Three checkpoint inhibitor drugs have been approved by the US Food and Drug Administration for use in specific types of cancers. While the results are promising, severe immunotherapy-related adverse ...events (irAEs) have been reported.
To conduct a systematic review of case reports describing the occurrence of irAEs in patients with cancer following checkpoint blockade therapy, primarily to identify potentially unrecognized or unusual clinical findings and toxicity.
We searched Medline, EMBASE, Web of Science, PubMed ePubs, and Cochrane CENTRAL with no restriction through August 2015.
Studies reporting cases of cancer develop irAEs following treatment with anti CTLA-4 (ipilimumab) or anti PD-1 (nivolumab or pembrolizumab) antibodies were included.
We extracted data on patient characteristics, irAEs characteristics, how irAEs were managed, and their outcomes.
191 publications met inclusion criteria, reporting on 251 cases. Most patients had metastatic melanoma (95.6%), and the majority were treated with ipilimumab (93.2%). Autoimmune colitis, hepatitis, endocrinopathies, and cutaneous irAEs were the most frequently reported irAEs in ipilimumab treated patients. A broad spectrum of toxicities were reported for almost every body system. Moreover, well-defined diseases such as sarcoidosis, polyarthritis, polymyalgia rheumatica/arteritis, lupus, celiac disease, dermatomyositis, and Vogt-Koyanagi-like syndrome were reported. The most frequent irAEs reported with anti-PD1 agents were dermatitis for pembrolizumab, and thyroid disease and pneumonitis for nivolumab. Complete resolution of adverse events occurred in most cases. However, persistent irAEs and death were reported, mainly in patients treated with ipilimumab.
Our study is limited by information available in the original reports.
Evidence from case reports shows that cancer patients develop irAEs following checkpoint blockade therapy, and can occasionally develop clearly defined autoimmune systemic diseases. While discontinuation of therapy and/or treatment can result in resolution of irAEs, long-term sequelae and death have been reported.
Objective
To estimate the incidence of immune checkpoint inhibitor–related myositis (ICI‐myositis) in cancer patients receiving ICIs, and to report associated clinical manifestations, patterns of ...care, and outcomes.
Methods
We identified a retrospective cohort of patients receiving ICIs between 2016 and 2019 seen at the University of Texas MD Anderson Cancer Center. Cases of ICI‐myositis were identified using International Classification of Disease codes and confirmed by reviewing medical records and pathology, as available.
Results
A total of 9,088 patients received an ICI. Thirty‐six patients (0.40%) were identified as having ICI‐myositis: 17 patients (47%) with ICI‐myositis alone and 19 (53%) with overlap manifestations (5 patients with myocarditis, 5 with myasthenia gravis, and 9 with both). The incidence of ICI‐myositis was 0.31% in those receiving ICI monotherapy and 0.94% in those receiving combination ICI therapy (relative risk 3.1 95% confidence interval 1.5–6.1). Twenty‐five patients (69%) received ≥1 treatment in addition to glucocorticoids: plasmapheresis in 17 patients (47%), intravenous immunoglobulin in 12 (33%), and biologics in 11 (31%). Patients with overlap conditions had worse outcomes than those with myositis alone, and 79% of them developed respiratory failure. Eight patients died as a result of ICI‐myositis, and all had overlap syndrome with myasthenia gravis or myocarditis (P < 0.05); 75% of these patients had a concomitant infection.
Conclusion
ICI‐myositis is a rare but severe adverse event. More than half of the patients presented with overlap manifestations and had deleterious outcomes, including respiratory failure and death. None of the patients with ICI‐myositis alone died as a result of adverse events. Optimal treatment strategies have yet to be determined.
Methotrexate for treating rheumatoid arthritis Lopez‐Olivo, Maria Angeles; Siddhanamatha, Harish R; Shea, Beverley ...
Cochrane database of systematic reviews,
06/2014, Letnik:
2014, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background
Methotrexate is a folic acid antagonist widely used for the treatment of neoplastic disorders. Methotrexate inhibits the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) ...and proteins by binding to dihydrofolate reductase. Currently, methotrexate is among the most commonly used drugs for the treatment of rheumatoid arthritis (RA). This is an update of the previous Cochrane systematic review published in 1997.
Objectives
To evaluate short term benefits and harms of methotrexate for treating RA compared to placebo.
Search methods
The Cochrane Musculoskeletal Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched from 1966 to 1997 and then updated to November 2013. The search was complemented with a bibliography search of the reference lists of trials retrieved from the electronic search.
Selection criteria
Randomized controlled trials and controlled clinical trials comparing methotrexate (MTX) monotherapy against placebo alone in people with RA. Any trial duration and MTX doses were included.
