Bone metastasis: mechanisms, therapies, and biomarkers.

Skeletal metastases are frequent complications of many cancers, causing bone complications (fractures, bone pain, disability) that negatively affect the patient's quality of life. Here, we first discuss the burden of skeletal complications in cancer bone metastasis. We then describe the pathophysiology of bone metastasis. Bone metastasis is a multistage process: long before the development of clinically detectable metastases, circulating tumor cells settle and enter a dormant state in normal vascular and endosteal niches present in the bone marrow, which provide immediate attachment and shelter, and only become active years later as they proliferate and alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells, promoting skeletal destruction. The molecular mechanisms involved in mediating each of these steps are described, and we also explain how tumor cells interact with a myriad of interconnected cell populations in the bone marrow, including a rich vascular network, immune cells, adipocytes, and nerves. We discuss metabolic programs that tumor cells could engage with to specifically grow in bone. We also describe the progress and future directions of existing bone-targeted agents and report emerging therapies that have arisen from recent advances in our understanding of the pathophysiology of bone metastases. Finally, we discuss the value of bone turnover biomarkers in detection and monitoring of progression and therapeutic effects in patients with bone metastasis.

A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure.

Leptin inhibition of bone mass accrual requires the integrity of specific hypothalamic neurons but not expression of its receptor on these neurons. The same is true for its regulation of appetite and energy expenditure. This suggests that leptin acts elsewhere in the brain to achieve these three functions. We show here that brainstem-derived serotonin (BDS) favors bone mass accrual following its binding to Htr2c receptors on ventromedial hypothalamic neurons and appetite via Htr1a and 2b receptors on arcuate neurons. Leptin inhibits these functions and increases energy expenditure because it reduces serotonin synthesis and firing of serotonergic neurons. Accordingly, while abrogating BDS synthesis corrects the bone, appetite and energy expenditure phenotypes caused by leptin deficiency, inactivation of the leptin receptor in serotonergic neurons recapitulates them fully. This study modifies the map of leptin signaling in the brain and identifies a molecular basis for the common regulation of bone and energy metabolisms. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

Predictive factors of effective tibial nerve release in tarsal tunnel syndrome.

BACKGROUND: Factors that may affect surgical decompression results in tarsal tunnel syndrome are not known. METHODS: A retrospective single-center study included patients who had undergone surgical tibial nerve release. The effectiveness of decompression was evaluated according to whether the patient would or would not be willing to undergo another surgical procedure in similar preoperative circumstances. RESULTS: The patients stated for 43 feet (51%) that they would agree to a further procedure in similar circumstances. Six feet with space-occupying lesions on imaging had improved results, but neurolysis failed in 9 feet with bone-nerve contact. Neurolysis was significantly less effective when marked hindfoot valgus (p = 0.034), varus (p = 0.014), or fasciitis (p = 0.019) were present. CONCLUSIONS: If imaging reveals a compressive space-occupying lesion, surgery has a good prognosis. In feet with static hindfoot disorders or plantar fasciitis, conservative treatment must be optimized. Bone-nerve contact should systematically be sought.

Distal phalangeal bone erosions observed by HR-pQCT in patients with psoriatic onycholysis.

OBJECTIVES: PsA prevalence among skin psoriasis is ∼30%. Nail psoriasis, especially onycholysis, is present in >70% of PsA and the risk of developing PsA is more than doubled in patients with nail involvement. We hypothesized that onycholysis may be associated with early bone erosions of the DIP joint without harbouring PsA symptoms. METHODS: We compared tendon thickness, assessed by US, and bone erosions, assessed by high-resolution peripheral quantitative CT, of the DIP joint in patients with psoriatic onycholysis without PsA (ONY) with those in patients with cutaneous psoriasis only (PSO). We used patients with PsA as reference (PsA group), and healthy age-matched controls (CTRL). Differences between groups were assessed by analysis of variance tests followed by post hoc analysis using the Scheffe method. RESULTS: Mean (s.e.m.) age of the 87 participants (61% males) was 45.2 (1.3) years. The mean extensor tendon thickness was significantly larger in ONY than in PSO patients. In the PsA group, 68% of patients exhibited erosions of three different shapes: V-, Omega- and U-shape. Association with erosions was greater in the ONY group than in the PSO group (frequency: 57 vs 14%; P < 0.001; mean number of erosions: 1.10 (0.35) vs 0.03 (0.03); P < 0.001). CONCLUSION: Onycholysis was associated with significant enthesopathy and bone erosions in our cohort. These data support the pathogenic role of enthesopathy in PsA. Onycholysis may be considered as a surrogate marker of severity in psoriasis. TRIAL REGISTRATION: ClinicalTrails.gov, https://clinicaltrials.gov, NCT02813720.

