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BACKGROUND: Recent studies indicate an association between immunosuppression for immune-related adverse events (irAEs) and impaired survival in patients who received immune checkpoint inhibitors. Whether this is related to corticosteroids or second-line immunosuppressants is unknown. In the largest cohort thus far, we assessed the association of immunosuppressant type and dose with survival in melanoma patients with irAEs. METHODS: Patients with advanced melanoma who received immunosuppressants for irAEs induced by first-line anti-PD-1 ± anti-CTLA-4 were included from 18 hospitals worldwide. Associations of cumulative and peak dose corticosteroids and use of second-line immunosuppression with survival from start of immunosuppression were assessed using multivariable Cox proportional hazard regression. RESULTS: Among 606 patients, 404 had anti-PD-1 + anti-CTLA-4-related irAEs and 202 had anti-PD-1-related irAEs. 425 patients (70 %) received corticosteroids only; 181 patients (30 %) additionally received second-line immunosuppressants. Median PFS and OS from starting immunosuppression were 4.5 (95 %CI 3.4-8.1) and 31 (95 %CI 15-not reached) months in patients who received second-line immunosuppressants, and 11 (95 %CI 9.4-14) and 55 (95 %CI 41-not reached) months in patients who did not. High corticosteroid peak dose was associated with worse PFS and OS (HRadj 1.14; 95 %CI 1.01-1.29; HRadj 1.29; 95 %CI 1.12-1.49 for 80vs40mg), while cumulative dose was not. Second-line immunosuppression was associated with worse PFS (HRadj 1.32; 95 %CI 1.02-1.72) and OS (HRadj 1.34; 95 %CI 0.99-1.82) compared with corticosteroids alone. CONCLUSIONS: High corticosteroid peak dose and second-line immunosuppressants to treat irAEs are both associated with impaired survival. While immunosuppression is indispensable for treatment of severe irAEs, clinicians should weigh possible detrimental effects on survival against potential disadvantages of undertreatment.
Subject(s)
Adrenal Cortex Hormones , Immune Checkpoint Inhibitors , Immunosuppressive Agents , Melanoma , Humans , Male , Female , Melanoma/drug therapy , Melanoma/immunology , Melanoma/mortality , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Immune Checkpoint Inhibitors/adverse effects , Middle Aged , Aged , Adrenal Cortex Hormones/therapeutic use , Adrenal Cortex Hormones/adverse effects , Adult , Retrospective Studies , Skin Neoplasms/drug therapy , Skin Neoplasms/immunology , Skin Neoplasms/mortality , Aged, 80 and overABSTRACT
OBJECTIVE: Assess the diagnostic utility of repeat sacroiliac joint (SIJ) magnetic resonance imaging (MRI) examinations following an inconclusive initial examination performed for suspected sacroiliitis. METHOD: Subjects with > 1 SIJ MRI examinations, an inconclusive first scan and at least 6 months interval between scans, were included. All scans were evaluated for the presence of structural/active SIJ lesions as well as any other pathology. Clinical data was extracted from the patients' clinical files, and any missing data was obtained by a telephone interview. Diagnosis and active/structural scores were compared between first and follow-up examinations (t test). RESULTS: Seventy-one subjects were included in the study, 77.4% females, mean age 41.0 ± 15 years, mean time interval between exams 30.4 ± 25.24 months. Twelve subjects performed > 2 scans. In only two subjects (2.81%), both females, MRI diagnosis changed from inconclusive to definite sacroiliitis. None of the subjects with > 2 scans had evidence of sacroiliitis in any of the following MRI examinations. Significant differences were observed between the scores of active SIJ lesion of the first and follow-up MRI (1.51/1.62, p = 0.02) but not for scores of structural lesions (1.22/1.68, p = 0.2). CONCLUSIONS: Repeat SIJ MRI when the first MRI is inconclusive for sacroiliitis is more valuable in ruling out than in securing diagnosis of sacroiliitis. We suggest that when MRI findings are inconclusive, decision-making should be based on clinical data.
