Immunomodulator use, risk factors and management of flares, and mortality for patients with pre-existing rheumatoid arthritis after immune checkpoint inhibitors for cancer.

OBJECTIVE: To investigate immunomodulator use, risk factors and management for rheumatoid arthritis (RA) flares, and mortality for patients with pre-existing RA initiating immune checkpoint inhibitors (ICI) for cancer. METHODS: We performed a retrospective cohort study of all patients with RA meeting 2010 ACR/EULAR criteria that initiated ICI for cancer at Mass General Brigham or Dana-Farber Cancer Institute in Boston, MA (2011-2022). We described immunomodulator use and changes at baseline of ICI initiation. We identified RA flares after baseline, categorized the severity, and described the management. Baseline factors were examined for RA flare risk using Fine and Gray competing risk models. We performed a landmark analysis to limit the potential for immortal time bias, where the analysis started 3 months after ICI initiation. Among those who survived at least 3 months, we examined whether RA flare within 3 months after ICI initiation was associated with mortality using Cox regression. RESULTS: Among 11,901 patients who initiated ICI for cancer treatment, we analyzed 100 pre-existing RA patients (mean age 70.3 years, 63 % female, 89 % on PD-1 monotherapy, 50 % lung cancer). At ICI initiation, 71 % were seropositive, 82 % had remission/low RA disease activity, 24 % were on glucocorticoids, 35 % were on conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and 10 % were on biologic or targeted synthetic DMARDs. None discontinued glucocorticoids and 3/35 (9 %) discontinued DMARDs in anticipation of starting ICI. RA flares occurred in 46 % (incidence rate 1.84 per 1000 person-months, 95 % CI 1.30, 2.37); 31/100 flared within 3 months of baseline. RA flares were grade 1 in 16/46 (35 %), grade 2 in 25/46 (54 %), and grade 3 in 5/46 (11 %); 2/46 (4 %) required hospitalization for RA flare. Concomitant immune-related adverse events occurred in 15/46 (33 %) that flared. A total of 72/100 died during follow-up; 21 died within 3 months of baseline. Seropositivity had an age-adjusted sdHR of 1.95 (95 % CI 1.02, 3.71) for RA flare compared to seronegativity, accounting for competing risk of death. Otherwise, no baseline factors were associated with RA flare, including cancer type, disease activity, RA duration, and deformities. 9/46 (20 %) patients had their ICI discontinued/paused due to RA flares. In the landmark analysis among 79 patients who survived at least 3 months, RA flare in the first 3 months was not associated with lower mortality (adjusted HR 1.24, 95 % CI 0.71, 2.16) compared to no RA flare. CONCLUSION: Among patients with pre-existing RA, few changed immunomodulator medications in anticipation of starting ICI, but RA flares occurred in nearly half. RA flares were mostly mild and treated with typical therapies. Seropositivity was associated with RA flare risk. A minority had severe RA flares requiring disruption of ICI, and RA flares were not associated with mortality.

Mortality and immune-related adverse events after immune checkpoint inhibitor initiation for cancer among patients with pre-existing rheumatoid arthritis: a retrospective, comparative, cohort study.