Hyaluronan derivative HYMOVIS® increases cartilage volume and type ii collagen turnover in osteoarhritic knee: data from MOKHA study.

BACKGROUND: The objective of this pilot study was to identify biological, clinical or structural biomarkers of an intra-articular hyaluronic acid injection efficacy (HYMOVIS®) for the design of a larger placebo-controlled clinical trial studying the disease-modifying activity of this treatment. METHODS: Forty six patients with symptomatic knee Osteoarthritis (OA) were enrolled in this open-label, prospective, multicenter, pilot study. Patients received two treatment cycles of intra-articular injections (3 mL) of HYMOVIS® (8 mg/mL of hyaluronic acid hexadecylamide) at 6 months interval. Each treatment cycle involved two intra-articular injections 1 week apart. All patients had Magnetic Resonance Imaging (MRI) of the target knee at baseline and 1 year, and blood samples to assess joint biomarkers. The primary outcome was the change in type II collagen-specific biomarkers (Coll2-1, Coll2-1NO2 and CTX-II) after HYMOVIS® treatment versus baseline. Secondary endpoints included levels changes in aggrecan chondroitin sulfate 846 epitope (CS-846), Cartilage Oligomeric Matrix Protein (COMP), procollagen type II N-terminal propeptide (PIIANP), Matrix Metalloprotease (MMP)-3, Myeloperoxidase (MPO) and Interleukin (IL)-6 serum biomarkers, the ratio Coll2-1/PIIANP, CTX-II/PIIANP, variation of MRI cartilage volume, and Knee injury and Osteoarthritis Outcome Score (KOOS) index. RESULTS: Coll2-1 serum levels significantly increased overtime while Coll2-1NO2 levels were only increased at D360. Serum PIIANP levels also progressively and significantly enhanced with time. In contrast, other serum biomarker levels including CTX-II, CS-846, COMP, MMP-3, MPO or IL-6 did not change significantly overtime. Interestingly, the ratios Coll2-1/PIIANP and CTX-II/PIIANP decreased, indicating a decrease of cartilage catabolism. Compared to baseline value, MRI cartilage volume and thickness increased in lateral femoral and lateral trochlea compartments and not in medial compartment. These results, in addition to an improvement of T2 mapping score suggest a positive structural effect of the product. Interestingly, WORMS effusion score, an indicator of synovitis, significantly decreased. Finally, global KOOS score and subscales significantly increased overtime while pain at rest, walking pain and patients or investigators global assessment of disease activity decreased. The safety profile was favorable with a low incidence of injection-site pain. CONCLUSION: HYMOVIS®, a well-tolerated intra-articular treatment, significantly enhanced type II collagen turnover as suggested by the increase in Coll2-1 and PIIANP levels and cartilage volume observed by MRI in lateral knee compartment. Importantly, this study provides critical information for the design of a larger phase III clinical trial investigating Disease Modifying effect of HYMOVIS®. TRIAL REGISTRATION: http://www.isrctn.com/ISRCTN12227846 11/02/2015.

Total Hip Arthroplasty for Periacetabular Metastatic Disease. An Original Technique of Reconstruction According to the Harrington Classification.