Subject(s)
Sacroiliitis , Spondylarthritis , Female , Humans , Child, Preschool , Male , Sacroiliac Joint/diagnostic imaging , Sacroiliac Joint/pathology , Sacroiliitis/diagnostic imaging , Sacroiliitis/pathology , Magnetic Resonance Imaging/methods , Spondylarthritis/pathologyABSTRACT
BACKGROUND: The link between ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) is well-established, with concurrent prevalence estimates ranging from 5-10%. However, there are still significant gaps in our understanding, and a comprehensive treatment guideline for these co-diagnosed patients has yet to be established. Our objective was to explore patterns of treatment alterations following the diagnosis of AS in patients previously diagnosed with IBD, and vice versa. Additionally, we sought to determine how these modifications influence clinical outcomes in both conditions. METHODS: This retrospective data-based cohort study included patients with coexisting IBD and AS that were diagnosed between the years 2009-2022 and were followed by the gastroenterology and the rheumatology units of the Sheba Medical Center, Israel. The data were extracted from the electronic health record and included demographic information, medication history, treatment modification at the time of second diagnosis, and the characteristics and activity of both IBD and AS at the index time and at the 3-month mark. RESULTS: The study included a total of 68 patients, with a male predominance (40 patients, 59%). The median age was 43 years (IQR 31-55) and 78% had Crohn's disease (CD). The median duration between the diagnosis of the first disease to the second one was 4 years (IQR 1-9.5). A significant proportion of patients (85%) underwent treatment modification at their second diagnosis. Out of the total cohort, 28% initiated biological therapy, 17.6% switched their biologic regimen, and 16.2% discontinued NSAIDS. Patients who underwent biologic modifications at time of the second diagnosis (the initiation/switch/augmentation of a concurrent regimen) experienced significantly higher rates of clinical improvement in either IBD or AS at the 90-day follow-up compared to patients who did not (68% vs. 32%, p = 0.004), and biologic modification was found to be an independent predictor for clinical improvement (OR 3.69, CI 1.08-12.58, p = 0.037). CONCLUSIONS: Our findings suggest that biologic therapy modification at the time of the second diagnosis was associated with a higher rate of improvement in AS/IBD at the 90-day follow-up.
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Objective: We aimed to characterize the course of COVID-19 in autoimmune inflammatory rheumatic disease (AIIRD) patients in Israel, taking into consideration several remarkable aspects, including the outcomes of the different outbreaks, the effect of vaccination campaigns, and AIIRD activity post-recovery. Methods: We established a national registry of AIIRD patients diagnosed with COVID-19, including demographic data, AIIRD diagnosis, duration and systemic involvement, comorbidities, date of COVID-19 diagnosis, clinical course, and dates of vaccinations. COVID-19 was diagnosed by a positive SARS-CoV-2 polymerase chain reaction. Results: Israel experienced 4 outbreaks of COVID-19 until 30.11.2021. The first three outbreaks (1.3.2020 - 30.4.2021) comprised 298 AIIRD patients. 64.9% had a mild disease and 24.2% had a severe course; 161 (53.3%) patients were hospitalized, 27 (8.9%) died. The 4th outbreak (delta variant), starting 6 months after the beginning of the vaccination campaign comprised 110 patients. Despite similar demographic and clinical characteristics, a smaller proportion of AIIRD patients had negative outcomes as compared to the first 3 outbreaks, with regards to severity (16 patients,14.5%), hospitalization (29 patients, 26.4%) and death (7 patients, 6.4%). COVID-19 did not seem to influence the AIIRD activity 1-3 months post-recovery. Conclusions: COVID-19 is more severe and has an increased mortality in active AIIRD patients with systemic involvement, older age and comorbidities. Vaccination with 3 doses of the mRNA vaccine against SARS-CoV-2 protected from severe COVID-19, hospitalization and death during the 4th outbreak. The pattern of spread of COVID-19 in AIIRD patients was similar to the general population.
Subject(s)
COVID-19 , Rheumatic Diseases , Humans , COVID-19/epidemiology , COVID-19/prevention & control , Israel/epidemiology , SARS-CoV-2 , COVID-19 Testing , COVID-19 Vaccines , Rheumatic Diseases/epidemiology , VaccinationABSTRACT
Aim: The aim of this study was to test the reliability of the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT) 2.0 questionnaire in Hebrew. Methods: UCLA SCTC GIT 2.0 was translated into Hebrew using the translation-retranslation method. The Hebrew version of the UCLA SCTC GIT 2.0 and the Hebrew version of the Short Form 36 (SF-36) were administered to 19 Hebrew-speaking patients with systemic sclerosis. Internal reliability was assessed using Cronbach's alpha. The Hebrew questionnaire was then tested for external validity using Spearman's correlation coefficient. Correlations (rho) ⩽ 0.29 were considered small, 0.30 to 0.49 were moderate, and those ⩾0.50 were considered large. Differences were considered statistically significant at p < 0.05. Results: A group of 19 patients treated at Sheba Medical Center meeting the ACR/EULAR classification system for systemic sclerosis were included in the study. The mean age of the participants was 60.4 ± 12 years with a female predominance (84%). Diffuse cutaneous scleroderma accounted for 10 of the participants (54%), 7 had limited cutaneous scleroderma (36%) with 2 having an overlap syndrome (10%). The Cronbach's alpha value for the UCLA SCTC GIT 2.0 scale was 0.908 showing reliability. In addition, the UCLA SCTC GIT 2.0 showed correlation to the SF-36. Conclusion: The translation of the Hebrew UCLA SCTC GIT 2.0 scale was reliable and valid with a total Cronbach's alpha score among the participants of 0.908. Cronbach's alpha was particularly reliable in reflux, bloating, social function, and emotional well-being. Our results suggest that our Hebrew version of the UCLA SCTC GIT 2.0 scale can be used as a tool in future studies with Hebrew-speaking patients. In the abstract conclusion, it states that "Cronbach's alpha was particularly reliable in reflux, bloating, social function, and emotional well-being." The related data should be listed in the results section and then an interpretation of the results should be listed in the conclusions section. Please revise.
