Objective
To determine if the baseline presence of autoantibodies to peptidylarginine deiminase 4 (PAD4) predicts therapeutic response to biologic and conventional disease‐modifying antirheumatic ...drugs (DMARDs) in patients with rheumatoid arthritis (RA) in whom methotrexate (MTX) monotherapy was unsuccessful.
Methods
Baseline serum from 282 RA patients in whom MTX monotherapy was unsuccessful was screened for the presence of anti‐PAD4 antibodies by immunoprecipitation. Clinical response to either triple DMARD (MTX, sulfasalazine, and hydroxychloroquine) or MTX/etanercept combination therapy was determined at 24 and 48 weeks post–treatment initiation. Disease activity was measured using the Disease Activity Score 28‐joint assessment (DAS28), and erosive disease was quantified using the Sharp/van der Heijde scoring method. Generalized estimating equations (GEEs) were used to model the clinical responses to treatment in patients with and those without baseline anti‐PAD4 antibodies.
Results
Anti‐PAD4 antibody positivity was associated with male sex, a history of never smoking, and anti–citrullinated protein antibodies. At baseline, patients with anti‐PAD4 antibodies had longer disease duration and significantly more radiographic joint damage than anti‐PAD4–negative patients, but did not differ in disease activity according to the DAS28. In unadjusted analyses and multivariable GEE models, patients with anti‐PAD4 antibodies exhibited greater improvements in DAS28 (adjusted P = 0.02 and P = 0.008, respectively) and less radiographic progression (adjusted P = 0.01 and P = 0.002, respectively) compared to anti‐PAD antibody–negative patients, independent of treatment received.
Conclusion
Although anti‐PAD4 antibodies were associated with worse baseline radiographic joint damage, suggesting a history of active or undiagnosed disease, treatment escalation therapy was more effective in reducing disease activity and slowing the progression of joint damage in this patient subset.
Objective
Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We compared 5‐year adverse event (AE) incidence rates (IRs) between patients initiating ...tofacitinib and those initiating new biological disease‐modifying antirheumatic drugs (bDMARDs) within the United States (US) Corrona RA registry.
Methods
IRs (number of first events/100 patient‐years) of major adverse cardiovascular events (MACE), serious infection events (SIEs), herpes zoster (HZ), malignancies, and death were estimated among tofacitinib and bDMARD initiators, regardless of dose/schedule, between November 6, 2012 (US Food and Drug Administration tofacitinib approval), and July 31, 2018 (follow‐up through January 31, 2019). Propensity score (PS) methods were used to control for nonrandom prescribing practices. Hazard ratios (HRs) were calculated to compare rates using multivariable‐adjusted Cox regression. Different risk windows were used for acute (MACE, SIEs, HZ, and venous thromboembolic events VTEs) and long‐term (malignancy and death) events. VTEs were assessed descriptively.
Results
For MACE, SIEs, and HZ, 1999 (3152.1 patient‐years) and 8358 (12 869.4 years) tofacitinib and bDMARD initiators were included, respectively; for malignancy/death, 1999 (4505.6 patient‐years) and 6354 (16 670.8 patient‐years) initiators were included, respectively. AE rates were similar across cohorts, except for HZ, which was significantly higher with tofacitinib versus bDMARDs (PS‐trimmed adjusted HR 2.32; 95% confidence interval CI 1.43‐3.75). There were 45 (zero serious) and 88 (five serious) HZ events with tofacitinib and bDMARDs, respectively. Sensitivity analyses demonstrated similar results. VTE IRs (95% CI) were 0.29 (0.13‐0.54) and 0.33 (0.24‐0.45) for tofacitinib and bDMARDs, respectively.
Conclusion
In this registry analysis, both cohorts had similar MACE, SIE, malignancy, death, and VTE rates; HZ rates were higher for tofacitinib initaitors than for bDMARD initiators.