Data collection and analysis
Two review authors independently determined which studies were eligible for inclusion, extracted data and assessed risk of bias. Outcomes were pooled using mean differences (MDs) for continuous variables or standardized mean differences (SMDs) when different scales were used to measure the same outcome. Pooled risk ratio (RR) was used for dichotomous variables. Fixed‐effect models were used throughout, although random‐effects models were used for outcomes showing heterogeneity.
Main results
Five trials with 300 patients were included in the original version of the review. An additional two trials with 432 patients were added to the 2013 update of the review for a total of 732 participants. The trials were generally of unclear to low risk of bias with a follow‐up duration ranging from 12 to 52 weeks. All trials included patients who have failed prior treatment (for example, gold therapy, D‐penicillamine, azathioprine or anti‐malarials); mean disease duration that ranged between 1 and 14 years with six trials reporting more than 4 years; and weekly doses that ranged between 5 mg and 25 mg.
Benefits
Statistically significant and clinically important differences were observed for most efficacy outcomes. MTX monotherapy showed a clinically important and statistically significant improvement in the American College of Rheumatology (ACR) 50 response rate when compared with placebo at 52 weeks (RR 3.0, 95% confidence interval (CI) 1.5 to 6.0; number needed to treat (NNT) 7, 95% CI 4 to 22). Fifteen more patients out of 100 had a major improvement in the ACR 50 outcome compared to placebo (absolute treatment benefit (ATB) 15%, 95% CI 8% to 23%).
Statistically significant improvement in physical function (scale of 0 to 3) was also observed in patients receiving MTX alone compared with placebo at 12 to 52 weeks (MD ‐0.27, 95% CI ‐0.39 to ‐0.16; odds ratio (OR) 2.8, 95% CI 0.23 to 32.2; NNT 4, 95% CI 3 to 7). Nine more patients out of 100 improved in physical function compared to placebo (ATB ‐9%, 95% CI ‐13% to ‐5.3%). Similarly, the proportion of patients who improved at least 20% on the Short Form‐36 (SF‐36) physical component was higher in the MTX‐treated group compared with placebo at 52 weeks (RR 1.5, 95% CI 1.0 to 2.1; NNT 9, 95% CI 4 to 539). Twelve more patients out of 100 showed an improvement of at least 20% in the physical component of the quality of life measure compared to placebo (ATB 12%, 95% CI 1% to 24%). No clinically important or statistically significant differences were observed in the SF‐36 mental component.
Although no statistically significant differences were observed in radiographic scores (that is, Total Sharp score, erosion score, joint space narrowing), radiographic progression rates (measured by an increase in erosion scores of more than 3 units on a scale ranging from 0 to 448) were statistically significantly lower for patients in the MTX group compared with placebo‐treated patients (RR 0.31, 95% CI 0.11 to 0.86; NNT 13, 95% CI 10 to 60). Eight more patients out of 100 showed less damage to joints measured by an increase in erosion scores compared to placebo (ATB ‐8%, 95% CI ‐16% to ‐1%). In the one study measuring remission, no participants in either group met the remission criteria. These are defined by at least five of (≥ 2 months): morning stiffness of < 15 minutes, no fatigue, no joint pain by history, no joint tenderness, no joint swelling, and Westergren erythrocyte sedimentation rate (ESR) of < 20 mm/hr in men and < 30 mm/hr in women.
Harms
Patients in the MTX monotherapy group were twice as likely to discontinue from the study due to adverse events compared to patients in the placebo group, at 12 to 52 weeks (16% versus 8%; RR 2.1, 95% CI 1.3 to 3.3; NNT 13, 95% CI 6 to 44). Compared to placebo, nine more people out of 100 who took MTX withdrew from the studies because of side effects (ATB 9%, 95% CI 3% to 14%). Total adverse event rates at 12 weeks were higher in the MTX monotherapy group compared to the placebo group (45% versus 15%; RR 3.0, 95% CI 1.4 to 6.4; NNT 4, 95% CI 2 to 17). Thirty more people out of 100 who took MTX compared to those who took placebo experienced any type of side effect (common or rare) (ATB 30, 95% CI 13% to 47%). No statistically significant differences were observed in the total number of serious adverse events between the MTX group and the placebo group at 27 to 52 weeks. Three people out of 100 who took MTX alone experienced rare but serious side effects compared to 2 people out of 100 who took a placebo (3% versus 2%, respectively).
Authors' conclusions
Based on mainly moderate to high quality evidence, methotrexate (weekly doses ranging between 5 mg and 25 mg) showed a substantial clinical and statistically significant benefit compared to placebo in the short term treatment (12 to 52 weeks) of people with RA, although its use was associated with a 16% discontinuation rate due to adverse events.