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BACKGROUND: An association between diffuse idiopathic skeletal hyperostosis (DISH) and a history of coronary artery disease (CAD) was previously reported. PURPOSE: To investigate the association between DISH and CAD as assessed using the coronary artery calcification score (CACS) and the CAD-Reporting and Data System (CAD-RADS) score in patients with symptomatic chest pain. MATERIAL AND METHODS: Consecutive cardiac CT scans performed before and after IV contrast administration were evaluated for CACS (Agatston method), CAD-RADS, and the presence of DISH. The association of DISH with the presence and extent of CACS/CAD-RADS scores was analyzed with and without adjustment for known atherosclerotic risk factors. RESULTS: The study cohort included 268 individuals (157 men, 111 women; median age = 54 years). DISH was present in 65 (24.3%) individuals. CACS was significantly higher in the DISH group compared to the non-DISH group in the univariate analysis (median CACS DISH = 2, range = 0-80.5 vs. median CACS non-DISH = 0, range = 0-11; P < 0.005) but this association did not persist on multivariate analysis. There was a positive trend toward higher CAD-RADS scores in the DISH group (P = 0.03) but after adjustment for age, male sex, and family history, this tendency was not significant. CONCLUSION: No independent association was found between the presence of DISH and CACS and CAD-RADS scores. Our findings suggest a more complex and possibly non-causal relationship between coronary artery disease and DISH.
Subject(s)
Coronary Artery Disease , Hyperostosis, Diffuse Idiopathic Skeletal , Vascular Calcification , Humans , Male , Female , Middle Aged , Coronary Artery Disease/diagnostic imaging , Hyperostosis, Diffuse Idiopathic Skeletal/complications , Hyperostosis, Diffuse Idiopathic Skeletal/diagnostic imaging , Coronary Angiography/methods , Risk Assessment/methods , Tomography, X-Ray Computed/adverse effects , Risk FactorsABSTRACT
BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive disease associated with mutations in the Mediterranean fever gene (MEFV) that manifests with recurrent episodes of febrile serositis. Fabry's disease (FD) is an X-linked lysosomal storage disease caused by mutations in the alpha-galactosidase A gene and presents with a wide range of gastrointestinal, skin, vascular, renal and neurological manifestations. FMF and FD share similar manifestations, which may lead to misdiagnosis of one as the other; mostly FD is misdiagnosed as FMF. Moreover, various overlapping manifestations may stem from comorbidities, commonly coupled to FMF (such as Behcet's disease, inflammatory bowel disease, glomerulonephritis, fibromyalgia, and multiple sclerosis), as well as from colchicine adverse effects, which may add to the diagnostic confusion. Thus, we postulated that screening FMF for FD will lead to the identification of patients falsely diagnosed with FMF or who, in addition to FMF, suffer from FD that was previously missed. METHODS: To identify missed FD among the FMF population, we performed chemical and genetic analyses for FD in blood samples obtained from a cohort of FMF patients followed in the specialized FMF center of our institution. To increase the likelihood of detecting patients with FD, we enriched the surveyed FMF population with patients exhibiting manifestations shared by patients with FD or who deviate from the typical FMF presentation. RESULTS AND CONCLUSIONS: Of 172 surveyed FMF patients in a cohort derived from a clinic dedicated to FMF, none had FD. Thus, the postulation of increased odds for detecting FD in patients with FMF was not confirmed. Further exploration for FD in FMF population, is nevertheless recommended.