Background: Patients with pre-existing rheumatoid arthritis initiating immune checkpoint inhibitors for cancer might be at risk of increased mortality, rheumatoid arthritis flares, and other immune-related adverse events (AEs). We aimed to determine whether pre-existing rheumatoid arthritis was associated with higher mortality and immune-related AE risk in patients treated with immune checkpoint inhibitors. Methods: This retrospective, comparative cohort study was conducted at the Mass General Brigham Integrated Health Care System and the Dana-Farber Cancer Institute in Boston (MA, USA). We searched data repositories to identify all individuals who initiated immune checkpoint inhibitors from April 1, 2011, to April 21, 2021. Patients with pre-existing rheumatoid arthritis had to meet the 2010 American College of Rheumatology-European Alliance of Associations for Rheumatology (ACR-EULAR) criteria. For each pre-existing rheumatoid arthritis case, we matched up to three non-rheumatoid arthritis comparators at the index date of immune checkpoint inhibitor initiation by sex (recorded as male or female), calendar year, immune checkpoint inhibitor target, and cancer type and stage. The coprimary outcomes were time from index date to death and time to the first immune-related AE, measured using an adjusted Cox proportional hazards model. Deaths were identified by medical record and obituary review. Rheumatoid arthritis flares and immune-related AE presence, type, and severity were determined by medical record review. Findings: We identified 11 901 patients who initiated immune checkpoint inhibitors for cancer treatment between April 1, 2011, and April 21, 2021; of those, 101 met the 2010 ACR-EULAR criteria for rheumatoid arthritis. We successfully matched 87 patients with pre-existing rheumatoid arthritis to 203 non-rheumatoid arthritis comparators. The median age was 71·2 years (IQR 63·2-77·1). 178 (61%) of 290 participants were female, 112 (39%) were male and 268 (92%) participants were White. PD-1 was the most common immune checkpoint inhibitor target (80 [92%] of 87 patients with rheumatoid arthritis vs 188 [93%] of 203 comparators). Lung cancer was the most common cancer type (43 [49%] vs 114 [56%]), followed by melanoma (21 [24%] vs 50 [25%]). 60 (69%) patients with rheumatoid arthritis versus 127 (63%) comparators died (adjusted hazard ratio [HR] of 1·16 [95% CI 0·86-1·57]; p=0·34). 53 (61%) patients with rheumatoid arthritis versus 99 (49%) comparators had any all-grade immune-related AE (adjusted HR 1·72 [95% CI 1·20-2·47]; p=0·0032). There were two (1%) grade 5 immune-related AEs (deaths) due to myocarditis, both in the comparator group. Rheumatoid arthritis flares occurred in 42 (48%) patients with rheumatoid arthritis, and inflammatory arthritis occurred in 14 (7%) comparators (p<0·0001). Those with rheumatoid arthritis were less likely to have rash or dermatitis (five [6%] vs 28 [14%]; p=0·048), endocrinopathy (two [2%] vs 22 [11%]; p=0·0078), colitis or enteritis (six [7%] vs 28 [14%] comparators; p=0·094), and hepatitis (three [3%] vs 19 [9%]; p=0·043). Interpretation: Patients with pre-existing rheumatoid arthritis initiating immune checkpoint inhibitors had similar risk of mortality and severe immune-related AEs as matched comparators. Although patients with pre-existing rheumatoid arthritis were more likely to have immune-related AEs, this finding was mostly due to mild rheumatoid arthritis flares. These results suggest that this patient population can safely receive immune checkpoint inhibitors for cancer treatment. Funding: None.

Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis.

OBJECTIVES: To compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA). METHODS: The retrospective multicentre observational study included patients with a diagnosis of ICI-IA treated with a tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX); patients with pre-existing autoimmune disease were excluded. The primary outcome was time to cancer progression from ICI initiation; the secondary outcome was time to arthritis control from DMARD initiation. Cox proportional hazard models were used to compare medication groups, adjusting for confounders. RESULTS: 147 patients were included (mean age 60.3 (SD 11.9) years, 66 (45%) women). ICI-IA treatment was TNFi in 33 (22%), IL6Ri 42 (29%) and MTX 72 (49%). After adjustment for time from ICI initiation to DMARD initiation, time to cancer progression was significantly shorter for TNFi compared with MTX (HR 3.27 (95% CI 1.21 to 8.84, p=0.019)) while the result for IL6Ri was HR 2.37 (95% CI 0.94 to 5.98, p=0.055). Time to arthritis control was faster for TNFi compared with MTX (HR 1.91 (95% CI 1.06 to 3.45, p=0.032)) while the result for IL6Ri was HR 1.66 (95% CI 0.93 to 2.97, p=0.089). A subset analysis in patients with melanoma gave similar results for both cancer progression and arthritis control. CONCLUSION: The treatment of ICI-IA with a biologic DMARD is associated with more rapid arthritis control than with MTX, but may be associated with a shorter time to cancer progression.

Improvement of pregnancy counselling and contraception counselling and documentation in a single rheumatology academic practice: a quality improvement project.

The purpose of this quality improvement project was to improve the rate of pregnancy counselling and documentation regarding the risk of being on teratogenic medications, including leflunomide, mycophenolate, methotrexate or cyclophosphamide in women of childbearing age (17-50 years). Our goal was to increase documentation rates by 25% in 6 months. We first performed an EMR chart review of 103 women who were seen in the 6 months prior to intervention by faculty at a single rheumatology academic centre. We then determined how many of those women had documented contraception or pregnancy counselling, which included written documentation anywhere in the note or ICD codes which were specific to pregnancy counselling or contraception counselling. Interventions were then implemented. The percentage of women who had documented pregnancy counselling did not change preintervention and postintervention; preintervention 37% of women received documented pregnancy counselling and postintervention 35% of women received documented pregnancy counselling. The percentage of women who had documented contraception counselling did however change preintervention and postintervention; preintervention 37% of women received documented contraception counselling and postintervention 51% of women received documented contraception counselling, which is a 14% improvement.

