIVES Immune checkpoint inhibitors (ICIs) can successfully treat cancer, but their use can be hindered by serious immune-related adverse events. We report six patients receiving ICIs who presented with de novo myositis. METHODS We identified patients with myositis who were receiving ICIs between January 2004 and September 2016 at The University of Texas MD Anderson Cancer Center. RESULTS Six patients developed de novo myositis. The mean age was 64.3 years and five patients were male. Cancer types included melanoma, urothelial carcinoma, renal cell carcinoma, and prostate cancer. ICI regimens included single-agent ipilimumab (n = 1), pembrolizumab (n = 1), or atezolizumab (n = 1); nivolumab and ipilimumab (n = 3). The median time to development of de novo myositis from first infusion was 5.4 weeks (range: 2.1-17.1 weeks). All patients with myositis had elevated levels of creatinine kinase, ranging from 514 to 13,710U/L. Two of them developed rhabdomyolysis, one with concurrent myocarditis. Five patients were treated with 1-2mg/kg corticosteroids, with variable response rates; one patient received nonsteroidal anti-inflammatory drugs. Two patients with myositis died as a result of cancer progression. CONCLUSION We found several occurrences of de novo myositis following ICI therapy. These preliminary data suggest that myositis can occur early after onset of ICI therapy with serious adverse outcomes.

Improvement of Smoking Abstinence Rates with Increased Varenicline Dosage

Purpose/Background It is unclear whether increasing the dose of varenicline beyond the standard dose of 2 mg/d would improve smoking abstinence. Methods We examined the effect of 3 mg/d of varenicline on smoking abstinence among smokers who had reduced their smoking by 50% or more in response to 2 mg/d for at least 6 weeks but had not quit smoking. Of 2833 patients treated with varenicline, dosage of a subset of 73 smokers was increased to 3 mg/d after 6 weeks. We used a propensity score analysis involving multiple baseline covariates to create a comparative sample of 356 smokers who remained on 2 mg/d. All smokers received concurrent and similar smoking-cessation counseling. Results At 3 months, we found higher 7-day point prevalence smoking-abstinence rate in the 3-mg group (26%) than in the 2-mg group (11.5%, &khgr;2 = 10.60, P < 0.001; risk ratio [RR], 2.3; 95% confidence interval [CI], 1.4–3.6). The difference in abstinence rates remained significant at the 6-month (P < 0.001; RR, 2.6; 95% CI, 1.6–3.9) and 9-month follow-up (P < 0.001; RR, 2.2; 95% CI, 1.4–3.3). Conclusions A relatively small increase in the daily dose of varenicline seems to offer a benefit for those who are not able to achieve total abstinence after approximately 6 weeks of 2 mg/d.

Coronary Lesions in Takayasu Arteritis With Chronic Myelogenous Leukemia ― Intravascular Assessment With Optical Coherence Tomography and Fractional Flow Reserve ―

Received April 24, 2018; revised manuscript received May 22, 2018; accepted May 29, 2018; released online June 28, 2018 Time for primary review: 22 days Department of Cardiology (T.D., D.V.B., E.M., C.I.), Department of General Internal Medicine (J.T.), The University of Texas MD Anderson Cancer Center, Houston, TX, USA Mailing address: Cezar Iliescu, MD, FACC, FSCAI, Associate Professor, Department of Cardiology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1451 Houston, TX 77030, USA. E-mail: ciliescu@mdanderson.org ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp Coronary Lesions in Takayasu Arteritis With Chronic Myelogenous Leukemia ― Intravascular Assessment With Optical Coherence Tomography and Fractional Flow Reserve ―

OP0032 Malignancies and serious infections in randomised controlled trials of janus kinase inhibitors in patients with rheumatoid arthritis: a systematic review and meta-analysis