Subject(s)
Fabry Disease , Familial Mediterranean Fever , Humans , Familial Mediterranean Fever/complications , Familial Mediterranean Fever/diagnosis , Familial Mediterranean Fever/genetics , Pyrin/genetics , Fabry Disease/diagnosis , Fabry Disease/genetics , Fabry Disease/complications , alpha-Galactosidase/genetics , Colchicine , MutationABSTRACT
OBJECTIVES: Ankylosing spondylitis (AS) is a chronic progressive and debilitating form of arthritis with associated extra-articular features including uveitis, intestinal and lung apical inflammation and psoriasis. Putative associations between AS and neurologic disorders has been relatively overlooked. The purpose of this study is to assess the link between AS and major neurologic disorders and whether treatment with Tumor-Necrosis-Factor inhibitors (TNFi) has an impact on that association. METHODS: A retrospective cross-sectional study was carried out based on the Clalit Health Services (CHS) computerized database. AS patients were compared to age- and gender-matched controls with respect to the proportion of Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, and multiple sclerosis (MS). The impact of AS therapy (biologic vs conventional therapy) was assessed as well. RESULTS: 4082 AS patients and 20,397 age- and gender-matched controls were identified. AS was associated with a higher prevalence of AD (odds-ratio(OR) 1.46 [95%Confidence-interval(CI) 1.13-1.87], p = 0.003), epilepsy (OR 2.33 [95%CI 1.75-3.09] p < 0.0001) and PD (OR 2.75 [95%CI 2.04-3.72], p < 0.0001), whereas no statistically significant association was found for MS. Association with PD remained significant in the multivariate analysis (OR 1.49 [95%CI 1.05-2.13],p = 0.027). Within AS patients, the use of TNFi (OR 0.10 [95%CI 0.01-0.74], p = 0.024) were associated with a lowered risk of developing AD. CONCLUSION: AS is positively associated with AD, PD, and epilepsy but not MS. AS patients treated with TNFi have lower rates of AD.
Subject(s)
Antirheumatic Agents , Dementia , Spondylitis, Ankylosing , Antirheumatic Agents/therapeutic use , Cross-Sectional Studies , Dementia/drug therapy , Humans , Retrospective Studies , Spondylitis, Ankylosing/complications , Spondylitis, Ankylosing/drug therapy , Spondylitis, Ankylosing/epidemiology , Tumor Necrosis Factor Inhibitors , Tumor Necrosis Factor-alphaABSTRACT
Familial Mediterranean fever (FMF), the most frequent monogenic autoinflammatory disease, is manifested with recurrent and chronic inflammation and amyloid A (AA) amyloidosis, driven by overproduction of interleukin 1 (IL-1) through an activated pyrin inflammasome. Consequently, non-responsiveness to colchicine, the cornerstone of FMF treatment, is nowadays addressed by IL-1- blockers. Each of the two IL-1 blockers currently used in FMF, anakinra and canakinumab, has its own merits for FMF care. Here we focus on anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, and explore the literature by using PubMed regarding the utility of anakinra in certain conditions of FMF. Occasionally we enrich published data with our own experience. To facilitate insights to anakinra role, the paper briefs some clinical, genetic, pathogenetic, and management aspects of FMF. The clinical settings of FMF covered in this review include colchicine resistance, AA amyloidosis, renal transplantation, protracted febrile myalgia, on- demand use, leg pain, arthritis, temporary suspension of colchicine, pediatric patients, and pregnancy and lactation. In many of these instances, either because of safety concerns or a necessity for only transient and short-term use, anakinra, due to its short half-life, is the preferred IL-1 blocker.
Subject(s)
Amyloidosis , Familial Mediterranean Fever , Amyloidosis/etiology , Child , Colchicine/therapeutic use , Familial Mediterranean Fever/drug therapy , Female , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin-1 , Serum Amyloid A ProteinABSTRACT
OBJECTIVES: To validate in a large cohort with right-sided aorta the theory that thoracic right-sided flowing osteophytes in DISH results from a 'protective' effect of the pulsating descending left-sided thoracic aorta. METHODS: Chest CTs of patients with DISH and right-sided aorta and controls with DISH and left-sided aorta were evaluated and compared on each intervertebral space (IS) for the location of the aorta (right, left, centre) and the location of the osteophyte relative to the aorta (contralateral, ipsilateral, bilateral). RESULTS: The study and control cohorts included 31 and 35 subjects, respectively (male 22/9 and female 27/8; median age 64.8/65.3 years; P = 0.86). Osteophytes contralateral to the aorta's location were recorded in the majority of ISs in both the study and control groups (47% and 60%, respectively; P > 0.05), while ipsilateral osteophytes were recorded in 6.9% and 7.7%, respectively (P = 0.002). Bilateral osteophytes located to the right and the left of the aorta were significantly more prevalent in the study group compared with the controls (17.2% and 5.4%, respectively; P = 0.04). CONCLUSIONS: Aortic pulsation plays an important role in inhibiting the development of osteophytes and results in the majority of contralateral osteophytes on both right-sided and left-sided aortas. However, since both ipsilateral and bilateral osteophytes were not at all rare in both groups, other parameters, which are yet to be established, probably contribute to the location of osteophytes.
