Corticosteroids and other immunosuppressants for immune-related adverse events and checkpoint inhibitor effectiveness in melanoma.

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.

Screening for Fabry's disease in a high-risk subpopulation of FMF.

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.

TNF inhibitors have a protective role in the risk of dementia in patients with ankylosing spondylitis: Results from a nationwide study.

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.

The Preferential Use of Anakinra in Various Settings of FMF: A Review Applied to an Updated Treatment-Related Perspective of the Disease.

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.

Bisphosphonates Related Ocular Side Effects: A Case Series and Review of Literature.

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.

The prevalence of sacroiliitis on abdominal MRI examinations of patients with Takayasu arteritis.

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.

Immune checkpoint inhibitor-associated sarcoidosis: A usually benign disease that does not require immunotherapy discontinuation.

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.

High Body Mass Index is Associated with Shorter Retention of Tumor Necrosis Factor-Alpha Blocker Treatment in Rheumatoid Arthritis.

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.

Immune-Mediated Disease Flares or New-Onset Disease in 27 Subjects Following mRNA/DNA SARS-CoV-2 Vaccination.

BACKGROUND: Infectious diseases and vaccines can occasionally cause new-onset or flare of immune-mediated diseases (IMDs). The adjuvanticity of the available SARS-CoV-2 vaccines is based on either TLR-7/8 or TLR-9 agonism, which is distinct from previous vaccines and is a common pathogenic mechanism in IMDs. METHODS: We evaluated IMD flares or new disease onset within 28-days of SARS-CoV-2 vaccination at five large tertiary centres in countries with early vaccination adoption, three in Israel, one in UK, and one in USA. We assessed the pattern of disease expression in terms of autoimmune, autoinflammatory, or mixed disease phenotype and organ system affected. We also evaluated outcomes. FINDINGS: 27 cases included 17 flares and 10 new onset IMDs. 23/27 received the BNT - 162b2 vaccine, 2/27 the mRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female. Among the 27 cases, 21 (78%) had at least one underlying autoimmune/rheumatic disease prior the vaccination. Among those patients with a flare or activation, four episodes occurred after receiving the second-dose and in one patient they occurred both after the first and the second-dose. In those patients with a new onset disease, two occurred after the second-dose and in one patient occurred both after the first (new onset) and second-dose (flare). For either dose, IMDs occurred on average 4 days later. Of the cases, 20/27 (75%) were mild to moderate in severity. Over 80% of cases had excellent resolution of inflammatory features, mostly with the use of corticosteroid therapy. Other immune-mediated conditions included idiopathic pericarditis (n = 2), neurosarcoidosis with small fiber neuropathy (n = 1), demyelination (n = 1), and myasthenia gravis (n = 2). In 22 cases (81.5%), the insurgence of Adverse event following immunization (AEFI)/IMD could not be explained based on the drug received by the patient. In 23 cases (85.2%), AEFI development could not be explained based on the underlying disease/co-morbidities. Only in one case (3.7%), the timing window of the insurgence of the side effect was considered not compatible with the time from vaccine to flare. INTERPRETATION: Despite the high population exposure in the regions served by these centers, IMDs flares or onset temporally-associated with SARS-CoV-2 vaccination appear rare. Most are moderate in severity and responsive to therapy although some severe flares occurred. FUNDING: none.

Familial Mediterranean fever (FMF)-response to TNF-blockers used for treatment of FMF patients with concurrent inflammatory diseases.

OBJECTIVE: Familial Mediterranean fever (FMF) is the most common interleukin 1 (IL-1)-driven monogenic autoinflammatory disease. Yet published data also suggest that tumor necrosis factor (TNF) may have a role in the pathogenesis of FMF and may serve as a target for treatment. In the present study we evaluate this hypothesis. METHODS: To this goal, we studied the incidental effect on FMF of TNF-directed treatment, administered to colchicine-refractory FMF patients for the management of a concurrent inflammatory disease. The rates of FMF patients and of treatments with complete or nearly complete FMF response were determined, based on the number of FMF attacks during TNF-blocker exposures. The possible effect of various FMF and non-FMF features on the outcome was determined using comparative analysis. Patients were identified and data were retrieved using electronic files from the FMF clinic. RESULTS: Twenty-six patients were identified, each receiving ≥1 of four TNF-blockers for a mean duration of 27.6±16.4months. The TNF-blockers were found to induce complete or nearly complete FMF response in 10 (38.5%) of the patients, and in 13 of 50 (26%) exposures. No clinical, genetic, demographic, or therapeutic feature could predict which FMF patient would respond favorably to TNF-blocker therapy. CONCLUSION: This study suggests that TNF-blockers may be beneficial for a small proportion of colchicine-resistant FMF patients.

The utility of PET/CT in large vessel vasculitis.