Background Two JAK inhibitors are currently approved by different agencies worldwide for their use in patients with rheumatoid arthritis. The safety profile of these agents has been of interest since the approval of the first JAK inhibitor, particularly the risk of developing malignancies or serious infections. Objectives We conducted a systematic review and meta-analysis of phase 2 and phase 3 trials to evaluate these two outcomes in patients receiving JAK inhibitors for rheumatoid arthritis. Methods We performed a search in 5 electronic databases and also searched clinicaltrials.gov, Food and Drug Administration, and European Medicines Agency. In addition, the bibliography list of included studies was also screened to search for further citations not retrieved from other sources. We included controlled trials evaluating the efficacy of a JAK inhibitor (i.e., tofacitinib baricitinib, filgonitinib, peficinitinib, ABT-494, or decenotinib). Two reviewers independently screened studies, evaluated their risk of bias, and extracted data. Primary outcome data included number and type of malignancies and infections and time point of occurrence when available. The reported publications was considered the primary source of data for all trials. Serious infections were defined as those meeting the criteria for a serious adverse events such as a fatal, life threatening, or leading to hospitalisation. Results Thirty-one trials were analysed, reporting data on 13 945 patients. Follow-up of the included trials ranged between 4 and 52 weeks with a median of 24 weeks. The risk of attrition bias was judged low for most studies. The reported rates of malignancies and serious infections across studies ranged from 0% and 0.7% to 2.0%, and 5.4%, respectively. Most commonly reported malignancies were lung cancer, melanoma, nonmelanoma skin cancer, basal cell and squamous cell carcinoma. Patients receiving the combination of JAK inhibitor plus methotrexate or JAK inhibitor monotherapy had higher rates of malignancies, compared with methotrexate between 12 and 24 weeks before the rescue treatment was implemented, but the difference did not reach statistical significance (odds ratio (OR) 2.48, 95% confidence interval (CI) 0.76 to 8.11 and 1.39, 95% CI: 0.21 to 9.11, respectively). Regarding serious infections, the JAK inhibitor groups had similar rates to those observed in the control groups (OR 0.90, 95% CI: 0.38 to 0.92, 95% CI: 0.35 to 2.43, respectively). However, there was a dose-response effect with higher rates of serious infections observed in those patients receiving higher doses of JAK inhibitors. Conclusions Although not reaching statistical significance, in the currently available RCTs, the rates of malignancy were higher in the JAK inhibitors groups compared to their controls. The rates of serious infections were similar between JAK inhibitor groups and their controls, but were dose-dependent. Future studies should aim to indirectly compare each JAK inhibitor to evaluate if these safety signals are also drug dependent and to assess risk per type of malignancy or infection. Disclosure of Interest M. Lopez-Olivo: None declared, J. Tayar: None declared, N. Zamora: None declared, G. Pratt: None declared, M. Suarez-Almazor Consultant for: Pfizer, Endo Pharmaceuticals, and Bristol-Myers Squibb

FRI0604 Successful treatment of arthritis induced by checkpoint inhibitors with anti–interleukin-6 receptor antibody: a case series

Background Immune checkpoint inhibitors (CPIs) have significantly improved outcomes for patients with various cancers. However, CPIs are associated with immune-related adverse events (irAEs). Two to three percent of patients receiving a CPI develop arthritis. In general, severe irAEs are treated with a high-dose steroid and a tumor necrosis factor inhibitor (TNFi), usually infliximab; however, TNFi treatment is sometimes contraindicated and, furthermore, entails a theoretical concern of impairing antitumor immunity. Therefore, evidence showing the clinical benefits of non-TNFi biologics in the treatment of irAEs is of immediate interest. Objectives We described the effects of anti-IL-6R antibody for the treatment of arthritis-irAE. Methods Three patients receiving CPI developed arthritis and were treated with anti-IL-6R antibody. Patients were followed up to 15 months. Results All patients had metastatic melanoma (Table 1). No patient had a history of autoimmune disease at the time of initiation of CPI treatment. One patient developed arthritis 8 weeks after the completion of anti-CTLA-4 antibody treatment. Two patients were receiving anti-PD-1 antibody when they developed arthritis. Patient 2 continued to receive anti-PD-1 antibody despite of arthritis-irAE while patient 3 discontinued anti-PD-1 antibody due to arthritis-irAE. The pattern of arthritis was symmetric polyarthritis involving small and large joints. Patient 1 had a positive rheumatoid factor (unknown baseline) and patient 3 had a positive ANA (known positive prior to CPI treatment). All patients were treated with anti-IL-6R antibody, which was well tolerated. All patients experienced a 40–100% reduction in global assessment, swollen joint count, and tender joint count, and these effects were maintained for up to 15 months of treatment (Figure 1). As of December 2016, all patients were alive; one patient was in complete remission and two patients had experienced progression of their melanoma.Table 1. Patient demographic and clinical characteristics Patient 1 2 3 Age, years 71 65 46 Sex Male Male Female Race Caucasian Caucasian Caucasian Tumor Metastatic melanoma Metastatic melanoma Metastatic melanoma CPI Anti-CTLA4 antibody Anti-PD-1 antibody Anti-PD-1 antibody Onset of arthritis-irAEs (days after initiation of CPI) 100 19 49 Pattern of arthritis Symmetric polyarthritis involving small joints Symmetric polyarthritis involving small and large joints Symmetric polyarthritis involving small joints History of autoimmune disease prior to CPI treatment No No No, but known positive ANA Autoantibody results ANA, CCP neg ANA, CCP, RF neg CCP, RF, Ro, dsDNA neg RF: 27 (UNL: 15.9) ANA 1:640 (homogenous) La pos Discontinuation of CPI treatment due to arthritis-irAE N/A No Yes Duration of anti-IL-6R antibody therapy, months 12 15 3 Tumor response to CPI as of December 2016 (RECIST 1.1) Complete remission Progressive disease Progressive disease CPI, immune checkpoint inhibitor; UNL, upper normal limit; ANA, antinuclear antibody; CCP, anti-cyclin citrullinated antibody; RF, rheumatoid factor; Ro, anti-SSA antibody; dsDNA, anti–double-stranded DNA antibody; La, anti-SSB antibody; N/A, not applicable. Conclusions These three cases suggest that anti-IL-6R antibody is an effective alternative to TNFi for the treatment of arthritis-irAE. Acknowledgements None Disclosure of Interest None declared