High prevalence of diffuse idiopathic skeletal hyperostosis (DISH) among obese young patients - A retrospective observational study.

OBJECTIVE: Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by ossification of ligaments and entheses, and most commonly affects the spinal column. The prevalence of DISH is increasing with age and is considered uncommon before the age of 50 years, with an estimated prevalence of less than 5 %. DISH is known to be highly associated with metabolic syndrome and obesity. We aim to assess the prevalence of DISH among young (≤50 yr.) patients suffering from severe obesity (BMI of 35 kg/m2 or higher). METHODS: A retrospective analysis assessing chest and spine radiographs (including Computed Tomography, CT) of patients with BMI≥35 visiting the bariatric ambulatory clinic in an academic medical center from 2013 to 2022. Patients included in the analysis were 31-50 years old. Diagnosis of DISH was made according to the Resnick criteria. The prevalence of DISH was calculated. Demographic, clinical and laboratory data were collected and compared between the DISH and non-DISH groups. RESULTS: 183 young (mean age: 40.4; 118 females, 64.2 %) obese (BMI median: 40.6; range 35-73) patients were included in the radiographic review. DISH was diagnosed in 33 patients (18.0 %; 95 % CI: 13.1-24.2 %) which was significantly higher than the expected 10 % (Z = 3.62, p<.001); another 8 patients (4.4 %; 95 % CI: 2.2-8.4 %) were considered as "near DISH" (not fulfilling yet the Resnick criteria) as it represents a pre-disease state. Patients diagnosed with DISH were significantly older than patients without DISH (t = 4.54, p<.001), as the prevalence of DISH increased by age (linear association=14.95, p<.001). There was a statistically significantly higher prevalence of hypertension (χ2 = 8.30, p<.004), smoking (χ2 = 4.69, p<.03) and OSA (χ2 = 6.16, p<.013) in the DISH group as compared to their non-DISH counterparts. CONCLUSION: The prevalence of DISH among obese young patients was 18 %, which is much higher than in the general population. Early-onset DISH should be regarded as a musculoskeletal obesity-related complication.

Imaging of diffuse idiopathic skeletal hyperostosis (DISH).

Diffuse idiopathic skeletal hyperostosis (DISH) is a condition characterised by calcification and ossification of ligaments and entheses. The condition usually affects the axial skeleton, in particular, at the thoracic segment, though also other portions of the spine are often involved. DISH often involves also peripheral tendinous and/or entheseal sites either alone, or in association with the involvement of peripheral joints. At times, new bone formation involves the bone itself, but sometimes it involves joints not usually affected by osteoarthritis (OA) which result in bony enlargement of the epiphysis, joints space narrowing and a reduced range of motion. Because of the entheseal involvement, DISH can be mistaken for seronegative spondyloarthropathies or for a "simple" OA. Furthermore, other implications for the recognition of DISH include spinal fractures, difficult intubation and upper endoscopies, decreased response rates in DISH with concomitant spondyloarthritides, and increased likelihood to be affected by metabolic syndrome and cardiovascular diseases. This Atlas is intended to show the imaging finding in DISH in patients diagnosed with the condition by the Resnick classification criteria.

Microangiopathy and forearm arterial blood flow in systemic sclerosis: a controlled study.

OBJECTIVE: The aim of the study was to evaluate the interrelationship between the micro- and macrovasculature. METHODS: This is a cross-sectional study that examined SSc patients and fibromyalgia (FM) patients as controls. We assessed forearm peripheral vascular status and nailfold capillaroscopy. We evaluated the association between nailfold capillaroscopy pattern of microvasculopathy reflected as microangiopathy evolution score and macrovascular changes in the forearm vessels examined by color Doppler ultrasound. We assessed relevant clinical and laboratory data, as well as intima-media thickness (IMT) and internal diameter (ID) in the radial and ulnar arteries in millimeters, and calculated the ratio IMT\ID peak systolic velocity and end-diastolic velocity were used for the calculation of the resistance index. RESULTS: We examined 73 patients: 50 patients with SSc and 23 patients with FM. Ten patients with SSc had arterial occlusions compared to 1 among FM patients (p = 0.082). The SSc group had a statistically significantly higher mean IMT to ID ratio (p < 0.001). There was no correlation between microangiopathy evolution score for both hands, RI, or mean IMT/ID ratio. Total microangiopathy evolution score was not associated with arterial occlusions. CONCLUSIONS: Our study demonstrated a high prevalence of macrovascular disease in SSc; no correlation was found between microvasculopathy and macrovascular disease, suggesting that different pathogenic mechanisms might operate in different vessels size. Key Points • This study demonstrated a high prevalence of macrovascular arterial forearm disease in systemic sclerosis patients. • This study found no correlation between capillaroscopic microangiopathy evolution score (MES) and macrovascular abnormalities. • Our findings suggest that different pathogenic mechanisms might operate in different vessels size.