The emergence of checkpoint inhibitors has created a paradigm shift for the treatment of various malignancies. However, although these therapies are associated with improved survival rates, they also ...carry the risk of immune-related adverse events (irAEs). Moderate to severe irAEs are typically treated with glucocorticoids, sometimes with the addition of immunosuppressants as steroid-sparing therapy. However, it is unclear how glucocorticoids and immunosuppressants may impact cancer survival and the efficacy of immune checkpoint therapy on cancer. In this narrative review, we discuss the effects of glucocorticoids and immunosuppressants including methotrexate, hydroxychloroquine, azathioprine, mycophenolate mofetil, tumor-necrosis factor (TNF)-inhibitors, interleukin-6 inhibitors, interleukin-1 inhibitors, abatacept, rituximab, and Janus kinase inhibitors (JAKi) on cancer-specific outcomes in the setting of immune checkpoint inhibitor use.
Abstract
Immune checkpoint inhibitors have advanced the treatment paradigm of various cancers, achieving remarkable survival benefits. However, a myriad of immune-related adverse events (irAE) has ...been recognized in almost every organ system, presumably because of persistent immune system activation. Rheumatic symptoms such as arthralgia or myalgia are very common. More specific irAE are increasingly being reported. The most frequent ones are inflammatory arthritis, polymyalgia-like syndromes, myositis and sicca manifestations. These rheumatic irAE can develop in ∼5–10% of patients treated with immune checkpoint inhibitors, although true incidence rates cannot be estimated given the lack of prospective cohort studies, and likely underreporting of rheumatic irAE in oncology trials. In this review, we will provide a summary of the epidemiologic data reported for these rheumatic irAE, until more robust prospective longitudinal studies become available to further define the true incidence rate of rheumatic irAE in patients receiving these novel cancer therapies.
Background
The biologic disease‐modifying anti‐rheumatic drugs (DMARDs) are very effective in treating rheumatoid arthritis (RA), however there is a lack of head‐to‐head comparison studies.
...Objectives
To compare the efficacy and safety of abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab in patients with RA.
Methods
This ‘Overview of Reviews’ was done by including all Cochrane Reviews on Biologics for RA available in The Cochrane Library. We included only data on standard dosing regimens for these biologic DMARDs from placebo‐controlled trials. The primary efficacy and safety outcomes were ACR50 and withdrawals due to adverse events. We calculated Odds Ratios (OR) for efficacy and safety outcomes and combined estimates of events across the placebo groups as the expected Control Event Rate (CER). Indirect comparisons of biologics were performed for efficacy and safety using a hierarchical generalized linear mixed model (GLMM) incorporating the most important study‐level characteristic (i.e. type of biologic) as a fixed factor and study and study*drug interaction as random factors.
Main results
From the six available Cochrane reviews, we obtained data from seven studies on abatacept, eight on adalimumab, five on anakinra, four on etanercept, four on infliximab, and three on rituximab.
The indirect comparison estimates showed similar efficacy for the primary efficacy outcome for all biologics with three exceptions. Anakinra was less efficacious than etanercept with a ratio of ORs (95% CI; P value) of 0.34 (0.14, 0.81; P=0.015); and likewise adalimumab was more efficacious than anakinra, 2.20 (1.01, 4.75; P=0.046).
In terms of safety, adalimumab was more likely to lead to withdrawals compared to etanercept, with a ratio of ORs of 1.89 (1.18 to 3.04; P = 0.009); anakinra more likely than etanercept, 2.05 (1.27 to 3.29; P = 0.003); and likewise etanercept less likely than infliximab, 0.37 (0.19 to 0.70; P = 0.002).
Authors' conclusions
Based upon indirect comparisons, anakinra seemed less efficacious than etanercept and adalimumab. Etanercept seemed to cause fewer withdrawals due to adverse events than adalimumab, anakinra and infliximab. Significant heterogeneity in characteristics of trial populations imply that these finding must be interpreted with caution. These findings can inform physicians and patients regarding their choice of biologic for treatment of RA.
Objective
Patients with cancer and systemic lupus erythematosus (SLE) may have worse outcomes than those without SLE, given their comorbidities. We examined survival in elderly women with breast ...cancer (BC) and SLE and hypothesized that survival would be decreased compared with women with BC but without SLE.
Methods
We identified patients with BC and SLE and patients with BC without SLE in the Texas Cancer Registry and Surveillance, Epidemiology, and End Results, linked to Medicare claims. Overall survival (OS) was estimated after matching (age and cancer stage) and in multivariable Cox proportional hazards models adjusting for other cancer characteristics, treatment, and comorbidities. Two additional cohorts of women without cancer with and without SLE were also studied.