18F-FDG PET/CT occupies a growing role in the diagnosis of large vessel vasculitis (LVV), illustrating enhanced uptake in the lining of large vessels. A retrospective single center study was conducted of patients who underwent 18F-FDG PET/CT scans between 2009 and 2019 at Sheba Medical Center, Israel. The imaging results were analyzed for evidence of LVV. We reviewed the PET/CT scans of 126 patients and identified 57 studies that either showed evidence of active LVV or that had been performed in patients previously treated for systemic vasculitis. In 6 patients with fevers of unknown origin and elevated inflammatory markers, PET/CT revealed LVV. Six of 13 patients previously treated for systemic vasculitis demonstrated persistent large vessel uptake. LVV was identified in 8 patients with other autoimmune diseases, and in 4 diagnosed with infectious aortitis. In 26 patients who underwent malignancy surveillance, PET/CT revealed more localized large vessel wall inflammation. Our results illustrate that PET/CT may identify large vessel wall inflammation in patients with a suspicion of LVV, and incidentally in patients who undergo malignancy surveillance. PET/CT may also help delineate the presence and extent of vessel inflammation in patients with LVV and in those with other autoimmune diseases.

Treat-to-target concept implementation for evaluating rheumatoid arthritis patients in daily practice.

OBJECTIVE: We aimed to assess the implementation of the treat-to-target (T2T) concept in rheumatoid arthritis (RA) patients in daily practice. METHODS: All RA patients visiting one of the 7 academic medical centers in Israel in June 2015 with at least 3 previous clinic visits were included in this study. A common questionnaire was used to collect data from patients' medical records, and two independent rheumatologists evaluated the collected data for the implementation of the T2T concept. The associations between T2T implementation and the categorical and continuous variables were assessed. RESULTS: The study included 724 patients with a mean (standard deviation) age of 62.6 (13.97) years and 575 (80.4%) of them were women. Four centers used more than one scoring method, with Disease Activity Score-28 and Clinical Disease Activity Index) being most commonly used. Only 276 (38.1%) patients had disease score results in ≥3 visits, and the T2T recommendations were implemented for 245 (33.8%) of the 724 patients. The rate of implementation was higher in younger (p=0.028) rheumatoid factor-positive patients (p=0.011) and varied between centers (11.1%-87% p<0.0001). T2T implementation did not correlate to gender, place of residence, education, tobacco use, treatment regimens, and presence of erosions or comorbidities. CONCLUSION: The T2T concept was implemented on only 33.8% of patients and was not affected by RA disease severity. Further studies are needed to determine the reasons for this deviation from the T2T standard of care for RA as well as its consequences.

International Consortium for Health Outcome Measurement Set of Outcomes That Matter to People Living With Inflammatory Arthritis: Consensus From an International Working Group.

OBJECTIVE: The implementation of value-based health care in inflammatory arthritis requires a standardized set of modifiable outcomes and risk-adjustment variables that is feasible to implement worldwide. METHODS: The International Consortium for Health Outcomes Measurement (ICHOM) assembled a multidisciplinary working group that consisted of 24 experts from 6 continents, including 6 patient representatives, to develop a standard set of outcomes for inflammatory arthritis. The process followed a structured approach, using a modified Delphi process to reach consensus on the following decision areas: conditions covered by the set, outcome domains, outcome measures, and risk-adjustment variables. Consensus in areas 2 to 4 were supported by systematic literature reviews and consultation of experts. RESULTS: The ICHOM Inflammatory Arthritis Standard Set covers patients with rheumatoid arthritis (RA), axial spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis (JIA). We recommend that outcomes regarding pain, fatigue, activity limitations, overall physical and mental health impact, work/school/housework ability and productivity, disease activity, and serious adverse events be collected at least annually. Validated measures for patient-reported outcomes were endorsed and linked to common reporting metrics. Age, sex at birth, education level, smoking status, comorbidities, time since diagnosis, and rheumatoid factor and anti-citrullinated protein antibody lab testing for RA and JIA should be collected as risk-adjustment variables. CONCLUSION: We present the ICHOM inflammatory arthritis Standard Set of outcomes, which enables health care providers to implement the value-based health care framework and compare outcomes that are important to patients with inflammatory arthritis.

Intravenous immunoglobulins for rheumatic disorders and thromboembolic events-a case series and review of the literature.