BACKGROUND: Periacetabular metastatic disease requires complex acetabular reconstruction. The complication rate for these frail patients is high. Various cement-rebar reinforced techniques allowing cemented total hip arthroplasty (THA) have been described. The optimal procedure has not yet been identified. METHODS: A continuous series of 131 THAs performed in 126 patients with periacetabular metastatic disease was prospectively included in this study. After bone metastasis curettage and cementation, an original technique of acetabular reconstruction was performed using a dual mobility cup cemented into an acetabular reinforcement device (ie, Kerboull cross-plate or Burch-Schneider antiprotrusio cage) according to the Harrington classification. Functional outcome for independent ambulation in the community, pain relief, and occurrence of dislocation or mechanical failure of the acetabular reconstruction were assessed. RESULTS: At a mean follow-up of 33 ± 17 months, the improvement in the preoperative to postoperative functional outcome and pain relief was significant (P < .001). The dislocation rate was 2%. Two of the 3 cases of dislocation occurred in acetabular reconstructions associated with a proximal femoral arthroplasty. No mechanical failure or aseptic loosening of the acetabular reconstruction was observed. CONCLUSION: This study emphasized that our original technique combining bone metastasis curettage and cementation, acetabular reinforcement device and cemented dual mobility cup was effective to restore a painless functional independence and ensure a durable acetabular reconstruction able to face to adjuvant radiation therapy and mechanical solicitations for long survivors. In addition, dual mobility cup limited the risk of dislocation in patients undergoing THA for periacetabular metastatic disease.

Serum Sclerostin Increases After Acute Physical Activity.

Physical activity has a major impact on bone density and on osteoporosis prevention. Sclerostin is produced by osteocytes and inhibits bone formation. The impact of exercise on sclerostin secretion has not been studied so far. This pilot study aimed to explore circulating sclerostin levels immediately after acute exercise. Healthy young women practicing physical activity less than 120 min per week were enrolled. The exercise was a 45-min, low-speed, treadmill running test. Blood samples were taken at rest before exercise and within 5 min after the end of exercise. We assessed serum creatinine, 25-OH vitamin D, alkaline phosphatase, C-telopeptide of type I collagen, bone-specific alkaline phosphatase, and sclerostin. Sclerostin stability at rest was also validated over the same period of time among women fulfilling the same inclusion criteria. The study included 23 participants (mean ± SD age: 22.9 ± 1.5 years) for the exercise test and 9 participants for the resting test (26.1 ± 3.1 years). There was no difference in body mass index between the two groups. Sclerostin increased after exercise in comparison to baseline (mean ± SEM: 410 ± 27 vs. 290 ± 19 pg/mL; p < 0.001) corresponding to an increase of +44.3 ±5.5%. In the resting test, sclerostin remained stable (303 ± 20 vs. 294 ± 20 pg/mL, p = 0.76). There was a substantial increase in serum sclerostin in untrained healthy young women immediately after physical activity. These results suggest the existence of an acute release of systemic sclerostin in response to physical activity.

Novel biological markers of bone: from bone metabolism to bone physiology.

Biochemical markers of bone turnover have been used for decades in the management of bone diseases, to assess the prognosis of these conditions and to monitor treatments. The new markers, however, also reflect specific physiological mechanisms in the bone or other organs. Periostin may be more specific to the periosteum; cathepsin K is an osteoclastic enzyme that may be involved in the cardiovascular system and joints; Dickkopf-1 is involved in bone formation and vascular calcification; sclerostin is a major regulator of bone formation in response to mechanical loading and may also play a role in chronic kidney disease bone and mineral disorder; sphingosine-1-phosphate is a lipid mediator interacting with bone resorption. Some of the bone markers are in fact hormones produced by the bone that affect various physiological and pathological functions in other organs. Thus, osteocalcin is produced by osteoblasts and participates in the regulation of insulin sensitivity and fertility in men. Fibroblast growth factor 23 is produced by osteocytes to regulate phosphorus and 1,25(OH)2D3, but it also plays a major role in the adverse consequences of declining renal function, in particular with respect to the myocardium. Micro RNAs are single-stranded RNAs that regulate several pathways, including the development timing, organogenesis, cell apoptosis, proliferation and differentiation. Their serum concentration may reflect the links between bone physiology and certain conditions in other organs, for example, the cardiovascular system.

Combination of anti-angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis.