Subject(s)
Hyperostosis, Diffuse Idiopathic Skeletal , Osteophyte , Humans , Male , Female , Middle Aged , Osteophyte/diagnostic imaging , Spine , Aorta/diagnostic imaging , Aorta, Thoracic/diagnostic imagingABSTRACT
OBJECTIVES: Evidence suggests a possible association between the COVID-19 vaccine and autoimmune disease flares or new onset of various autoinflammatory manifestations, such as pericarditis and myocarditis. The objective of this study was to assess the safety of an mRNA-based BNT162b2 anti-COVID-19 vaccine in individuals with FMF, a prototypic autoinflammatory disease. METHODS: Patients participating in this study fulfilled the criteria for diagnosis of FMF, were older than 18 years and received at least one dose of the vaccine. Data on baseline characteristics, features of FMF, post-vaccination side effects, and disease flares were acquired using electronic medical files and telephone interviews. RESULTS: A total of 273 FMF patients were recruited for the study. >95% were vaccinated with two doses of the vaccine. The rates of local reactions following the first and second vaccine doses were 65.5% and 60%, respectively, and 26% and 50.4%, respectively, for systemic adverse events. These rates are lower than those reported for the general population from real-world and clinical trial settings. Postvaccination FMF activity remained stable in most patients. None of the patients reported an attack of pericarditis or myocarditis, considered the most serious vaccine-associated adverse events. Patients with a more active FMF disease and patients harboring the M694V mutation had a significantly higher rate of post-vaccination systemic side effects and attacks. CONCLUSION: The BNT162b2 mRNA COVID-19 vaccine is safe in patients with FMF. Our results support the administration of this vaccine to FMF patients according to guidelines applicable to the general population.
Subject(s)
BNT162 Vaccine , COVID-19 , Familial Mediterranean Fever , Myocarditis , Pericarditis , BNT162 Vaccine/adverse effects , COVID-19/prevention & control , Familial Mediterranean Fever/genetics , Humans , Myocarditis/complications , Pericarditis/complications , RNA, MessengerABSTRACT
OBJECTIVE: To evaluate the frequency of sacroiliitis in older subjects. MATERIALS AND METHODS: Consecutive MRI examinations of the sacroiliac joints (SIJs) performed for suspected sacroiliitis (2005-2019) in patients ≥ 18 years were retrospectively evaluated for the presence of active/structural lesions and were categorized for the presence/absence of sacroiliitis. Clinical and imaging parameters were compared between subjects with sacroiliitis according to age groups < 40 years, 40-55, and > 55 years. Clinical parameters including inflammatory back pain (IBP) and other spondyloarthritis (SpA) features were retrieved from the medical records. RESULTS: A total of 431 patients with SIJs MRI were evaluated: median age, 44 [IQR 35-54]; female:male 267(62%):164(38%). Sacroiliitis was diagnosed in 89 (20.6%) subjects-median age, 41 years [IQR 32-54], 52% females- and was equally prevalent among the different age groups: > 40 years old, 23.6%; 40-55, 20%; and > 55 years old, 17%, p = 0.43, with active/structural lesions equally dispersed. Older patients (> 55) started suffering from back pain at an older age and had a longer delay in diagnosis. Gender distribution, the presence of IBP, and other SpA features were no different in patients < 45 and > 55 years of age. CONCLUSIONS: The frequency of sacroiliitis on SIJs-MRI in subjects > 55 years is similar to its frequency in younger subjects and is associated with the same type and magnitude of active and structural MRI lesions. Clinical parameters such as IBP and additional SpA features are similarly prevalent in older and younger subjects suggesting they suffer from the same disease and differing only in age of presentation.
Subject(s)
Sacroiliitis , Spondylarthritis , Adult , Aged , Back Pain/diagnostic imaging , Back Pain/epidemiology , Female , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Retrospective Studies , Sacroiliac Joint/diagnostic imaging , Sacroiliitis/diagnostic imaging , Spondylarthritis/diagnostic imagingABSTRACT
BACKGROUND: Takayasu arteritis (TA), a systemic large-vessel vasculitis, was reported to have high incidence of spondyloarthropathy. PURPOSE: To evaluate the prevalence of inflammatory sacroiliitis in patients with TA that underwent abdominal/pelvic magnetic resonance imaging (MRI) examinations as part of their vasculitis work-up. MATERIAL AND METHODS: Consecutive abdominal/pelvic MRI examinations of 34 patients with TA fulfilling the 1990 ACR criteria and 34 age- and gender-matched controls performed between 2008 and 2020 were retrospectively reviewed for the presence sacroiliitis. The presence of active and structural lesions was scored twice (with a one-month interval between reads) by one reader. Structural lesions were also evaluated on computed tomography, when available, and correlated to MRI findings. Clinical data were extracted from the patients' clinical files. MRI scores were compared between the study and control groups and correlated with the clinical data. RESULTS: Sacroiliitis was evident in 11.7% of the TA group examinations compared to 0.3% in the control group (P = 0.6). Participants with TA had significantly more erosions and fat deposition compared to the control group (Study: 0.01/0.03, Control: 0/0, P = 0.03/0.003, respectively). However, mean sacroiliitis score was not significantly different (Study: 1.06, Control: 0.78, P = 0.015). Of the four patients with TA and sacroiliitis, 3 (75%) had a diagnosis of inflammatory bowel disease (IBD). CONCLUSION: Sacroiliitis was detected in 11.7% of abdominal MRI examinations of patients with TA, 75% of which had associated IBD, suggesting that both IBD and sacroiliitis should be routinely screened in the TA population as their presence may influence treatment decisions.