Portal Vein Thrombosis and Thrombocytopenia in Eosinophilic Granulomatosis with Polyangiitis: A Paradox?

A 36-year-old woman with eosinophilic granulomatosis with polyangiitis (EGPA) presented with necrotic skin lesions and pulmonary infiltrates. There was eosinophilic vasculitis on skin biopsy, and substantial tissue eosinophilia in her bone marrow. She had unexplained worsening thrombocytopenia, which prompted a thrombophilia work-up. However, abnormalities in liver enzymes led to the extraordinary finding of portal vein thrombosis. Thrombocytopenia resolved with treatment with low molecular weight heparin. This case highlights the risk of hypercoagulability in eosinophilia specifically, and in EGPA. We suggest that thrombosis should be ruled out in all cases of EGPA. LEARNING POINTS: Eosinophilia is a hypercoagulable state.Thrombocytopenia is not part of eosinophilic granulomatosis with polyangiitis (EGPA) and may herald thrombosis.Thromboembolism should be ruled out in the setting of EGPA with eosinophilia.Prompt diagnosis can prevent unnecessary procedures.

Antitumor Necrosis Factor-α Therapy Associated with Inflammatory Bowel Disease: Three Cases and a Systematic Literature Review.

OBJECTIVE: Antitumor necrosis factor-α (anti-TNF-α) therapy is the most prescribed biologic agent therapy in rheumatology and gastroenterology. However, a number of serious side effects have been reported with these drugs. Only a handful of cases of new-onset inflammatory bowel disease (IBD), mostly in children diagnosed with juvenile idiopathic arthritis (JIA), have been reported during anti-TNF-α therapy. We present 3 cases of adult IBD following anti-TNF-α therapy and a literature review on this topic. METHODS: We searched PubMed MESH for all relevant terms, papers were reviewed, and patient-specific data were extracted. Relevant clinical data were calculated and presented. RESULTS: The PubMed search resulted in 137 articles, of which 11 articles and 4 cited publications were included in our analysis. We found 53 cases of IBD after anti-TNF-α therapy reported in the literature; most of them were case series collected retrospectively from national databases or studies. Almost all the patients developed IBD after the introduction of etanercept (ETN); 2 patients with rheumatoid arthritis were also included. The average age at IBD onset was 17.3 years and the average time from ETN introduction to IBD onset was 27 months (± 24). Gastrointestinal symptoms have been reported as improving or subsiding in most of the patients after discontinuing ETN. CONCLUSION: Although this manifestation is not common, it should be taken into consideration as an adverse effect of ETN. Rheumatologists, and in particular rheumatologists treating adult patients, should be aware of this possible complication. Further investigation about the pathogenic process underlying this phenomenon is warranted.

The impact of concomitant diffuse idiopathic skeletal hyperostosis on the achievement of minimal disease activity in subjects with psoriatic arthritis.

Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by ossification of different entheses. Psoriatic arthritis (PsA) is a seronegative spondyloarthritis associated with psoriasis. Given the possible overlap of the two diseases, we assessed whether DISH presence may affect PsA clinical outcomes. Also, predictors of DISH presence in the cohort were investigated. Consecutive PsA patients from two Italian Rheumatology Research Units were enrolled. Subjects were splitted into two groups, according to the current treatment (TNF-α blockers or traditional DMARDs). All patients underwent a rheumatologic examination, blood sample collections and spine radiographs. Information about traditional vascular risk factors was recorded. In each patient, the presence of minimal disease activity was evaluated and the presence of DISH was established according to the Resnick and Niwayama criteria. Among the 80 enrolled subjects (57.5 % men, mean age 56.5 ± 11.1 years), the overall prevalence of DISH was 30.0 %. Patients with DISH were older, with higher BMI and waist circumference. DISH subjects showed worsen BASMI, HAQ and ESR. In a multivariate regression model, BASMI was a significant predictor of DISH presence (OR 3.027, 95 % CI 1.449-6.325, p = 0.003). The prevalence of MDA was lower in DISH patients than in no-DISH (16.7 vs 41.1 %, p = 0.041), and the presence of DISH was a predictor of not achieving MDA (OR 3.485, 95 % CI 1.051-11.550, p = 0.041). PsA subjects with DISH showed worsen indices of spine mobility and articular function and lower prevalence of minimal disease activity than no-DISH patients.

Ultrasonography of peripheral entheses in the diagnosis and understanding of diffuse idiopathic skeletal hyperostosis (DISH).

The aim of this study was to investigate musculoskeletal ultrasound (MSUS) as a diagnostic modality in DISH and to explore whether it might help in elucidating its pathogenesis and events that precede the calcification/ossification process. Fifty patients with DISH and 34 patients with osteoarthritis of the lower limbs without DISH were investigated. Data regarding demographics and traditional cardiovascular risk factors were collected from all patients. An ultrasonography was performed according to the Glasgow Ultrasound Enthesitis Scoring System (GUESS) by observers who were blinded to the diagnosis or the clinical findings in the patients. The total mean GUESS score for patients with DISH was 14.12 ± 5.2 and for patients without DISH 5.32 ± 4.99 (P < 0.0001). Univariate logistic regression analysis found a strong association between the GUESS and the probability of having DISH (P < 0.0001). The area under the ROC curve (AUC) revealed that the GUESS accuracy in diagnosing DISH was 88.53% with sensitivity and specificity of 92 and 70.6%, respectively, at a cutoff value of 6.36. A stepwise logistic regression analysis of the statistically significant items in the GUESS isolated four items, and the presence of either all of them or the first three items yielded the likelihood of having DISH to be 98.8 and 90.6%, respectively. The GUESS and the stepwise logistic regression analysis of the GUESS items demonstrated a high likelihood of having DISH. MSUS might help to identify entheseal changes in DISH. Further studies are needed to confirm these results.

Hospitalizations of patients treated with anti-tumor necrosis factor-α agents -- a retrospective cohort analysis.

OBJECTIVE: To assess the association between treatment with anti-tumor necrosis factor-α (TNF-α) agents and the occurrence of hospitalizations, their causes and complications, compared to treatment with traditional disease-modifying antirheumatic drugs in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). METHODS: A retrospective cohort study was conducted of patients with RA, AS, and PsA treated with anti-TNF-α agents between April 2002 and December 2007. Patients were assessed during the period of anti-TNF-α treatment (Group B) and compared to an equivalent period before initiation of anti-TNF-α therapy (Group A). All hospitalization charts were reviewed and diagnoses, comorbidities, concomitant medications, and clinical course were analyzed. Statistical analysis was performed using multivariate mixed Poisson regression. RESULTS: In the study period of 57 months, 735 hospitalization events of 327 patients were analyzed. Statistically significant decreases were seen in the total number of hospitalization events as well as hospitalizations due to exacerbation of rheumatic diseases in Group B compared to Group A (44.4 vs 74.2 and 21.9 vs 47.5 per 100 patient-years, respectively; p < 0.0001). More infectious events (7.4 in Group B compared to 4.6 per 100 patient-years in Group A; p = 0.043) were associated with anti-TNF-α treatment, older age, and underlying disease, because patients with RA had higher rates of infections compared to patients with PsA and patients with AS. CONCLUSION: The overall effect of anti-TNF-α therapy was a significant decline in total hospitalization events. The decrease was more prominent in patients with RA than in patients with AS and patients with PsA, and reflected the significant decrease in hospitalizations due to rheumatic disease exacerbation. The decrease was more pronounced than the observed increase in infectious events.

[Guidelines for the diagnosis and treatment of the fibromyalgia syndrome].