The clinical efficacy of anti-angiogenic monotherapies in metastatic breast cancer is less than originally anticipated, and it is not clear what the response of bone metastasis to anti-angiogenic therapies is. Here, we examined the impact of neutralizing tumor-derived vascular endothelial growth factor (VEGF) in animal models of subcutaneous tumor growth and bone metastasis formation. Silencing of VEGF expression (Sh-VEGF) in osteotropic human MDA-MB-231/B02 breast cancer cells led to a substantial growth inhibition of subcutaneous Sh-VEGF B02 tumor xenografts, as a result of reduced angiogenesis, when compared to that observed with animals bearing mock-transfected (Sc-VEGF) B02 tumors. However, there was scant evidence that either the silencing of tumor-derived VEGF or the use of a VEGF-neutralizing antibody (bevacizumab) affected B02 breast cancer bone metastasis progression in animals. We also examined the effect of vatalanib (a VEGF receptor tyrosine kinase inhibitor) in this mouse model of bone metastasis. However, vatalanib failed to inhibit bone metastasis caused by B02 breast cancer cells. In sharp contrast, vatalanib in combination with bevacizumab reduced not only bone destruction but also skeletal tumor growth in animals bearing breast cancer bone metastases, when compared with either agent alone. Thus, our study highlights the importance of targeting both the tumor compartment and the host tissue (i.e., skeleton) to efficiently block the development of bone metastasis. We believe this is a crucially important observation as the clinical benefit of anti-angiogenic monotherapies in metastatic breast cancer is relatively modest.

Tailoring a specific medical leadership development program for faculty members: the Lyon-Ottawa experience.

The development of leadership skills has been the topic of several position statements over recent decades, and the need of medical leaders for a specific training was emphasized during the COVID-19 crisis, to enable them to adequately collaborate with governments, populations, civic society, organizations, and universities. However, differences persist as to the way such skills are taught, at which step of training, and to whom. From these observations and building on previous experience at the University of Ottawa, a team of medical professors from Lyon (France), Ottawa, and Montreal (Canada) universities decided to develop a specific medical leadership training program dedicated to faculty members taking on leadership responsibilities. This pilot training program was based on a holistic vision of a transformation model for leadership development, the underlying principle of which is that leaders are trained by leaders. All contributors were eminent French and Canadian stakeholders. The model was adapted to French faculty members, following an inner and outer analysis of their specific needs, both contextual and related to their time constraints. This pilot program, which included 10 faculty members from Lyon, was selected to favor interactivity and confidence in older to favor long-term collaborations between them and contribute to institutional changes from the inner; it combined several educational methods mixing interactive plenary sessions and simulation exercises during onescholar year. All the participants completed the program and expressed global satisfaction with it, validating its acceptability by the target. Future work will aim to develop the program, integrate evaluation criteria, and transform it into a graduating training.

Etanercept may induce neurosarcoidosis in a patient treated for rheumatoid arthritis.

BACKGROUND: TNFα blockers have drastically improved rheumatoid arthritis prognosis by preventing joint destruction in DMARD resistant patients. Altering cytokine balance in immune diseases may expose to paradoxical adverse events. CASE PRESENTATION: We present the case of a 40-year-old woman, with a confirmed erosive and seropositive RA, successfully treated by TNFα blocker (etanercept) for seven years, and who developed a severe neurosarcoidosis. She had lymphocytic meningitis, bilateral peripheral facial paralysis and anosmia, associated with bilateral hilar lymph nodes, papilloedema, anterior uveitis and elevated serum angiotensin-converting enzyme level. Magnetic resonance imaging showed a bilateral thickening of the Gasser's ganglia walls and enhanced signal of the vestibulocochlear, the facial and the proximal portion of trijeminal nerves. CONCLUSION: This case raised the issue of the imputability of etanercept in the development of neurosarcoidosis. Neurological symptoms onset in patients on TNFα blockers should lead to exclude infections, induced lupus but also paradoxical neurosarcoidosis.

Implementation and effectiveness of pharmacist-led interviews at patient hospital admission in a rheumatology department.

OBJECTIVES: Medication reconciliation is time-consuming and its complete deployment can be difficult. The implementation of a simplified process, such as patient interviews at admission without full reconciliation, may contribute to improve patient care. The objective of the present study was to describe the feasibility and assess the potential effectiveness of implementing pharmacist-led interviews at patient admission to a rheumatology department. METHODS: This is a prospective observational study of pharmacist-led interviews at patient admission conducted between April 2015 and May 2017 in the 34-bed rheumatology department of Edouard Herriot Hospital, a French university hospital. These interviews were structured to explore patient medication management at home. The main outcome was the number of medication errors at admission. Other outcomes were the total number of interviews, the number of interviews with at least one new item of information provided by the patient, the number of interviews with at least one medication error detected, and the number of interviews leading to a modification of the hospital medication order. RESULTS: A total of 247 interviews were carried out; there was an increase in the number of interviews over the study period (n=54 in 2015, n=98 in 2016, and n=95 for the first 5 months of 2017). Among the interviews conducted, 135 (55%) provided new information concerning patient medication management and 117 medication errors were identified in hospital orders (0.47/patient). There were 76 interviews (31%) with at least one medication error; all led to a medication order modification. CONCLUSIONS: The study found that pharmacist-led interviews at patient admission were effective in detecting medication errors. They could be an alternative to a full medication reconciliation process in targeted situations. When the patient interview does not provide sufficiently robust information, full medication reconciliation may be performed.