Systematic Appraisal of the American College of Rheumatology Clinical Practice Guidelines.

OBJECTIVE: Because the American College of Rheumatology (ACR) practice guidelines affect the United States' and international treatment practice, we used the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument to characterize the quality of the guidelines and to identify potential areas for improvement. METHODS: Using the six quality domains in the AGREE II online tool, four reviewers assessed the practice guidelines available at the ACR website and the immediately previous version to summarize the domain scores for each guideline and examine trends over time. RESULTS: As of April 2016, the ACR website listed nine guidelines, four with immediate previous versions. Based on AGREE II, the minimum and maximum for each domain (with higher being better) of the current guidelines were 78-99 for Scope and Purpose, 57-99 for Stakeholder Involvement, 87- 96 for Rigor of the Methodology, 83-99 for Clarity of Presentation, 49-78 for Applicability, 69-85 for Editorial Independence, and 71-96 overall. Over time, although the average domain quality of the guidelines improved for all, the Applicability and Editorial Independence domains had the least amount of improvement. For the four guidelines with previous versions, the mean (SD) absolute improvements for each domain were 18 (±11) for Scope and Purpose, 13 (±8) for Stakeholder Involvement, 38 (±22) for Rigor of the Methodology, 25 (±15) for Clarity of Presentation, 22 (±12) for Applicability, 24 (±17) for Editorial Independence, and 31 (±5) overall. CONCLUSION: Based on the AGREE II instrument, the ACR guidelines have achieved high quality over the past 16 years. The Applicability and Editorial Independence domains have the greatest potential for future improvement.

α1-Antitrypsin deficiency in a patient diagnosed with granulomatosis with polyangiitis.

Granulomatosis with polyangiitis is a rare type of vasculitis that affects small-sized and medium-sized vessels. Any organ system can become affected, but it most commonly affects the upper airways, lungs and kidneys. The α1-antitrypsin deficiency is another rare disease that involves a genetic deficiency in the enzyme antitrypsin, which is produced in the liver and protects the lung against proteinases. The simultaneous occurrence of these two diseases is very rare and has been described. We present a case of granulomatosis with polyangiitis limited to the upper airways, and α1-antitrypsin deficiency occurring in the same patient. The patient presented with recurrent upper airway infections. The patient was treated with steroids and azathioprine which prevented recurrence of symptoms. High clinical suspicion of the concomitant occurrence of α1-antitrypsin deficiency in patients with vasculitis is essential to provide patients with adequate screening and treatment.

Preliminary evidence shows that folic acid fortification of the food supply is associated with higher methotrexate dosing in patients with rheumatoid arthritis.

BACKGROUND: Fortification of the diet with folate has been used in the United States since 1997 to prevent neural tube defects in newborn babies. However, an increase in dietary folate intake could theoretically reduce the effectiveness of the anti-folate medication, methotrexate (MTX) in treating rheumatoid arthritis (RA) and other inflammatory diseases. OBJECTIVE: To investigate whether dietary fortification with folic acid interferes with MTX function in patients with RA. METHODS: We computed MTX dose per patient per year for the years 1988 to 1999 and plotted these against time, comparing the overall mean MTX dose before and after 1997, when dietary fortification with folic acid was instituted in the USA. Thirty-six subjects met eligibility criteria. RESULTS: Mean annual MTX dose was stable between 1988 and 1996 (12.4 +/- 4.0mg), but then rose linearly from 1997 to 1999 (16.6 +/- 5.1 mg, p < 0.001). CONCLUSIONS: This preliminary study suggests that folic acid supplementation may contribute to higher MTX dosing in patients with RA.

Considerations in the treatment of early osteoarthritis.

Osteoarthritis is the most common form of arthritis and it is one of the leading causes of disability in all elderly populations. It results in enormous societal burden, including the need for joint replacement at an annual cost to the community of billions of dollars. Two factors that predicate the formulation of a treatment strategy for an individual with "early" osteoarthritis include the risk for toxicity from long duration of exposure to pharmaceuticals and the desirability of a treatment with the potential to reduce the rate of disease progression. These considerations favor approaches that avoid or minimize chronic pharmaceutical use in favor of safer interventions, especially ones where current evidence suggests the potential of a disease-modification effect. These should include socio-behavioral interventions that promote weight optimization and exercise, consideration of orthotics, general dietary recommendations to increase vitamin D and C intake, and an emphasis towards topical or intermittent use of pharmaceutical agents rather than long term nonsteroidal anti-inflammatory drug use.