Inclusion body myositis, viral infections, and TDP-43: a narrative review.

The ubiquitous RNA-processing molecule TDP-43 is involved in neuromuscular diseases such as inclusion body myositis, a late-onset acquired inflammatory myopathy. TDP-43 solubility and function are disrupted in certain viral infections. Certain viruses, high viremia, co-infections, reactivation of latent viruses, and post-acute expansion of cytotoxic T cells may all contribute to inclusion body myositis, mainly in an age-shaped immune landscape. The virally induced senescent, interferon gamma-producing cytotoxic CD8+ T cells with increased inflammatory, and cytotoxic features are involved in the occurrence of inclusion body myositis in most such cases, in a genetically predisposed host. We discuss the putative mechanisms linking inclusion body myositis, TDP-43, and viral infections untangling the links between viruses, interferon, and neuromuscular degeneration could shed a light on the pathogenesis of the inclusion body myositis and other TDP-43-related neuromuscular diseases, with possible therapeutic implications.

ERN ReCONNET points to consider for treating patients living with autoimmune rheumatic diseases with antiviral therapies and anti-SARS-CoV-2 antibody products.

Recent studies have shown that people who are immunocompromised may inadvertently play a role in spurring the mutations of the virus that create new variants. This is because some immunocompromised individuals remain at risk of getting COVID-19 despite vaccination, experience more severe disease, are susceptible to being chronically infected and remain contagious for longer if they become infected and considering that immunocompromised individuals represent approximately 2% of the overall population, this aspect should be carefully considered. So far, some autoimmune rheumatic disease (ARD) patients with COVID-19 have been treated with antiviral therapies or anti-SARS-CoV-2 antibody products. However, there is no homogeneous approach to these treatment strategies. This issue was addressed within the European Reference Network (ERN) on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ReCONNET) in a discussion among experts and patient's representatives in the context of the rare and complex connective tissue diseases (rCTDs) covered by the Network. ERN ReCONNET is one of the 24 ERNs launched by the European Commission in 2017 with the aim of tackling low prevalence and rare diseases that require highly specialised treatment and promoting concentration of knowledge and resources through virtual networks involving healthcare providers (HCPs) across the European Union (EU). Considering the urgent need to provide guidance not only to the rCTDs community, but also to the whole ARDs community, a multidisciplinary Task Force, including expert clinicians and European Patient Advocacy Group (ePAG) Advocates, was created in the framework of ERN ReCONNET with the aim of developing overarching principles (OP) and points-to-consider (PtC) on a homogenous approach to treat immunocompromised patients with ARDs (with a particular focus on CTDs) affected by COVID-19 using antiviral therapies and anti-SARS-CoV-2 antibody products. The present work reports the final OP and PtC agreed by the Task Force.

Frail Silk: Is the Hughes-Stovin Syndrome a Behçet Syndrome Subtype with Aneurysm-Involved Gene Variants?

Hughes-Stovin syndrome is a rare disease characterized by thrombophlebitis and multiple pulmonary and/or bronchial aneurysms. The etiology and pathogenesis of HSS are incompletely known. The current consensus is that vasculitis underlies the pathogenic process, and pulmonary thrombosis follows arterial wall inflammation. As such, Hughes-Stovin syndrome may belong to the vascular cluster with lung involvement of Behçet syndrome, although oral aphtae, arthritis, and uveitis are rarely found. Behçet syndrome is a multifactorial polygenic disease with genetic, epigenetic, environmental, and mostly immunological contributors. The different Behçet syndrome phenotypes are presumably based upon different genetic determinants involving more than one pathogenic pathway. Hughes-Stovin syndrome may have common pathways with fibromuscular dysplasias and other diseases evolving with vascular aneurysms. We describe a Hughes-Stovin syndrome case fulfilling the Behçet syndrome criteria. A MYLK variant of unknown significance was detected, along with other heterozygous mutations in genes that may impact angiogenesis pathways. We discuss the possible involvement of these genetic findings, as well as other potential common determinants of Behçet/Hughes-Stovin syndrome and aneurysms in vascular Behçet syndrome. Recent advances in diagnostic techniques, including genetic testing, could help diagnose a specific Behçet syndrome subtype and other associated conditions to personalize the disease management.