Over the past years, considerable progress has been made in understanding the pathogenesis of the fibromyatgia syndrome and the evidence based approach to the diagnosis and management has been significantty extended. The purpose of the current project is to develop practicat and evidence based guidetine recommendations for the Israeli health care system. A panet of physicians with clinical and research experience in the fibromyalgia field was convened under the auspices of the Israeli Rheumatology Association. A systematic review was performed on the current literature regarding the diagnosis and treatment of fibromyalgia. Using an interactive discussion procedure, recommendations were reached and expert opinion was introduced where evidence was considered incomplete. The panel recommendations underline the importance of concomitant and integrated medical therapy, such as serotonin and noradrenaline reuptake inhibitor (SNRI) anti-depressants or gamma-aminobutyric acid (GABA) related anti-epileptics, with regular aerobic physical exercise.

Serum iron and iron stores in non-anemic patients with fibromyalgia.

The aim of the study was to assess iron serum levels and markers of iron stores in non-anemic fibromyalgia (FM) patients and to evaluate their impact on the prevalence and clinical manifestations of FM patients. Eighty-four patients with primary FM and 87 controls were investigated. Demographic and clinical data were collected from all participants. All patients completed the fibromyalgia impact questionnaire (FIQ). Patients evaluated the effect of the disease on their daily activity (DA) and judged the severity (DS) of the disease on a 0-10 scale. Venous blood was tested for serum iron, transferrin, ferritin, and soluble transferrin receptors (sTfR). Iron deficiency was defined if any of the following were present: serum iron <40 µg/dL, serum ferritin levels <10 ng/mL, or sTfR levels >28.1 nmol/L. Analysis at a cutoff level of serum ferritin levels ≤30 ng/mL and sTfR/ferritin ratio was also performed. Hemoglobin, iron, transferrin, sTfR, ferritin levels, and sTfR/ferritin ratios did not differ between the groups. The mean FIQ score was 57.13 ± 20.21 and the DA and DS scores were 6.79 ± 2.97 and 6.74 ± 3.09, respectively. No correlations were found between the parameters studied and the FIQ or its ten individual items. Thirty-eight controls (43.7%) and 23 FM patients (27.4%) had ferritin levels of ≤30 (p < 0.04). Within the FM group, lower levels were associated with lower total FIQ score and FIQ subscale scores. Patients with FM do not have reduced serum levels of iron or surrogate markers of iron stores. At present, there is no evidence to support iron supplementation in the treatment of FM.

Trauma and work-related pain syndromes: risk factors, clinical picture, insurance and law interventions.

In the past decade, major progress has been made in our understanding of fibromyalgia syndrome (FMS). Various triggers have been implicated as contributing to symptom development in FMS when genetically susceptible individuals are challenged. A substantial amount of data points towards the association between trauma and chronic widespread pain/fibromyalgia syndrome (CWP/FMS). There is abundant data suggesting that the pathogenesis of CWP/FMS might be related to cervical spine injury. Furthermore, several persistent local pain conditions may progress to CWP/FMS. These conditions may share a common pathogenic mechanism namely, central sensitisation. Physical trauma and emotional trauma co-exist in many traumatic events and may interact in the pathogenesis of CWP/FMS.

Hepatotoxicity of tocilizumab and anakinra in rheumatoid arthritis: management decisions.

BACKGROUND: Elevation of liver enzymes in rheumatoid arthritis patients treated with tocilizumab (Actemra(®)) or anakinra (Kineret(®)) is a well-documented phenomenon. However, characterization of liver histology has not been defined in most cases. Similarly, the factors involved in decisions regarding discontinuation of treatment and outcome have not been discussed in the literature to any significant extent. CASES: Two women with rheumatoid arthritis refractory to standard therapies are reported here. One was treated with tocilizumab and the other with anakinra, and both developed toxic liver effects. Liver biopsy in both cases showed focal necrosis of hepatocytes - a hallmark of drug toxicity - with steatosis and early fibrosis. Inflammatory infiltrates were prominent in the patient treated with anakinra but not in the tocilizumab-treated patient. However, FibroTest (Assistance publique - Hôpitaux de Paris, Paris, France) in the latter patient showed an inflammatory activity of A2 and was staged as F2, and the histology also showed hemorrhagic areas. Although both patients were overweight and both had been exposed to steroids, the steatosis and steatohepatitis were considered to be related to drug hepatotoxicity. Other possible etiologies for liver injury were excluded. Discontinuation of anakinra led to rapid normalization of liver enzymes. The patient receiving tocilizumab developed hepatosplenomegaly but had normal liver enzymes. In spite of the hepatosplenomegaly, the tocilizumab treatment was continued since the patient had not responded to other drugs. There was a good response to the tocilizumab treatment and the liver biopsy showed only insignificant, reversible liver injury. At follow-up at 6-months the patient remains stable. CONCLUSION: As cases showing tocilizumab or anakinra liver toxicity are appearing more frequently to the authors, a full assessment for liver injury is recommended in patients given those drugs, with careful consideration of the decision to continue or discontinue treatment. Further studies with long-term follow-up analysis are mandatory to guide appropriate management strategies.