Subject(s)
Magnetic Resonance Imaging , Sacroiliitis/diagnostic imaging , Takayasu Arteritis/diagnostic imaging , Abdomen/diagnostic imaging , Adult , Aged , Bone Marrow Diseases/diagnostic imaging , Case-Control Studies , Edema/diagnostic imaging , Female , Humans , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/diagnostic imaging , Male , Middle Aged , Pelvis/diagnostic imaging , Prevalence , Retrospective Studies , Sacroiliac Joint/diagnostic imaging , Sacroiliitis/complications , Sacroiliitis/epidemiology , Takayasu Arteritis/complications , Tomography, X-Ray Computed , Young AdultABSTRACT
OBJECTIVE: To describe the clinical features of patients with bisphosphonate related ocular side effects (BROSE). METHODS: The medical records of all patients with BROSE between January 2009 and December 2019 were reviewed. RESULTS: Nine cases with BROSE were identified. All subjects were female. Median age at diagnosis was of 69 years. The leading indication for bisphosphonate treatment was osteoporosis (n=7), Paget's disease of bone (n=1) and breast cancer (n=1). Six (66.67%) patients presented with uveitis, one (11%) episcleritis and two (22%) with orbital inflammation. Five events (55.5%) occurred within 10 days of initiating the bisphosphonate and the rest (44.44%) developed within 2 weeks to 3 years later. Four (44.44%) patients had concurrent thyroid disease. An association was found between underlying thyroid disease or autoimmunity. CONCLUSION: BROSE is an uncommon complication of bisphosphonate therapy occurring more frequently in patients with an autoimmune predisposition.
Subject(s)
Diphosphonates , Eye Diseases , Aged , Female , Humans , Male , Diphosphonates/adverse effects , Eye Diseases/chemically inducedABSTRACT
BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease that may affect the heart and the autonomic nervous system (ANS). There is little knowledge regarding the degree of ANS involvement in SSc patients with unknown cardiac disease. OBJECTIVES: To evaluate cardiac and pupillary autonomic functions in patients before cardiac involvement has emerged. METHODS: The study comprised 19 patients with SSc and 29 healthy controls. Heart rate variability (HRV) analysis for time and frequency domains, as well as deep breathing test and Ewing maneuvers, were performed in all patients. Automated pupillometry for the evaluation of pupillary diameter and pupillary light reflex was completed in 8 SSc patients and 21 controls. RESULTS: Both groups had similar characteristics, except for medications that were more commonly or solely prescribed for SSc patients. Compared with control subjects, the SSc patients had significantly lower HRV parameters of NN50 (15.8 ± 24.4 vs. 33.9 ± 33.1, P = 0.03), pNN50 (4.9 ± 7.4% vs.10.8 ± 10.8%, P = 0.03), and triangular index (11.7 ± 3.4 vs. 15.7 ± 5.8, P = 0.02). Abnormal adaptive responses in heart rate changes were recorded during deep breathing tests and Ewing maneuvers. There was no significant difference in any of the pupillometric indices or other HRV parameters within groups. CONCLUSIONS: SSc patients may manifest cardiac autonomic dysfunction, while their autonomic pupillary function is seemingly spared. The role of certain medications, the significance of differential organ involvement, as well as the prognostic value of our findings should be evaluated in future studies.