PFAPA Syndrome: Clinical, Laboratory and Therapeutic Features in a Single-Centre Cohort.

Objective: The aim of this study is to describe a group of Romanian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome. Materials: This consisted of 39 children diagnosed with PFAPA syndrome according to Thomas' criteria (eight patients with an age at diagnosis <1 year and 31 patients with an age at diagnosis >1 year). Methods: Retrospective analysis of the patients with PFAPA syndrome was focused on clinical features, laboratory findings and therapeutic methods. Comparison between the two groups divided by age at onset was also investigated. Results: Median age at onset was 1.58 years, and median age at diagnosis was 2.97 years. The mean interval between episodes was 35.5 days and the mean duration per febrile episode was 4.1 days. The median diagnosis delay was 2.42 years. The patients presented pharyngitis (100%), adenitis (94.8%) and aphthous lesions (66.7%). The frequency of febrile attacks was higher in children with an age at diagnosis under 1 year (p = 0.0287). Younger age was associated with the presence of aphthae. The mean value of C-reactive protein (CRP) was 7.9mg/dl and the mean value of leucocytes was 14,839/mm3. In 95% of patients given oral corticosteroids, remission of symptoms was reported within 24 h. In three patients, tonsillectomy was performed with complete remission of the disease. Conclusion: We present a cohort of children with PFAPA syndrome, with clinical and laboratory features similar to those described in the literature. Febrile attacks had a higher incidence in children with younger age at the onset of the disease. The patients had a favorable response to corticosteroids.

Osteogenesis imperfecta and rheumatoid arthritis: connective issues.

The coexistence of osteogenesis imperfecta and inflammatory arthritis has been very rarely described. Nevertheless, systemic inflammation has been found in osteogenesis imperfecta. The COL1A1 mutations may affect collagen synthesis as well as post-translational modifications, extracellular matrix interactions, and receptor-mediated signaling. Major collagen binding ligands forming the interactome, such as cytokines, cell adhesion molecules, matrix metalloproteinases, proteoglycans, and other molecules, are autoimmunity targets involved in rheumatoid arthritis pathogenesis. Cross-talk between bone remodeling and inflammatory pathways involving osteoclasts is important in osteogenesis imperfecta and rheumatoid arthritis. In osteogenesis imperfecta, the structural abnormalities and repeated traumatism, including fractures, could activate locally the innate immunity and trigger arthritis, similar to post-traumatic arthritis. Currently, the therapy of osteogenesis imperfecta is a suboptimally met need. Understanding the complex putative pathogenic links between osteogenesis imperfecta and inflammatory arthritis could hopefully lead to new therapeutic targets. Raising awareness regarding a possible association between osteogenesis imperfecta and arthritis could help improve the quality of life in these patients.

Inclusion Body Myositis and Neoplasia: A Narrative Review.

Inclusion body myositis (IBM) is an acquired, late-onset inflammatory myopathy, with both inflammatory and degenerative pathogenesis. Although idiopathic inflammatory myopathies may be associated with malignancies, IBM is generally not considered paraneoplastic. Many studies of malignancy in inflammatory myopathies did not include IBM patients. Indeed, IBM is often diagnosed only after around 5 years from onset, while paraneoplastic myositis is generally defined as the co-occurrence of malignancy and myopathy within 1 to 3 years of each other. Nevertheless, a significant association with large granular lymphocyte leukemia has been recently described in IBM, and there are reports of cancer-associated IBM. We review the pathogenic mechanisms supposed to be involved in IBM and outline the common mechanisms in IBM and malignancy, as well as the therapeutic perspectives. The terminally differentiated, CD8+ highly cytotoxic T cells expressing NK features are central in the pathogenesis of IBM and, paradoxically, play a role in some cancers as well. Interferon gamma plays a central role, mostly during the early stages of the disease. The secondary mitochondrial dysfunction, the autophagy and cell cycle dysregulation, and the crosstalk between metabolic and mitogenic pathways could be shared by IBM and cancer. There are intermingled subcellular mechanisms in IBM and neoplasia, and probably their co-existence is underestimated. The link between IBM and cancers deserves further interest, in order to search for efficient therapies in IBM and to improve muscle function, life quality, and survival in both diseases.