Nonarticular tenderness and functional status in patients with diffuse idiopathic skeletal hyperostosis.

OBJECTIVE: To investigate the degree of nonarticular tenderness and functional status in patients with diffuse idiopathic skeletal hyperostosis (DISH). We assessed these variables' correlation with their clinical, radiographic, and constitutional measurements and with metabolic syndrome (MS). METHODS: Eighty-seven patients with DISH were compared with 65 controls without DISH. Examination of nonarticular tenderness was performed by thumb palpation. Tenderness was scored for the 18 fibromyalgia tender points (TP), and 4 control points. Nonarticular tenderness was expressed by the number of TP and by the total tenderness score (TTS). The Short Health Assessment Questionnaire (HAQ II) was administered to all participants. Clinical and laboratory data were collected from all patients. Patients were classified as having MS by both the National Cholesterol Education Program and World Health Organization definitions. RESULTS: There was a statistically significant difference in TTS between controls and patients with DISH. The mean tenderness of many individual TP was significantly higher in the DISH group compared with the control group. TP counts, TTS, and body mass index (BMI) positively correlated with the HAQ II. There was a linear trend in intensity of T-spine bony bridges (BB) and the total number of TP as well as many individual TP. Patients with DISH were more likely to be affected by MS. No correlation was found between TP count, TTS, and MS. CONCLUSION: Patients with DISH have a lower pain threshold than patients who do not have DISH. TP count and TTS correlate with the functional status, BMI, waist circumference, and high-grade BB. No correlation was observed between pain threshold and MS.

Metabolic syndrome and cardiovascular risk in patients with diffuse idiopathic skeletal hyperostosis.

OBJECTIVES: To assess the likelihood of patients with diffuse idiopathic skeletal hyperostosis (DISH) to be affected by metabolic syndrome (MS) and to evaluate the risk for the development of coronary heart disease (CHD) in these patients. METHODS: Ninety-five patients without cardiovascular disease were enrolled, including 47 patients with established DISH and 48 age- and sex-matched patients without DISH. Data regarding body build, use of medications, concomitant diseases, blood pressure, and smoking habits were collected. Blood tests included fasting glucose, insulin levels, and lipid profile. Patients were classified as having MS based on the definitions of the World Health Organization (WHO-MS), and The National Cholesterol Education Program Adult Treatment Panel III (NCEP-MS). Risk assessment for the development of CHD was performed using the Framingham risk scoring system. RESULTS: Patients with DISH had a significantly higher body mass index and waist circumference, while no significant differences were observed for serum total cholesterol, high-density lipoprotein, low-density lipoprotein, or triglyceride serum levels. NCEP-MS and WHO-MS were significantly more prevalent in DISH patients compared with the control group (P = 0.001 and 0.007, respectively). The odds ratio of patients with DISH meeting the NCEP-MS was 3.88 and for WHO-MS was 3.61. The Framingham score for CHD was higher in DISH patients (P = 0.004), conferring a significantly higher 10-year CHD risk (P = 0.007). CONCLUSIONS: Patients with DISH have a significantly higher likelihood to be affected by MS than non-DISH patients. They also have a significantly higher CHD risk. Patients with DISH should be encouraged to take measures to reduce cardiovascular disease risks.

Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial.

