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Familial Mediterranean fever (FMF) is characterized by episodes of acute inflammation; however, in approximately 30% of patients with FMF inflammation persists even during the attack-free periods. In this Review, the authors discuss the markers and risk factors for persistent chronic inflammation in these patients, summarize the clinical outcomes of such inflammation, and suggest a new potential treatment strategy. Familial Mediterranean fever (FMF) is the most common of the hereditary periodic fever syndromes. Although the typical clinical course of FMF is characterized by bouts of painful inflammation, this presentation represents only the tip of the iceberg. In many patients inflammation can persist in attack-free periods, as shown by high levels of acute-phase proteins, cytokines and inflammation-induced proteins. This subclinical inflammation puts patients at risk of developing complications such as anemia, splenomegaly, decreased bone mineral density, heart disease and life-threatening amyloid A amyloidosis, among others. In this article, we review the published data on markers and other factors involved in the persistence of inflammation in patients with FMF during attack-free periods, examine the risk factors for the development of this subclinical inflammation, summarize the complications of chronic inflammation in FMF and propose a new strategy for treatment, based on these data. Key Points The hallmark feature of familial Mediterranean fever (FMF) is acute, painful episodes of inflammation, but chronic subclinical inflammation may persist between attacks Chronic subclinical inflammation in patients with FMF might lead to complications, including amyloid A amyloidosis, anemia, splenomegaly and decreased bone density In addition to the prevention of acute attacks, treatment of FMF should be aimed at decreasing the chronic subclinical inflammation and impeding its deleterious clinical outcome Serum amyloid A protein is a sensitive marker of chronic inflammation in FMF that should be measured and the levels taken into account in treatment decisions

Background As indications for sodium-glucose co-transporter-2 inhibitors (SGLT2i) are expanding, a growing number of older adults have become candidates for treatment. We studied the safety profile of SGLT2i among older adults. Methods A retrospective, pharmacovigilance study of the FDA’s global database of safety reports. To assess reporting of pre-specified adverse events following SGLT2i among adults (< 75 years) and older adults (≥ 75), we performed a disproportionality analysis using the sex-adjusted reporting odds ratio (adj.ROR). Results We identified safety reports of 129,795 patients who received non-insulin anti-diabetic drugs (NIAD), including 24,253 who were treated with SGLT2i (median age 60 [IQR: 51–68] years, 2,339 [9.6%] aged ≥ 75 years). Compared to other NIAD, SGLT2i were significantly associated with amputations (adj.ROR = 355.1 [95%CI: 258.8 − 487.3] vs adj.ROR = 250.2 [79.3 − 789.5]), Fournier gangrene (adj.ROR = 45.0 [34.5 − 58.8] vs adj.ROR = 88.0 [27.0 − 286.6]), diabetic ketoacidosis (adj.ROR = 32.3 [30.0 − 34.8] vs adj.ROR = 23.3 [19.2 − 28.3]), genitourinary infections (adj.ROR = 10.3 [9.4 − 11.2] vs adj.ROR = 8.6 [7.2 − 10.3]), nocturia (adj.ROR = 5.5 [3.7 − 8.2] vs adj.ROR = 6.7 [2.8 − 15.7]), dehydration (adj.ROR = 2.5 [2.3 − 2.8] vs adj.ROR = 2.6 [2.1 − 3.3]), and fractures (adj.ROR = 1.7 [1.4 − 2.1] vs adj.ROR = 1.5 [1.02 − 2.1]) in both adults and older adults, respectively. None of these safety signals was significantly greater in older adults (P interaction threshold of 0.05). Acute kidney injury was associated with SGLT2i in adults (adj.ROR = 1.97 [1.85 − 2.09]) but not in older adults (adj.ROR = 0.71 [0.59 − 0.84]). Falls, hypotension, and syncope were not associated with SGLT2i among either adults or older adults. Conclusion In this global post-marketing study, none of the adverse events was reported more frequently among older adults. Our findings provide reassurance regarding SGLT2i treatment in older adults, although careful monitoring is warranted.