To report the temporal association between a series of thromboembolic events and intravenous immunoglobulin infusion in patients with rheumatic diseases, and to review the literature on the subject. The clinical presentation, course, and outcome of thromboembolic events occurring post-immunoglobulin infusion in nine patients is described. A web-based literature review using the PubMed database from 1996 to 2017 was performed, searching for the keywords: thrombosis, thromboembolism, intravenous immunoglobulin, pulmonary embolism, deep vein thrombosis, cerebrovascular event, and acute myocardial infarction. Nine patients who had suffered a thromboembolic event within a week after receiving an intravenous immunoglobulin infusion (Omr-IgG-am™, OMRIX) were identified among our joint cohort. All patients except one were female ranging in age from 22 to 69 years. Five had progressive systemic sclerosis (one of them had progressive systemic sclerosis with antiphospholipid syndrome, and another had an overlap of progressive systemic sclerosis with systemic lupus erythematosus), the sixth had monoclonal IgM autoimmune neuropathy, the seventh had systemic lupus erythematosus with antiphospholipid syndrome, the eighth had granulomatosis with polyangiitis (GPA) and the ninth had overlap autoimmune syndrome. Six of the patients had an arterial thrombosis: an acute myocardial infarction in four, a brachial artery thrombosis in the fifth, and a cerebrovascular attack in the sixth. Three patients sustained a venous thrombosis and/or an acute pulmonary embolism (one of them had a DVT with the PE). Two events occurred during the IVIG infusion, three within an hour after the last infusion of the 5-day course, one occurred a few hours after the initiation of the IVIG therapy, another occurred 3 days after receiving the final infusion of the 10th course, and two events occurred a week after the treatment course has ended. Fifty-five percent of the patients had no thrombogenic risk factors other than their rheumatic condition, and most of them had received numerous, uneventful IVIG treatment courses before sustaining the thromboembolic event. No immediate deaths occurred among this cohort. Thromboembolic events after IVIG infusions, although infrequent, may occur in rheumatic patients, even in the absence of other recognizable risk factors for thromboembolism. The reported events had occurred despite complying with recommended guidelines for IVIG administration, which include a lengthy 8-h infusion and division of the total dose. No correlation was found between the number and frequency of the infusions to the thromboembolic events. Heightened awareness of possible thromboembolic events in rheumatic patients is encouraged for at least a week following IVIG administration.

Degenerative changes of the thoracic spine do exist in patients with diffuse idiopathic skeletal hyperostosis: a detailed thoracic spine CT analysis.

Background Degenerative intervertebral disease (DID) is an exclusion criterion in the Resnick and Niwayama radiographic classification for diffuse idiopathic skeletal hyperostosis (DISH). However, although DID was previously described in DISH, no systematic computed tomography (CT) analysis has been reported so far. Purpose To assess for the presence and prevalence of such changes on CT examinations of the thoracic spine of individuals with DISH. Material and Methods Intervertebral space (D1-L1) on chest CT examinations of DISH patients was retrospectively evaluated for the presence of DID. Parameters evaluated were disc space height, disc protrusion, subchondral cysts/sclerosis, Schmorl nodes, vacuum phenomenon, and posterior elements including costovertebral and facet joints. Parameters were compared with two age- and gender-matched control groups of individuals whose entire spine CT lacked evidence of DISH (Control 1 individuals < 2 flowing osteophytes, Control 2 individuals < 4 and ≥ 2 flowing osteophytes). Results A total of 158 participants (DISH/Control 1/Control 2 = 54/54/50; 106 men, 52 women; average age = 70.6 years) were evaluated. Average intervertebral disc height was significantly lower in the DISH group compared with both control groups (DISH/Control 1/Control 2 = 4.55/5.13/5.01 mm, P < 0.001). Costovertebral degenerative changes were more prevalent in DISH patients ( P < 0.05) and, except for vacuum phenomenon (more prevalent in controls), other DID changes were as prevalent in DISH as in controls. Conclusion The presence of degenerative intervertebral changes on thoracic CT should not deter from diagnosing DISH. Thus, the radiographic Resnick and Niwayama DISH criteria cannot be directly adapted to CT.

Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: The use of immune checkpoint inhibitors (ICI) has grown incessantly since they were first approved in 2014. These monoclonal antibodies inhibit T cell activation, yielding a dramatic tumor response with improved survival. However, immunotherapy is frequently hampered by immune adverse events (iAE) such as hypophysitis, colitis, hepatitis, pneumonitis and rash. Until recently, rheumatic side effects were only infrequently reported. AIM: To describe the rheumatic manifestations encountered among patients treated with ICIs in a large tertiary cancer center in Israel METHODS: The cancer center's patient registry was screened for patients who had ever been treated with ipilimumab, pembrolizumab and/or nivolumab with relevant data gathered from clinical charts. RESULTS: Rheumatic manifestations were encountered in 14 of 400 patients (3.5%) who had received immunotherapy between January 1st 2013 and April 30th, 2017. The most common rheumatic manifestation was inflammatory arthritis (85%) for which a third (4/11) had a clear cut predisposing factor such as a personal or family history of psoriasis, a prior episode of uveitis or ACPA positivity. Pulmonary sarcoidosis and biopsy-proven eosinophilic fasciitis were diagnosed in two additional patients. Treatment with NSAIDS was mostly unsuccessful while steroid therapy was beneficial in doses ≥20 mg/d. Methotrexate enabled steroid tapering without an excess of side effects or tumor progression in the short follow-up available. Overall, rheumatic manifestations tended to occur later in the course of immunotherapy as compared to other iAE. CONCLUSIONS: Our findings underscore that rheumatic iAE are part of the side effect profile of ICIs and require heightened awareness as these therapies are becoming the standard of care for various malignancies. We show that these appear later in the course of iAEs and respond preferentially to high dose steroids. MTX appears effective as a steroid sparing agent.