Subject(s)
Autonomic Nervous System Diseases , Heart Diseases , Heart Rate , Pupil Disorders , Reflex, Pupillary , Scleroderma, Systemic , Adult , Autonomic Nervous System Diseases/diagnosis , Autonomic Nervous System Diseases/etiology , Autonomic Nervous System Diseases/physiopathology , Case-Control Studies , Electrocardiography, Ambulatory/methods , Female , Heart Diseases/diagnosis , Heart Diseases/etiology , Humans , Israel/epidemiology , Male , Neurologic Examination/methods , Predictive Value of Tests , Prognosis , Pupil Disorders/diagnosis , Pupil Disorders/etiology , Scleroderma, Systemic/complications , Scleroderma, Systemic/diagnosis , Scleroderma, Systemic/physiopathologyABSTRACT
BACKGROUND: Tocilizumab is an anti-IL-6 therapy widely adopted in the management of the so-called "cytokine storm" related to SARS-CoV-2 virus infection, but its effectiveness, use in relation to concomitant corticosteroid therapy and safety were unproven despite widespread use in numerous studies, mostly open label at the start of the pandemic. METHODS: We performed a systematic review and meta-analysis of case-control studies utilising tocilizumab in COVID-19 on different databases (PubMed/MEDLINE/Scopus) and preprint servers (medRxiv and SSRN) from inception until 20 July 2020 (PROSPERO CRD42020195690). Subgroup analyses and meta-regressions were performed. The impact of tocilizumab and concomitant corticosteroid therapy or tocilizumab alone versus standard of care (SOC) on the death rate, need for mechanical ventilation, ICU admission and bacterial infections were assessed. RESULTS: Thirty-nine studies with 15,531 patients (3657 cases versus 11,874 controls) were identified. Unadjusted estimates (n = 28) failed to demonstrate a protective effect of tocilizumab on survival (OR 0.74 ([95%CI 0.55-1.01], p = 0.057), mechanical ventilation prevention (OR 2.21 [95%CI 0.53-9.23], p = 0.277) or prevention of ICU admission (OR 3.79 [95%CI 0.38-37.34], p = 0.254). Considering studies with adjusted, estimated, tocilizumab use was associated with mortality rate reduction (HR 0.50 ([95%CI 0.38-0.64], p < 0.001) and prevention of ICU admission (OR 0.16 ([95%CI 0.06-0.43], p < 0.001). Tocilizumab with concomitant steroid use versus SOC was protective with an OR of 0.49 ([95%CI 0.36-0.65], p < 0.05) as was tocilizumab alone versus SOC with an OR of 0.59 ([95%CI 0.34-1.00], p < 0.001). Risk of infection increased (2.36 [95%CI 1.001-5.54], p = 0.050; based on unadjusted estimates). CONCLUSION: Despite the heterogeneity of included studies and large number of preprint articles, our findings from the first eight of the pandemic in over 15,000 COVID-19 cases suggested an incremental efficacy of tocilizumab in severe COVID-19 that were confirmed by subsequent meta-analyses of large randomized trials of tocilizumab. This suggests that analysis of case-control studies and pre-print server data in the early stages of a pandemic appeared robust for supporting incremental benefits and lack of major therapeutic toxicity of tocilizumab for severe COVID-19.
Subject(s)
COVID-19 Drug Treatment , Pandemics , Antibodies, Monoclonal, Humanized , Humans , SARS-CoV-2 , Standard of Care , Treatment OutcomeABSTRACT
OBJECTIVE: To analyse the clinical patterns of sarcoidosis triggered by immune checkpoint inhibitors (ICIs) in patients with cancer. PATIENTS AND METHODS: The ImmunoCancer International Registry is a big data-sharing multidisciplinary network from 18 countries dedicated to evaluating the clinical research of immune-related adverse events related to cancer immunotherapies. RESULTS: We identified 32 patients with biopsy-proven sarcoidosis. Underlying cancer included mainly melanoma (n = 24). Cancer immunotherapy consisted of monotherapy in 19 cases (anti-PD-1 in 18 and ipilimumab in 1) or combined ipilimumab + nivolumab in 13. The time median interval between initiation of ICI and sarcoidosis diagnosis was 3 months (range, 2-29 months). The use of combined ICI was associated with a shorter delay in developing sarcoidosis symptoms. The disease was symptomatic in 19 (59%) cases with mostly cutaneous, respiratory and general symptoms. The organs involved included mainly the mediastinal lymph nodes (n = 32), the lungs (n = 11), the skin (n = 10) and the eyes (n = 5). Pulmonary computed tomography studies showed bilateral hilar lymphadenopathy in all cases. There was no severe manifestation. Specific systemic therapy was required in only 12 patients (37%): oral glucocorticoids in 9, and hydroxychloroquine in 3. ICIs were held in 25 patients (78%) and definitively discontinued in 18 (56%) patients. Seven patients continued ICI treatment with a second flare in one case. In six additional patients, an ICI was reintroduced with no harm, and sarcoidosis relapsed in one of them. CONCLUSION: Our study shows that ICI-related sarcoidosis seems to have a specific profile, possibly more benign than that of idiopathic sarcoidosis, and does not necessarily imply ICI discontinuation.