Background Gastrointestinal perforations have been reported in a small number of rheumatoid arthritis (RA) patients treated with Janus kinase (JAK) inhibitors in clinical trials. However, large‐scale postmarketing data repositories are needed to further investigate this potentially rare but serious adverse event. Methods A retrospective, pharmacovigilance study of the FDA adverse event reporting system (July 2014 to September 2023) assessing the reporting of gastrointestinal perforations following JAK inhibitors compared to biological disease‐modifying antirheumatic drugs (bDMARDs) in RA patients. The adjusted reporting odds ratio (adj.ROR) was calculated using a multivariable logistic regression model. Results Of 399,983 RA patients included in the study, 76,446 were treated with JAK inhibitors (tofacitinib, n = 52,365; upadacitinib, n = 21,856; baricitinib, n = 2225) and 323,537 were treated with bDMARDs (TNF inhibitors, rituximab, and abatacept). Overall, 230 cases of gastrointestinal perforation following JAK inhibitors were identified, with a median time of 9 (IQR: 4–22) months from treatment initiation. Compared with bDMARDs, JAK inhibitors were associated with a higher‐than‐expected reporting of gastrointestinal perforations (adj.ROR = 1.98[1.69−2.31]). Increased reporting of gastrointestinal perforations was observed among recipients of JAK inhibitors or bDMARDs who used steroids or non‐steroidal anti‐inflammatory drugs concurrently (adj.ROR = 2.82 [2.41–3.31]). Perforations of both the upper and lower gastrointestinal tract were significantly over‐reported (n = 51, adj.ROR = 1.55 [1.12–2.14], n = 143, adj.ROR = 1.78 [1.46–2.17], respectively). Furthermore, the safety signal was significant across all JAK inhibitors: tofacitinib (n = 125, adj.ROR = 1.52 [1.25–1.85]), upadacitinib (n = 84, adj.ROR = 2.73 [2.17–3.44]), and baricitinib (n = 21, adj.ROR = 5.38 [3.46–8.37]). Conclusion In this global pharmacovigilance study, all JAK inhibitors were associated with increased reporting of gastrointestinal perforations compared with bDMARDs in RA patients. Until more data on IBD patients emerge, careful surveillance and increased clinicians' awareness should also be advocated for this population.

Although Familial Mediterranean fever (FMF) is categorized as autosomal recessive, frequent exceptions to this model exist and therefore we aimed to search epigenetic modifications in this disease. Ten M694V homozygous FMF patients (the most severe phenotype) were recruited for this study. Patients with inflammatory flare were excluded. Total RNA was extracted from peripheral blood, and microRNA expression profiled using NanoString nCounter technology. These patients were compared to 10 healthy age- and sex-matched controls. Seven hundred nighty-eight mature human miRNAs were probed, 103 of which had expression levels above the negative control probes. Seven miRNAs showed significant differences in expression in samples from FMF patients compared to healthy controls: four miRNAs were upregulated (miR-144-3p, miR-21-5p, miR-4454, and miR-451a), and three were downregulated (miR-107, let-7d-5p, and miR-148b-3p). In this pilot study, we identified epigenetic modifications in clinically quiescent FMF patients. More studies are required for exploration of their contribution to FMF pathogenesis and their potential role as clinical biomarkers.

Rapid and sensitive screening tools for SARS-CoV-2 infection are essential to limit the spread of COVID-19 and to properly allocate national resources. Here, we developed a new point-of-care, non-contact thermal imaging tool to detect COVID-19, based on advanced image processing algorithms. We captured thermal images of the backs of individuals with and without COVID-19 using a portable thermal camera that connects directly to smartphones. Our novel image processing algorithms automatically extracted multiple texture and shape features of the thermal images and achieved an area under the curve (AUC) of 0.85 in COVID-19 detection with up to 92% sensitivity. Thermal imaging scores were inversely correlated with clinical variables associated with COVID-19 disease progression. In summary, we show, for the first time, that a hand-held thermal imaging device can be used to detect COVID-19. Non-invasive thermal imaging could be used to screen for COVID-19 in out-of-hospital settings, especially in low-income regions with limited imaging resources.

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.

Background Although familial Mediterranean fever (FMF) was originally defined as an autosomal recessive disorder, approximately 10–20% of FMF patients do not carry any FMF gene ( MEFV ) mutations. Fine phenotype characterization may facilitate the elucidation of the genetic background of the so called “FMF without MEFV mutations”. In this study we clinically and demographically characterize this subset. Methods MEFV mutation-negative FMF and control patients were recruited randomly from a cohort followed in a dedicated FMF clinic. The control subjects comprised 2 groups: 1. typical population of FMF, consisting of genetically heterogeneous patients manifesting the classical spectrum of FMF phenotype and 2. a severe phenotype of FMF, consisting of FMF patients homozygous for the p.M694V mutation. Results Forty-seven genetic-negative, 60 genetically heterogeneous and 57 p.M694V homozygous FMF patients were enrolled to the study. MEFV -mutation negative FMF patients showed a phenotype closely resembling that of the other 2 populations. It differed however from the p.M694V homozygous subset by its milder severity (using Mor et al. scoring method), as determined by the lower proportion of patients with chest and erysipelas like attacks, lower frequency of some of the chronic manifestations, lower colchicine dose and older age of disease onset. Conclusions MEFV mutation-negative FMF by virtue of its classical FMF phenotype is probably associated with a genetic defect upstream or downstream to MEFV related metabolic pathway.