OBJECTIVE: Adenosine exerts antiinflammatory effects via activation of the A3 adenosine receptor (A3AR), a Gi protein-associated cell-surface receptor, overexpressed in synovial tissue and peripheral blood mononuclear cells (PBMC) in patients with active rheumatoid arthritis (RA). CF101 is a highly specific orally bioavailable A3AR agonist. METHODS: This was a multicenter study, blinded to dose, designed to assess the clinical activity and safety of CF101 in active RA. Seventy-four patients were randomized to receive 0.1, 1.0, or 4.0 mg CF101 bid for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. A3AR expression levels were analyzed in PBMC from 18 patients. RESULTS: . Maximal responses were observed with 1.0 mg bid, lower at 0.1 and 4.0 mg bid. At 12 weeks, 55.6%, 33.3%, and 11.5% of the patients receiving 1.0 mg CF101 achieved ACR20%, 50%, and 70% responses, respectively. CF101 was generally well tolerated, with mild headache (4.1%), nausea (2.7%), and rash (2.7%) being the most common treatment-related adverse events. Statistically significant correlations between A3AR overexpression at baseline and ACR50 and ACR70 responses were observed. CONCLUSION: CF101 administered bid for 12 weeks resulted in improvement in signs and symptoms of RA that did not achieve statistical significance, and was safe and well tolerated. The expression level of A3AR was directly correlated with patient responses to CF101, suggesting its utilization as a biomarker for the pharmacodynamic and therapeutic effects of this novel agent. These findings require confirmation in a double-blind randomized placebo-controlled trial, currently under way.

Optimizing treatment with biologics.

Disability and joint damage in rheumatoid arthritis (RA) occur rapidly and early in the course of the disease. Disease activity is predominantly responsible for the disability in the early stages of RA. Nonreversible joint damage increases disability later in the course of RA. In recent years, several strategies that employed combination therapies with conventional disease modifying antirheumatic drugs (DMARD) were studied with the aim of rapidly bringing the disease under control. The ultimate goal was to alleviate symptoms and slow or halt the progression of joint damage. The introduction of highly efficient biologic agents allows introduction of a number of new strategies, including early administration of a biologic agent alone or in combination with high-dose methotrexate. Other options for the use of biologic therapies include the use of biologic agents for moderate disease, and early use of a biologic agent for induction of remission and subsequent treatment with a conventional DMARD. A strategy for tight control of disease with targeted outcomes for decision-making may offer further improvement in disease control irrespective of the treatment approach. The remarkably improved outcomes that can be achieved by initiating aggressive therapy early, with close monitoring of disease progression and modification of ineffective therapeutic strategies, support the use of biologics in the optimal management of RA.

Antinuclear antibodies measured by enzyme immunoassay in patients with systemic lupus erythematosus: relation to disease activity.

To evaluate the correlation between measurements of antinuclear antibodies serum levels by enzyme immunoassay (ANA-EIA), and the degree of systemic lupus erythematosus disease activity. To retest the performance of the test compared to measurement of antinuclear antibodies by immunofluorescence (ANA-IIF). Eighty-five sera from 71 patients with SLE were tested. Demographic, clinical, laboratory, and SLEDAI status were collected. The sera were tested for ANA-EIA and by ANA-IIF at 1:40 and 1:160 dilutions. Serum levels of ANA-EIA were compared to the overall SLEDAI score and to each of its components. A SLEDAI score of > or =6 was considered clinically significant. The sera of fifty-one healthy volunteers served as controls. Serum levels of ANA-EIA were significantly higher in patients with a SLEDAI score of > or =6 compared to the group of patients with a SLEDAI score of <6 (P = 0.004). High serum levels of ANA-EIA correlated significantly with elevated anti DS-DNA antibodies (P < 0.001), low C(3) or C(4) levels (P < 0.001), pyuria (P < 0.011), arthritis (P = 0.019), and new rash (P = 0.019). Levels of ANA-EIA were significantly higher in patients tested positive by IIF compared to those who tested negative. Higher serum levels of ANA-EIA correlated with clinically significant disease activity in patients with SLE. Higher serum levels of ANA-EIA also correlated with some single items of the SLEDAI. The results also reiterated the validity of ANA-EIA testing in patients with SLE. Further longitudinal studies are needed in order to test the hypothesis that serum ANA-EIA levels might reflect fluctuations in disease activity.