FDG PET-CT evaluation in neurolymphomatosis: imaging characteristics and clinical outcomes.

Neurolymphomatosis (NL) often represents unidentified non-Hodgkin lymphoma relapses. Considering its severity, early detection and treatment are crucial. We outline one hospital's 18F-FDG-PET-CT imaging findings of NL, along with the patients' clinical characteristics. Clinical records and imaging findings of 19 NL patients, PET-CT diagnosed, were retrospectively reviewed. Patient data, FDG-PET-CT findings and the presence of coexisting diseases, especially CNS involvement, were documented. Available MRI and clinical data verified the findings. All cases had increased linear FDG uptake along anatomic nerve sites. CTs showed varying degrees of corresponding soft-tissue-thickening. Clinical correlations also contributed to the diagnosis. In 4/19 patients, lymphoma presented with NL, in 15/19 it appeared with disease recurrence/progression. In 9/19, clinical symptoms suggested neural involvement while 10/19 had nonspecific symptoms. Eleven died of lymphoma within 0.9 years of diagnosis despite directed-therapy. Eight, however, survived up to 7.82 years post-diagnosis. Whole-body FDG-PET-CT can assist in early NL diagnosis, possibly enhancing survival.

Extrapyramidal signs in neurosarcoidosis versus multiple sclerosis: Is TNF alpha the link?

Specific inflammatory pathways and specifically Tumor Necrosis Factor alpha (TNF-α) have been associated with the neurodegeneration in Parkinson's disease (PD). TNFα is also known to play an important role in the pathogenesis of sarcoidosis and TNF blockers can ameliorate the disease. In contrast, multiple sclerosis (MS) is clearly exacerbated by anti- TNF-α medications. We have therefore hypothesized that Parkinson-like disease would be more common in neurosarcoidosis (NS) compared to MS. The aim of this case-control study was therefore to assess the frequency of extrapyramidal signs in patients with NS compared to MS patients. In order to do so the medical records of NS patients and of age and gender matched MS patients were reviewed and data regarding the clinical features, ancillary tests performed, treatment, and outcome were documented. Patients were then examined in a uniform manner for the presence of extrapyramidal signs. We found that in the NS group 8 patients had minor signs, one had mild functional disability and 3 subjects had significant extrapyramidal signs compatible with the diagnosis of Parkinson's disease. All extrapyramidal signs found in 5 of the MS group were minor. The proportional severity of extrapyramidal signs was significantly higher (p=0.045, chi square test) in the NS group compared to the MS group. We conclude that the specificity of extrapyramidal to NS raises the intriguing question of whether specific inflammatory pathways involving TNF-α play a role in the pathogenesis of PD and therefore may be a therapeutic target.

The prevalence and clinical effect of immunogenicity of TNF-α blockers in patients with axial spondyloarthritis.

OBJECTIVES: To evaluate the prevalence of immunogenicity of TNF-α blockers in axial spondyloarthritis (SpA) patients and to assess the effect of immunogenicity on drug levels and clinical response. METHPDS: Patients with axial SpA treated with either infliximab (INF), adalimumab (ADA) or etanercept (ETN) were recruited to our observational cross-sectional study. Demographic and clinical data were collected and disease activity scores were assessed. Drug trough levels and anti-drug antibodies were measured in serum samples and collected before the next administration. RESULTS: Thirty-nine patients with axial SpA with a mean age of 46.3±12.7 (10 women) were recruited to the study (14 receiving INF, 16 ADA and 9 ETN). Patients' mean therapy duration was 50.6 months (±46.4) and 6 (15%) of them were using MTX concomitantly with the TNF-α blockers. Anti-drug antibodies were found in 6 (15%) patients (4 with INF and 2 with ADA), all of which had undetectable drug level. No anti-drug antibodies were detected in patients treated with ETN. Immunogenicity was associated with higher BASDAI (Bath Ankylosing Spondylitis Disease Index), ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score) and ASDAS-ESR. CONCLUSIONS: Axial SpA patients failure to respond to TNF-α blockers may be at least partially related to immunogenicity. Measurement of anti-drug antibodies and drug levels in these patients may assist in determining further treatment strategies.