One Molecule for Mental Nourishment and More: Glucose Transporter Type 1-Biology and Deficiency Syndrome.

Glucose transporter type 1 (Glut1) is the main transporter involved in the cellular uptake of glucose into many tissues, and is highly expressed in the brain and in erythrocytes. Glut1 deficiency syndrome is caused mainly by mutations of the SLC2A1 gene, impairing passive glucose transport across the blood-brain barrier. All age groups, from infants to adults, may be affected, with age-specific symptoms. In its classic form, the syndrome presents as an early-onset drug-resistant metabolic epileptic encephalopathy with a complex movement disorder and developmental delay. In later-onset forms, complex motor disorder predominates, with dystonia, ataxia, chorea or spasticity, often triggered by fasting. Diagnosis is confirmed by hypoglycorrhachia (below 45 mg/dL) with normal blood glucose, 18F-fluorodeoxyglucose positron emission tomography, and genetic analysis showing pathogenic SLC2A1 variants. There are also ongoing positive studies on erythrocytes' Glut1 surface expression using flow cytometry. The standard treatment still consists of ketogenic therapies supplying ketones as alternative brain fuel. Anaplerotic substances may provide alternative energy sources. Understanding the complex interactions of Glut1 with other tissues, its signaling function for brain angiogenesis and gliosis, and the complex regulation of glucose transportation, including compensatory mechanisms in different tissues, will hopefully advance therapy. Ongoing research for future interventions is focusing on small molecules to restore Glut1, metabolic stimulation, and SLC2A1 transfer strategies. Newborn screening, early identification and treatment could minimize the neurodevelopmental disease consequences. Furthermore, understanding Glut1 relative deficiency or inhibition in inflammation, neurodegenerative disorders, and viral infections including COVID-19 and other settings could provide clues for future therapeutic approaches.

Case Report: Anti-N-Methyl-D-Aspartate Receptor Encephalitis Manifesting With an Isolated Psychiatric Episode and Normal Ancillary Tests.

The majority of patients with anti-N-Methyl-D-Aspartate receptor (NMDAR) encephalitis present with psychiatric symptoms and subsequently develop neurological features. However, isolated psychiatric episodes occur in <5% of affected individuals, less frequent at disease onset (<1%) compared to relapse (4%). We report the case of a previously healthy 24-year-old female who presented with psychotic symptoms and behavioral alterations. Despite therapy, she showed no improvement and subsequently developed catatonic features. While the ancillary tests were normal, the clinical warning signs raised the suspicion of anti-NMDAR encephalitis which we later confirmed. Given its strong association with underlying tumors, we screened the patient and found an ovarian teratoma. Once removed, the patient displayed a substantial improvement in the mental status. Besides being extremely rare, this case illustrates the need to maintain clinical suspicion of anti-NMDAR encephalitis even in the absence of neurological features or paraclinical anomalies.

Oral Microbiome: Getting to Know and Befriend Neighbors, a Biological Approach.