Peripheral but not axial muscle mass is associated with early mortality in bone metastatic lung cancer patients at diagnosis.

OBJECTIVES: Identification of sarcopenia is a key issue in oncology. Several methods may be used to evaluate muscle mass in patients. Routine cancer follow-up computed tomography (CT) provides axial muscle mass whereas whole-body densitometry (DEXA) measures appendicular lean mass (ALM). Up to now, no studies have assessed, in cancer patients, the correlation between CT and DEXA muscle mass indicators and compared their prognostic value. METHODS: We included patients with synchronous bone metastases from lung adenocarcinoma at diagnosis. Diagnosis was confirmed by bone biopsy. Skeletal muscle area was determined semi-automatically on initial CT scan at the T7, T12, and L3 vertebral level using Osirix® software. The skeletal muscle index (SMI) was calculated as the ratio of muscle area to height squared. Standardised ALM/height squared data were obtained by DEXA assessment within a 30-day window of CT. RESULTS: A total of 65 patients were included; 47 (72%) were male. Mean±SD age was 65±11.4years. DEXA was available for 46 patients. The performance status was good (<1) for 39 patients. SMI indicators were significantly correlated with each other (rho from 0.3 to 0.7) but moderately correlated with ALM (rho from 0.1 to 0.7). ALM had a good discriminatory ability on 6-month survival (AUC 0.87 [0.76; 0.97]). ALM was associated with early mortality (<6months) (HR=0.29, 95% CI [0.15; 0.57]; P<0.001) but not with later mortality (>6months). In contrast, no significant effect was found for SMI. CONCLUSIONS: Peripheral muscle mass (standardized ALM by DEXA) but not axial muscle mass (SMI assessed by CT) was associated with early mortality (<6months) suggesting that cancer-induced muscle loss would affect differently appendicular muscles and axial muscles.

Impact of Bone Metastases on Patients with Renal Cell Carcinoma or Melanoma Treated with Combotherapy Ipilimumab Plus Nivolumab.

(1) Background: Ipilimumab plus nivolumab (combo-ICI) improves overall survival (OS) in patients with advanced renal cell carcinoma (RCC) or melanoma. The impact of bone metastases (BM) on survival outcomes of combo-ICI-treated patients is unknown. (2) Methods: This single-center retrospective observational study involved 36 combo-ICI-treated patients with advanced RCC and 35 with melanoma. Clinical and laboratory data preceding the initiation of combo-ICI were collected. Univariate and multivariate Cox proportional hazard models were used to assess the effect of BM on overall survival (OS) and progression-free survival (PFS). (3) Results: zNine RCC and 11 melanoma patients had baseline BM. In unadjusted analysis, baseline BM was associated with a poorer OS in the RCC cohort. Baseline BM did not have any impact on survival outcomes in melanoma patients. After adjustment on baseline performance status and on neutrophil-to-lymphocyte ratio (NLR), the impact of BM was no longer significant, but a NLR ≥ 3 was significantly associated with a poorer OS in the RCC cohort. (4) Conclusions: The presence of baseline BM seems to be associated with worse outcomes in RCC combo-ICI-treated patients, while its effect might not be independent from the inflammatory state (approximated by the NLR). BM seems to have no impact on the outcomes of melanoma combo-ICI-treated patients.

Serological response to SARS-CoV-2 vaccination in patients with inflammatory rheumatic disease treated with disease modifying anti-rheumatic drugs: A cohort study and a meta-analysis.