To investigate whether among patients with a negative temporal artery biopsy (TAB) there are clinical features that may differentiate between patients with an eventual diagnosis of giant cell arteritis (GCA) and those without arteritis, and to assess the eventual diagnoses of patients without arteritis. Retrospective analysis of patients with a negative TAB performed between 1/1/2000 and 31/12/2015. Information collected included baseline clinical and laboratory data. Patients’ final diagnoses were obtained from medical records. Patients eventually diagnosed with GCA were compared with those without arteritis, and predictive features for GCA diagnosis were assessed. A total of 154 patients with a negative TAB were included in the study. Among them, 31 (20%) were eventually diagnosed with GCA. The leading alternative diagnoses of patients without arteritis were self-limited disease (23%), isolated polymyalgia rheumatica (PMR) (18%), and neurological conditions (17%). In the multivariate analysis, predictors for diagnosis of GCA among patients with a negative TAB included PMR (OR = 2.86, 95% CI 1.06–7.69), platelet count (OR = 1.28, 95% CI 1.07–1.53), and ACR score > 2 (OR = 13.4, 95% CI 4.27–42.03). Among patients with a negative TAB, the best predictors for diagnosis of GCA are fulfillment of the ACR criteria, a clinical diagnosis of PMR, and high platelet levels. These features may aid in the diagnostic work-up of patients with a negative TAB.

A growing number of familial Mediterranean fever (FMF) patients in Israel do not have a single country of origin for all four grandparents. We aimed to predict the Mediterranean fever gene ( MEFV ) variant most likely to be found for an individual FMF patient, by a machine learning approach. This study was conducted at the Sheba Medical Center, a referral center for FMF in Israel. All Jewish referrals included in this study carried an FMF associated variant in MEFV as shown by genetic testing performed between 2001 and 2017. We introduced the term ‘origin score’ to capture the dose and different combinations of the grandparents’ origin. A machine learning approach was used to analyze the data. In a total of 1781 referrals included in this study, the p.Met694Val variant was the most common, and the variants p.Glu148Gln and p.Val726Ala second and third most common, respectively. Of 26 countries of origin analyzed, those that increased the likelihood of a referral to carry specific variants were identified in North Africa for p.Met694Val, Europe for p.Val726Ala, and west Asia for p.Glu148Gln. Fourteen of the studied countries did not show a highly probable variant. Based on our results, it is possible to describe an association between modern day origins of the three most common MEFV variant types and a geographical region. A strong geographic association could arise from positive selection of a specific MEFV variant conferring resistance to endemic infectious agents.

A primary mechanism for activation of innate immunity is recognition of damage or pathogen associated molecular patterns by pattern recognition receptors (PRRs). Nucleic acid is a damage associated molecular pattern molecule that when internalized into a monocyte and recognized by intracellular nucleic acid sensing toll like receptors will cause production of type 1 interferon. The process by which DNA or RNA is delivered into the cytosol of monocytes in systemic lupus erythematosus remains incompletely understood, and therapeutic approaches to prevent DNA-mediated monocyte activation are needed. We identified two mechanisms for internalization of DNA by monocytes. IgG-bound DNA was internalized by interacting with Fc gamma receptor IIa, while high-mobility group box-1 protein-bound DNA was internalized by interacting with the receptor for advanced glycation end products. Both pathways contribute to an inflammatory phenotype in monocytes exposed to serum from patients with SLE. Moreover, both of these pathways can be inhibited by a pentapeptide, DWEYS, which is a DNA mimetope. In one instance DWEYS directly competes with DNA for antibody binding and in the other DWEYS binds high-mobility group box-1 and blocks its interaction with RAGE. Our data highlight distinct pathways involved in nucleic acid enters monocytes in SLE, and identify a potential therapeutic to prevent nucleic acid internalization in SLE.