Subject(s)
Immune Checkpoint Inhibitors/administration & dosage , Immunotherapy/adverse effects , Sarcoidosis/chemically induced , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Biopsy , Female , Humans , Immune Checkpoint Inhibitors/therapeutic use , Ipilimumab/adverse effects , Ipilimumab/therapeutic use , Lung/drug effects , Lymph Nodes/drug effects , Male , Melanoma/drug therapy , Middle Aged , Nivolumab/adverse effects , Nivolumab/therapeutic use , Skin Neoplasms/drug therapy , Young AdultABSTRACT
OBJECTIVES: To evaluate the efficacy of IL-1 blockers in a cohort of patients with colchicine-resistant familial Mediterranean fever (crFMF) treated consecutively with anakinra and canakinumab. METHODS: Patients with crFMF treated with anakinra and canakinumab in any order were identified using the computerised database of Sheba Medical Centre. Background characteristics of the patients, reason for switching IL-1 inhibitor, and frequency of attacks under colchicine only, anakinra, and canakinumab were extracted from the computerised patient files. Patients were then interviewed for patient-reported outcomes. RESULTS: A total of 46 patients in our clinic were prescribed canakinumab for crFMF after previous anakinra treatment, whereas no patients who switched treatment from canakinumab to anakinra were identified. Of those, 23/46 patients (50%) discontinued anakinra due to inadequate response (11 of them with secondary failure after a good initial response). Frequency of flares was significantly decreased following switch to canakinumab from anakinra treatment (p<0.01). After the switch to canakinumab, the median duration of flares, the severity of pain during a flare, and the patient's global assessment of disease activity were all significantly decreased (p≤0.01), according to the reports from the patients. CONCLUSIONS: Canakinumab is an effective treatment for FMF after failure of anakinra due to any cause.
Subject(s)
Familial Mediterranean Fever , Antibodies, Monoclonal, Humanized , Colchicine , Familial Mediterranean Fever/diagnosis , Familial Mediterranean Fever/drug therapy , Humans , Interleukin 1 Receptor Antagonist Protein , Interleukin-1 , Treatment OutcomeABSTRACT
PURPOSE: To evaluate the association between body mass index (BMI) and tumor necrosis factor α (TNF-α) blockers retention in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: This prospective cohort study analyzed data about patients with RA who initiated TNF blockers from the Israeli registry of inflammatory diseases from 2011 to 2019. Patients were grouped by BMI: normal (BMI <24.9 kg/m2), overweight (BMI 25-29.9 kg/m2), obese (BMI 30-34.9 kg/m2) and morbid obese (BMI ≥35 kg/m2). Treatment cessation due to inefficacy was defined as an "event" and therapy with a drug above 3 months was defined as a "course." Kaplan-Meier survival curve was used to describe drug survival. Event-free survival was calculated using Cox regression with a hazard ratio and confidence interval of 95%. RESULTS: The final analysis included 521 RA patients (80% females) treated with etanercept, infliximab, adalimumab or golimumab. Eight hundred and eighteen treatment initiations were included in the final analysis, 334 (41%) in the normal weight group, 261 (32%) in the overweight, 144 (17%) in the obese and 79 (10%) in the morbid obesity group. Three hundred and twenty-six (40%) treatment initiations were with etanercept, 215 (26%) with adalimumab 197 (24%) with infliximab, and 80 (10%) with golimumab. BMI was inversely associated with drug survival. Morbid obese patients were more likely to discontinue treatment compared with normal weight patients HR 2.28 (95% CI 1.67-3.10, p<0.01). This association remained significant for each drug type (except for golimumab) in a subgroup analysis. Adalimumab switch rate was higher compared to etanercept with HR =1.51 (95% CI 1.20-1.91, p<0.01), no other significant differences were noted between the other drugs. CONCLUSION: Morbid obese RA patients have lower TNF-α blocker retention compared to normal weight patients.
ABSTRACT
OBJECTIVE: FMF is an autoinflammatory disease of genetic origin. Colchicine is the mainstay of treatment for the prevention of attacks and long-term complications but 5-10% of FMF patients are resistant to colchicine therapy. The aim of our study was to investigate the real-life safety and efficacy of anakinra in a cohort of patients with colchicine-resistant FMF. METHODS: In this retrospective study, patients treated with anakinra for colchicine-resistant FMF between 2010 and 2018 were identified using the computerized database of Sheba Medical Center and enrolled in the study. Data from structured clinical files were analysed to evaluate the efficacy and safety outcomes. To assess efficacy, we used the Global Assessment Score (GAS), a measure comprised of three different domains: number of attacks per month, duration of attacks and number of sites involved in the attacks. Reported adverse events were compiled. RESULTS: A total of 44 patients (24 female) were treated with anakinra. Of these patients, 75% were homozygous for the M649V mutation. The mean duration of treatment was 18 months. The GAS decreased significantly from 6.6 (IQR 5.3-7.8) before treatment to 2 (IQR 0-4.2) while on treatment (P < 0.001). During anakinra treatment, six hospitalizations were reported (three due to related adverse effects). In addition, 11 patients suffered from injection site reactions (5 ceased treatment). Twelve patients reported mild side effects. CONCLUSION: Treatment with anakinra is beneficial for the majority of colchicine-resistant FMF patients and is relatively safe.