The oral microbiome, forming a biofilm that covers the oral structures, contains a high number of microorganisms. Biofilm formation starts from the salivary pellicle that allows bacterial adhesion-colonization-proliferation, co-aggregation and biofilm maturation in a complex microbial community. There is a constant bidirectional crosstalk between human host and its oral microbiome. The paper presents the fundamentals regarding the oral microbiome and its relationship to modulator factors, oral and systemic health. The modern studies of oral microorganisms and relationships with the host benefits are based on genomics, transcriptomics, proteomics and metabolomics. Pharmaceuticals such as antimicrobials, prebiotics, probiotics, surface active or abrasive agents and plant-derived ingredients may influence the oral microbiome. Many studies found associations between oral dysbiosis and systemic disorders, including autoimmune diseases, cardiovascular, diabetes, cancers and neurodegenerative disorders. We outline the general and individual factors influencing the host-microbial balance and the possibility to use the analysis of the oral microbiome in prevention, diagnosis and treatment in personalized medicine. Future therapies should take in account the restoration of the normal symbiotic relation with the oral microbiome.

Treatment of relapsing polychondritis: a systematic review.

OBJECTIVES: Due to the rarity of relapsing polychondritis (RP), no randomised clinical trial has been conducted to date and treatment remains empirical. We performed a systematic literature review to assess the efficacy of the main conventional immunosuppressants and biotherapies used in RP. METHODS: We searched MEDLINE for original articles without language restriction. Abstracts from American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) were also considered for inclusion. Observational studies and clinical trials reporting on the efficacy of conventional immunosuppressants and biotherapies in adult patients with RP were selected and pooled response rates for each treatment were computed. RESULTS: Of 304 articles and abstracts identified, 31 underwent full-text review, and 11 were included. The studies involved a total of 177 patients, exposed to a total of 247 lines of treatments. The main treatments studied (by number of lines) were: TNF inhibitors (TNFi), n=92; methotrexate (MTX), n=38; tocilizumab (TCZ), n=26; anakinra (ANA), n=21; rituximab (RTX), n=16; abatacept (ABT), n=14; cyclophosphamide (CYC), n=14; azathioprine (AZA), n=13. The pooled response rates across studies were: 72% [95% CI: 42-95] for ABT, 66% [95% CI: 49-82] for TCZ, 64% [95% CI: 53-74] for TNFi, 56% [95% CI: 37-73] for MTX, 47% [95% CI: 26-68] for ANA, 43% [95% CI: 20-68] for RTX. Based on more limited data, response rates for AZA and CYC ranged from 38 to 100% and from 25 to 100%, respectively. CONCLUSIONS: In this systematic review of available evidence regarding the treatment of relapsing polychondritis, ABT, TCZ and TNFi were the drugs associated with the best outcomes. ABT efficacy must be interpreted in light of the small number of patients treated. While MTX had slightly less efficacy, it is one of the drugs for which data are the most robust.

Rare within rare. Necrotising scleritis and peripheral ulcerative keratitis: eye-threatening complications of relapsing polychondritis.

OBJECTIVES: Relapsing polychondritis (RP) evolves with variable and intermittent involvement of cartilage and proteoglycan-rich structures. Ocular manifestations are present in up to two-thirds of RP patients. Necrotising scleritis (NS) and peripheral ulcerative keratitis (PUK) may be inaugural and may lead to eye perforation and vision loss. We aimed to review NS and PUK in RP, in order to characterise them, to identify successful treatment options and unmet needs. METHODS: A systematic review of the currently available evidence in PubMed, EMBASE and Scopus was performed according to PRISMA, including observational studies, single case reports and case series of NS/PUK in RP. Study design, number of patients, age, gender, treatment and outcome, were extracted. Two RP patients also provided their opinion. RESULTS: Five case reports and two case series were eligible for inclusion. We identified 10 RP patients with eye-threatening complications (NS and/or PUK), 9 adults (2 males, 7 females, aged 35-72, median age 57.6 years) and one paediatric patient (F, 11 years). Apart from glucocorticoids, cyclophosphamide was effective in 4 patients; infliximab, high-dose immunoglobulins, dapsone, or cyclosporine were also successfully employed in a case each. Surgical repair was reported in 2 cases. CONCLUSIONS: Ocular inflammation is often bilateral and recurring in RP; NS/PUK are rare complications. All patients who develop NS/PUK should be specifically questioned for RP signs and symptoms. Early institution of immunosuppressive therapies is mandatory. Increasing awareness, physicians' and patients' education and a multidisciplinary approach may help improve the prognosis of these serious complications of RP.

Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies.

OBJECTIVES: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. METHODS: We conducted a multicentre, international, retrospective cohort study. RESULTS: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. CONCLUSIONS: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

Anemia in Sports: A Narrative Review.

Recent years have brought about new understandings regarding the pathogenesis of anemia in sports. From hemodilution and redistribution considered to contribute to the so-called "sports anemia" to iron deficiency caused by increased demands, dietary restrictions, decreased absorption, increased losses, hemolysis, and sequestration, to genetic determinants of different types of anemia (some related to sport), the anemia in athletes deserves a careful and multifactorial approach. Dietary factors that reduce iron absorption (e.g., phytate, polyphenols) and that augment iron's bioavailability (e.g., ascorbic acid) should be considered. Celiac disease, more prevalent in female athletes, may underlie an unexplained iron deficiency anemia. Iron loss during exercise occurs in several ways: sweating, hematuria, gastrointestinal bleeding, inflammation, and intravascular and extravascular hemolysis. From a practical point of view, assessing iron status, especially in the athletes at risk for iron deficiency (females, adolescents, in sports with dietary restrictions, etc.), may improve the iron balance and possibly the performance. Hemoglobin and serum ferritin are measures that are easily employable for the evaluation of patients' iron status. Cutoff values should probably be further assessed with respect to the sex, age, and type of sport. A healthy gut microbiome influences the iron status. Athletes at risk of iron deficiency should perform non-weight-bearing, low-intensity sports to avoid inducing hemolysis.

Frenemies within: An Endocarditis Case in Behçet's Disease.

A 57-year female patient diagnosed with Behçet's disease, on azathioprine, was noticed to have at a routine examination antinuclear and antiphospholipid antibodies. An overlapping lupus-like syndrome was diagnosed; hydroxychloroquine and aspirin were added. Three years later, the patient presented with dyspnea and sweating, with no fever. A cardiac bruit was noted; a giant vegetation was detected by echocardiography. Laboratory revealed severe thrombocytopenia, antiphospholipid antibodies and low complement. Blood cultures were positive for Abiotrophia defectiva serology and also revealed a chronic Coxiella burnetii infection. Antibiotic therapy, low-dose anticoagulation and control of the underlying disease mildly improved the platelet count, which fully recovered only after cardiac valve replacement. However, the Behçet's disease, initially quiescent, flared after the therapy of infections. We discuss potential links between Behçet's disease and the occurrence of antinuclear and antiphospholipid antibodies and Coxiella endocarditis in this setting. We also highlight the differences between the endocarditis in Behçet's disease, antiphospholipid syndrome, Coxiella burnetii and Abiotrophia defectiva infection, respectively. Intracellular infections may modify the presentation of autoimmune diseases. Confounding clinical features of Coxiella persistent infection and non-bacterial thrombotic endocarditis in Behçet's disease warrant further insight.

Rare Causes of Arterial Hypertension and Thoracic Aortic Aneurysms-A Case-Based Review.

Thoracic aortic aneurysms may result in dissection with fatal consequences if undetected. A young male patient with no relevant familial history, after having been investigated for hypertension, was diagnosed with an ascending aortic aneurysm involving the aortic root and the proximal tubular segment, associated with a septal atrial defect. The patient underwent a Bentall surgery protocol without complications. Clinical examination revealed dorso-lumbar scoliosis and no other signs of underlying connective tissue disease. Microscopic examination revealed strikingly severe medial degeneration of the aorta, with areas of deep disorganization of the medial musculo-elastic structural units and mucoid material deposition. Genetic testing found a variant of unknown significance the PRKG1 gene encoding the protein kinase cGMP-dependent 1, which is important in blood pressure regulation. There may be genetic links between high blood pressure and thoracic aortic aneurysm determinants. Hypertension was found in FBN1 gene mutations encoding fibrillin and in PRKG1 mutations. Possible mechanisms involving the renin-angiotensin system, the role of oxidative stress, osteopontin, epigenetic modifications and other genes are reviewed. Close follow-up and strict hypertension control are required to reduce the risk of dissection. Hypertension, scoliosis and other extra-aortic signs suggesting a connective tissue disease are possible clues for diagnosis.