This commentary summarizes current knowledge on the clinical presentation, management, and outcomes of the inflammatory arthritis which may occur as an immune‐related adverse evet of immune ...checkpoint inhibitor therapy. Herein, we propose a new algorithm aimed at assisting oncologists in the diagnosis and management of this immune‐related adverse event.
To compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA).
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.
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.
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.
Immune checkpoint inhibitors are a major breakthrough in the field of oncology. Targets for approved immune checkpoint inhibitors are cytotoxic T-lymphocytes-associated antigen 4 (CTLA-4) and ...programmed cell death receptor 1/ programmed cell death ligand 1 (PD-1/PD-L1). Five patients (four males and one female) were treated with immune checkpoint inhibitors for advanced melanoma (stage III). None of them had prior history of autoimmune disorders, AIDS, or sarcoidosis. The PET/CT imaging studies showed new onset lymphadenopathy suspicious for malignancy. Four patients had cutaneous melanoma and one had vaginal melanoma. Three patients were treated with single agent (two Nivolumab, one Ipilimumab) and two with double agents (Ipilimumab and Pembrolizumab, or Ipilimumab and Nivolumab). PET/CT showed mediastinal multistational lymphadenopathy in four cases and peri-portal lymphadenopathy in one patient. Ultrasound-guided fine needle aspiration (FNA) biopsy showed numerous sarcoid-like granulomatous inflammation, while the fungal and mycobacterial infections were excluded. Cytomorphologically, the granulomas were numerous, mostly large, cellular and non-necrotizing. Multi-nucleated giant were rare or not seen at all. Cell blocks did not show any fibrosis. Other adverse effects included mouth sores, flu-like symptoms, arthritis, muscle aches, skin rashes, mild and severe colitis. The treatment was stopped and patients received prednisone. One patient developed severe adrenal insufficiency, which prolonged prednisone tapering. Their condition improved and lymphadenopathy was resolved in follow-up imaging. Sarcoid-like granulomatous inflammation is an adverse event in patients treated with immune checkpoint therapy such as Ipilimumab and Nivolumab. It can present as enlarged lymph nodes in PET/CT imaging suspicious for malignancy. FNA can serve as a minimally invasive tool to investigate the underlying cause of lymphadenopathy in this subset of patients.
•Immune checkpoint blockers are used for advanced malignant melanoma.•Sarcoid-like granulomatous inflammation is a rare adverse event of immune checkpoint blockers.•We report five cases of sarcoid-like granulomas due to immune checkpoint blocker therapy.•Image guided FNA of enlarged lymph nodes is a safe tool to confirm the diagnosis.
Immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy may vary substantially in their clinical presentation, including natural history, outcomes to ...treatment, and patterns. The application of clinical guidelines for irAE management can be challenging for practitioners due to a lack of common or consistently applied terminology. Furthermore, given the growing body of clinical experience and published data on irAEs, there is a greater appreciation for the heterogeneous natural histories, responses to treatment, and patterns of these toxicities, which is not currently reflected in irAE guidelines. Furthermore, there are no prospective trial data to inform the management of the distinct presentations of irAEs. Recognizing a need for uniform terminology for the natural history, response to treatment, and patterns of irAEs, the Society for Immunotherapy of Cancer (SITC) convened a consensus panel composed of leading international experts from academic medicine, industry, and regulatory agencies. Using a modified Delphi consensus process, the expert panel developed clinical definitions for irAE terminology used in the literature, encompassing terms related to irAE natural history (ie, re-emergent, chronic active, chronic inactive, delayed/late onset), response to treatment (ie, steroid unresponsive, steroid dependent), and patterns (ie, multisystem irAEs). SITC developed these definitions to support the adoption of a standardized vocabulary for irAEs, which will have implications for the uniform application of irAE clinical practice guidelines and to enable future irAE clinical trials.