INTRODUCTION: Vaccination is considered as a cornerstone of the management of COVID-19 pandemic. However, while vaccines provide a robust protection in immunocompetent individuals, the immunogenicity in patients with inflammatory rheumatic diseases (IRD) is not well established. METHODS: A monocentric observational study evaluated the immunogenicity of a two-dose regimen vaccine in adult patients with IRD (n=123) treated with targeted or biological therapies. Serum IgG antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins were measured after the second vaccination. In addition, a search for observational studies performed in IRD under biologic or targeted therapies up to September 31, 2021 (PROSPERO registration number: CRD42021259410) was undertaken in publication databases, preprint servers, and grey literature sources. Studies that reported sample size, study date, location, and seroprevalence estimate were included. A meta-analysis was conducted to identify demographic differences in the prevalence of SARS-CoV-2 antibodies. RESULTS: Of 123 patients (median age 66 IQR 57-75), 69.9% have seroconverted after vaccination. Seroconverted patients were older than non-seroconverted ones in our cohort. Rituximab was associated with a significantly low antibody response. Besides, we identified 20 seroprevalence studies in addition to our cohort including 4423 participants in 11 countries. Meta-analysis confirmed a negative impact of rituximab on seroconversion rate and suggested a less substantial effect of abatacept, leflunomide and methotrexate. CONCLUSION: Rituximab impairs serological response to SARS-CoV-2 vaccines in patients with IRD. This work suggests also a negative impact of abatacept, methotrexate or leflunomide especially when associated to biological therapy.

Practices among General Practitioners in Rheumatoid Arthritis (GEPRA-I): results of a region-wide online survey.

BACKGROUND: To assess current practice regarding the management of rheumatoid arthritis patients among general practitioners of a French region, and their perception about the deployment of a multidisciplinary collaboration. METHODS: A cross-sectional online survey was sent to the general practitioners of a French region. The questionnaire comprised of 3 sections to collect data regarding 1/demographics, 2/practice and knowledge in rheumatoid arthritis, and 3/perception about the deployment of a multidisciplinary collaboration. RESULTS: 1/A total of 247 general practitioners (M/F ratio: 1.4; mean age: 46.7 years) completed the survey. 2/More than half of general practitioners believed that their role was very or extremely important in disease diagnosis (72.5%), and management of comorbidities (67.2%). Among respondents, 6.1% considered that they did not face any difficulty concerning the patient management and 61.5% had already identified causes of non-adherence. 3/A total of 151 (61.1%) general practitioners were willing to participate in a multidisciplinary programme to improve medication adherence in rheumatoid arthritis. CONCLUSIONS: General practitioners are motivated to contribute to an overall management of rheumatoid arthritis patients. Nevertheless, they need professional education about rheumatoid arthritis treatment and training in motivational interviews before getting involved in a multidisciplinary collaboration.

Cryoglobulinemia in systemic lupus erythematosus: a retrospective study of 213 patients.

OBJECTIVES: The clinical value of cryoglobulinemia (CG) in systemic lupus erythematosus (SLE) is largely unknown. The aim of this retrospective study was to describe the characteristics of CG in SLE, its impact on SLE phenotype, and the features associated with cryoglobulinemic vasculitis (CryoVas) in SLE patients. METHODS: This retrospective study conducted in a French university hospital reviewed the data from 213 SLE patients having been screened for CG between January 2013 and December 2017. SLE patients positive for CG were compared to SLE patients without CG. Patients were classified as CryoVas using the criteria of De Vita et al. RESULTS: Of the 213 SLE patients included (mean age 29.2 years, female sex 85%), 142 (66%) had at least one positive CG in their history, 67% of them having a persistent CG at follow-up. CG was type III in 114 (80%) cases and type II in 27 (19%) cases. The mean concentration of the cryoprecipitate was 40mg/L (range 0-228). Patients with CG had significantly more C4 consumption. Among patients with CG, 21 (15%) developed a CryoVas. The clinical manifestations of patients with CryoVas were mainly cutaneous (purpura, ulcers, digital ischemia) and articular, without any death at follow-up. Severe manifestations of CG included glomerulonephritis in 1/21 (5%) patients and central nervous system involvement in 4/21 (19%) patients. A response to first-line treatments was observed in 12/13 (92%) patients, but relapses were observed for 3 of them. CONCLUSION: CG is frequent in SLE, but mostly asymptomatic. CryoVas features involve mostly joints, skin, and general symptoms. CryoVas in SLE appears to be a specific condition, with a low prevalence of neuropathy, membranoproliferative glomerulonephritis, and severe manifestations.