Long-term efficacy of immunoglobulins in small fiber neuropathy related to Sjögren's syndrome.

The most common peripheral nervous system manifestations in Sjogren's syndrome are small fiber sensory neuropathies (SFPN) and axonal sensorimotor polyneuropathies. Currently, treatment in small fiber neuropathy is mainly symptomatic and based on anti-depressors and anti-epileptics. The benefit of treatment with polyvalent immunoglobulins for SFPN has been reported in small series of patients, although transient in several cases. The medium-to-long-term effects of polyvalent immunoglobulins (Ig) in SFPN in patients with Sjogren's syndrome who are refractory to conventional treatments remain an unmet medical need. We present our experience related to the persistent improvement of Ig in a case series of SFPN in Sjogren's syndrome and relevant data in the literature regarding the benefits of immunoglobulins, for this indication.

Rheumatoid Arthritis and CLOVES Syndrome: A Tricky Diagnosis.

The PI3K/AKT/mTOR signaling pathway is significantly activated in rheumatoid arthritis. In addition, somatic activating mutations of the PI3K/AKT/mTOR pathway may result in PIK3CA-related overgrowth spectrum diseases, including CLOVES (Congenital Lipomatous Overgrowth, Vascular malformation, Epidermal nevi, Skeletal abnormalities/Scoliosis) syndrome. We describe the case of a young female patient, with anti-citrullinated peptide antibodies-positive rheumatoid arthritis, referred for persistent finger pain and stiffness. Examination revealed discrete macrodactyly involving two fingers, scoliosis, asymmetrical calves, venectasias, a shoulder nevus and triangular feet with a "sandal gap" between two toes. These mild dysmorphic features with early-onset and the history of surgeries for thoracic lipoma and venous malformation were strongly suggestive of CLOVES syndrome. Confirmatory mutation analysis was not performed, as blood or saliva testing is not contributive for tissue-specific localized effects in the PIK3CA-related overgrowth spectrum. Nevertheless, lack of detection of a PIK3CA mutation does not exclude the diagnosis in patients fulfilling clinical criteria. Due to the patient's wish to plan a pregnancy, therapy consisted in sulfasalazine and hydroxychloroquine, along with orthotic correction of leg length discrepancy. Overgrowth syndromes and arthritis may share common pathways. Mild macrodactyly should be differentiated from dactylitis. Diagnosing patients with minimal dysmorphic features within the PI3K-related overgrowth spectrum may help design better care strategies, in the quest for personalized medicine.

In utero exposure to Azathioprine in autoimmune disease. Where do we stand?

Azathioprine (AZA), an oral immunosuppressant, is safe during pregnancy. Some reports suggested different impairments in the offspring of mothers with autoimmune diseases (AI) exposed in utero to AZA. These observations are available from retrospective studies or case reports. However, data with respect to the long-term safety in the antenatally exposed child are still lacking. The aim of this study is to summarize the current knowledge in this field and to focus on the need for a prospective study on this population. We performed a PubMed search using several search terms. The actual data show that although the risk of congenital anomalies in offspring, as well as the infertility risk, are similar to those found in general population, there is a higher incidence of prematurity, of lower weight at birth and an intra-uterine delay of development. There is also an increased risk of materno- fetal infections, especially cytomegalovirus infection. Some authors raise the interrogations about neurocognitive impairment. Even though the adverse outcomes might well be a consequence of maternal illness and disease activity, interest has been raised about a contribution of this drug. However, the interferences between the external agent (in utero exposure to AZA), with the host (child genetic susceptibility, immune system anomalies, emotional status), environment (public health, social context, availability of health care), economic, social, and behavioral conditions, cultural patterns, are complex and represent confounding factors. In conclusion, it is necessary to perform studies on the medium and long-term outcome of children born by mothers with autoimmune diseases, treated with AZA, in order to show the safety of AZA exposure. Only large-scale population studies with long-term follow-up will allow to formally conclude in this field. TAKE HOME MESSAGES.