ObjectiveTo assess whether the polymyalgia rheumatica (PMR)-like syndrome reported as an immune related adverse event (irAE) from checkpoint inhibitor therapy is consistent with the 2012 European ...League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) provisional criteria for PMR.MethodsThe cases were derived from two sources. Group 1 represents reported cases from three contributing centres. Group 2 was derived from a systematic review of the literature searching for all cases reported as PMR or PMR-like illness associated with checkpoint inhibitor therapy. Cases were assessed for the quality of reporting and then analysed to determine whether they fulfilled the 2012 EULAR/ACR provisional criteria for PMR.ResultsA total of 49 patients were included for analysis. Among the entire group, 37 (75%) were designated ‘complete’ indicating that they had sufficient data to reliably apply the 2012 EULAR/ACR criteria. 28 (75%) cases fulfilled complete criteria for PMR. A number of cases also demonstrated some clinical features unusual for idiopathic PMR.ConclusionThis study suggests a high proportion of reported cases of checkpoint inhibitor-related PMR fulfil preliminary criteria for PMR, yet in one quarter clinical details were incomplete making verification problematic. Furthermore, in the absence of a gold standard for the diagnosis of PMR, the relationship of checkpoint inhibitor-related PMR to the idiopathic form remains unclear.
Abstract Objective Autoantibodies can be useful in predicting response to certain treatments in rheumatoid arthritis (RA). We aimed to evaluate initial response to tocilizumab (TCZ) by change in ...physician and patient-reported outcomes and laboratory parameters in a real-world cohort of patients with RA. We analyzed the data by autoantibody status to determine whether patients with seronegative RA had improved response to tocilizumab when compared to their seropositive counterparts. Methods Data from the CORRONA RA registry were analyzed. Patients were included if they were started on TCZ and had data from a follow-up visit 4–8 months after initiation, as well as having information on serologic status. Serologic status was determined by presence of anti-cyclic citrullinated peptide (CCP) antibodies. Changes in disease activity measures from baseline to follow-up visit were evaluated. Results Both CCP-negative and -positive groups had statistically significant improvement in physician-reported measurements (physician rating of disease activity and joint counts), patient-reported measures (disease activity, pain, and fatigue), and acute phase reactants after 4–8 months of treatment with tocilizumab. The magnitude of improvement, however, did not differ significantly by CCP status. Conclusion Tocilizumab led to statistically significant improvement in all patient- and physician-reported measures of disease activity evaluated in this cohort of patient with RA. The response to tocilizumab did not differ by CCP status.
Objective
To provide evidence‐based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs).
Methods
This guideline follows American ...College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation.
Results
This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence.
Conclusion
Application of these recommendations should consider patients’ individual risk for vaccine‐preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision‐making with patients is encouraged in clinical settings.
Dermatoses are common and potentially serious complications of programmed cell death receptor PD-1 immune checkpoint inhibitor (anti-PD-1 ICI) therapy. Understanding their incidence is necessary to ...support clinical awareness, diagnosis, and management.
To examine the incidence and odds of reported non-cancerous dermatoses in the setting of anti-PD-1 ICI therapy.
Cross-sectional study of anti-PD-1 (pembrolizumab or nivolumab) treated patients at a tertiary healthcare institution. Selected dermatologic events following immunotherapy were identified in the electronic medical record. Comparator arm were patients that developed these same dermatoses without receiving anti-PD-1 ICI therapy.
There were 13.7% (254/1857) patients that developed one of 28 dermatoses. Compared with the general population, patients treated with anti-PD-1 had a greater risk for development of mucositis (OR 65.7, 95% CI 35.0-123.3), xerostomia (OR 11.9, 95% CI 8.4-16.8), pruritus (11.3, 95% CI 8.9-14.3), and lichen planus/lichenoid dermatitis (OR 10.7, 95% CI 5.6-20.7).
We report the frequency of dermatoses encountered in the setting of ICI therapy, both common (pruritus, rash, vitiligo) and uncommon (scleroderma, urticaria).
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