Results
We identified 494 BC SLE cases and 145,517 BC non‐SLE cases, of whom we matched 9,708. Women with SLE were less likely to receive radiation, breast conserving surgery, or endocrine therapy. The 8‐year OS estimate for women with early BC (stages 0–II) with and without SLE was 52% (95% confidence interval 95% CI 45%–59%) and 74% (95% CI 73%–75%), respectively. In the Cox multivariable model, BC and SLE had increased risk of death (hazard ratio HR 1.65, 95% CI 1.38–1.98). Women with BC and SLE also had increased risk of death compared with women with SLE but without cancer (HR 1.42, 95% CI 1.05–1.92) after adjusting for SLE severity. Women with SLE and BC received less glucocorticoids, antimalarials, and immunosuppressants after cancer diagnosis than those without cancer.
Conclusion
Systemic lupus is a risk factor for increased mortality in women with early BC.
Background
Bisphosphonates and denosumab, as adjuvant therapy in breast cancer, have been associated in some studies with improved cancer outcomes. The potential benefits of these drugs used at the ...lower doses commonly given for osteoporosis have not been established. The objective of this study was to investigate the association between therapy with bone‐modifying agents (BMAs) and survival in older women with early breast cancer.
Methods
The authors conducted a retrospective cohort study of women aged ≥66 years with breast cancer who were included in the Surveillance, Epidemiology, and End Results and Texas Cancer Registry Medicare‐linked databases. Associations were examined between the receipt of BMAs at dosages indicated for osteoporosis within 2 years after diagnosis and overall and breast cancer‐specific survival. Cox proportional hazards models and propensity score adjustment and matching were used for the analyses.
Results
Of the 37,724 women included, 7925 (21%) received at least 6 months of a BMA within the first 2 years of breast cancer diagnosis, including bisphosphonates only in 6898 women (80.7%), denosumab only in 1204 (15.2%), and both classes of BMAs in 323 (4.1%). The median follow‐up was 64 months. The receipt of a bisphosphonate was associated with improved overall survival (hazard ratio HR, 0.87; 95% CI, 0.82‐0.93) and breast cancer‐specific survival (HR, 0.77; 95% CI, 0.64‐0.92) after multivariable adjustment. Benefits were primarily seen for patients who had stage II and III disease. No benefits were observed with denosumab (stage II: HR, 1.05 95% CI, 0.90‐1.22; stage III: HR, 1.09 95% CI, 0.66‐1.82).
Conclusions
Bisphosphonates at the doses recommended for osteoporosis are associated with improved survival in older postmenopausal women with early breast cancer.
In a large cohort of women with breast cancer aged ≥66 years in the Surveillance, Epidemiology, and End Results and Texas Cancer Registry databases, data linked to Medicare claims are examined to evaluate the association of therapy using bone‐modifying agents at the time of osteoporosis with survival. Bisphosphonates at the doses recommended for treating osteoporosis are associated with improved survival in older postmenopausal women with early breast cancer.
Objective
Biologic disease‐modifying antirheumatic drugs (bDMARDs) are immunosuppressants, and there have been concerns that they might impact tumor immunity in patients with cancer with rheumatoid ...arthritis (RA). The purpose of this study was to describe the utilization trends of bDMARD in patients with RA after breast cancer (BC) diagnosis.
Methods
We performed a retrospective cohort study of adults with RA and BC (2008 onward) from Optum's de‐identified Clinformatics® Data Mart Database (CDM); the Surveillance, Epidemiology, and End Results Program (SEER) Medicare; and the Texas Cancer Registry (TCR) Medicare databases. We evaluated bDMARD utilization trends during the first three years after BC. We conducted multivariable logistic regression to evaluate the association of utilization with patient characteristics.
Results
A total 1,412 patients were identified in CDM and 1,439 patients in SEER/TCR‐Medicare. During the three months before BC diagnosis, 28.2% (CDM) and 26.9% (SEER/TCR‐Medicare) patients had received bDMARDs. Within the first three years after diagnosis, 24.1% (CDM) and 26.4% (SEER/TCR‐Medicare) were receiving bDMARDs. About 70% of the patients in the two cohorts received glucocorticoids with no significant time trend increases. The largest predictor of bDMARD utilization was prior use before BC (CDM: odds ratio OR 27.15, 95% confidence interval CI 19.29–38.19; SEER/TCR: OR 18.98, 95% CI 13.72–26.26). Regional and distant BC compared to in situ or localized were also associated with lower bDMARDs utilization in SEER/TCR‐Medicare (OR 0.54, 95% CI 0.36–0.82; OR 0.31, 95% CI 0.13–0.77, respectively).
Conclusion
The utilization of tumor necrosis factor inhibitors and other bDMARDs in patients with RA and recent BC has not increased since 2008. Glucocorticoids utilization remained high. The largest predictor of bDMARD utilization was prior use before BC.
PDF