Osteogenesis imperfecta and rheumatoid arthritis: is there a link?

We present the cases of a mother and daughter with osteogenesis imperfecta, also diagnosed later with rheumatoid arthritis. In our patients finding and treating the over-imposed arthritis improved the joint pain initially attributed to osteogenesis imperfecta. Exploring joint inflammation in this setting could help ease the disease burden. PURPOSE: Osteogenesis imperfecta (OI) is a rare hereditary disease evolving with recurrent fractures upon minor trauma, blue sclerae, and hearing loss. Although inflammation was not generally considered a feature of the disease, systemic inflammation was recently reported in children with OI and in murine models of OI. METHOD: We present the cases of a mother and a daughter with OI, without a personal or family history of autoimmune diseases, who were also diagnosed with rheumatoid arthritis seropositive for anti-cyclic citrullinated peptide autoantibodies and rheumatoid factor. RESULTS: The genetic tests identified in both patients a deletion in COL1A1 gene (c.3399del, p.Ala1134Profs*105), not previously reported, not present in population databases, creating a premature translational stop signal in the COL1A1 gene in the collagen I major ligand binding region 3. In our patients finding and treating the over-imposed arthritis improved the joint pain initially attributed to OI. Possible pathogenic links between OI and RA are discussed. CONCLUSION: The prevalence of joint inflammation in OI is unknown and may be underestimated. As musculoskeletal involvement affects the quality of life in most OI patients, exploring this relation may help ease the disease burden.

Shear wave elastography as a new method to identify parotid lymphoma in primary Sjögren Syndrome patients: an observational study.

Parotid non-Hodgkin lymphoma (NHL) in primary Sjögren syndrome (pSS) has no specific biomarker for diagnosis. Salivary glands ultrasound (US) is largely used, but its contribution in detecting parotid NHL has not been established. The aim of our study was to determine the added value of bidimensional shear wave elastography (2D-SWE) in pSS diagnosis and to determine its accuracy in identifying parotid NHL. Grey-scale US (GSUS) and 2D-SWE of salivary glands were performed in 35 patients with pSS and 35 healthy controls. The GSUS scores were calculated and the mean of three SWE consecutive measurements was used to appreciate the gland stiffness. SWE increase the diagnostic rate at a cut-off of 6.45 kPa (from 88.6 to 94.2%, p < 0.001) only if applied in patients with insufficient GSUS criteria for pSS diagnosis. The parotid glands with NHL (8 patients, all mucosa-associated lymphoid tissue type) had hyperechoic bands in more than half of the glandular parenchyma (in 68.75% of the glands), large hypoechoic area > 20 mm (all glands), traced gland area over 5 cm2 (all glands), parotid US score greater than 13 (in 68.75% of the glands), and high stiffness (elasticity modulus 13.9 ± 4.08 vs 6.32 ± 2.24) (all p < 0.001). These findings give high sensitivity (92.3%), specificity (100%), and positive (100%) and negative predictive values (98.3%) for NHL identification. The rest of GSUS findings did not correlate with the classic risk factors for lymphoma development (all p > 0.05). 2D-SWE had added value for pSS diagnosis in cases where GSUS aspect is normal or nonspecific. The higher stiffness of parotid NHL can be used for early diagnosis, biopsy guidance, and, possible, for treatment monitoring.