Increased osteoclastic activity in acute Charcot’s osteoarthopathy: the role of receptor activator of nuclear factor-kappaB ligand

Aims/hypothesis Our aims were to compare osteoclastic activity between patients with acute Charcot’s osteoarthropathy and diabetic and healthy controls, and to determine the effect of the receptor activator of nuclear factor-kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG). Methods Peripheral blood monocytes isolated from nine diabetic Charcot patients, eight diabetic control and eight healthy control participants were cultured in the presence of macrophage-colony stimulating factor (M-CSF) alone, M-CSF and RANKL, and also M-CSF and RANKL with excess concentrations of OPG. Osteoclast formation was assessed by expression of tartrate-resistant acid phosphatase on glass coverslips and resorption on dentine slices. Results In cultures with M-CSF, there was a significant increase in osteoclast formation in Charcot patients compared with healthy and diabetic control participants (p = 0.008). A significant increase in bone resorption was also seen in the former, compared with healthy and diabetic control participants (p < 0.0001). The addition of RANKL to the cultures with M-CSF led to marked increase in osteoclastic resorption in Charcot (from 0.264 ± 0.06% to 41.6 ± 8.1%, p < 0.0001) and diabetic control (0.000 ± 0.00% to 14.2 ± 16.5%, p < 0.0001) patients, and also in healthy control participants (0.004 ± 0.01% to 10.5 ± 1.9%, p < 0.0001). Although the addition of OPG to cultures with M-CSF and RANKL led to a marked reduction of resorption in Charcot patients (41.6 ± 8.1% to 5.9 ± 2.4%, p = 0.001), this suppression was not as complete as in diabetic control patients (14.2 ± 16.5% to 0.45 ± 0.31%, p = 0.001) and in healthy control participants (from 10.5 ± 1.9% to 0.00 ± 0.00%, p < 0.0001). Conclusions/interpretation These results indicate that RANKL-mediated osteoclastic resorption occurs in acute Charcot’s osteoarthropathy. However, the incomplete inhibition of RANKL after addition of OPG also suggests the existence of a RANKL-independent pathway.     

Clinical features of Behcet’s disease in Mongolia: a multicenter study

Clinical Rheumatology - The aim of the present study is to investigate the clinical features of patients with Behcet’s disease (BD) in Mongolia. Patients were identified and examined from six...     

Clarithromycin in adult-onset Still’s disease: a study of 6 cases

Adult-onset Still’s disease (AOSD) is a rare rheumatological condition characterized by an acute systemic involvement. There are no treatment guidelines. Glucocorticoids (GC), methotrexate (MTX), cyclosporin A and biologic agents have been successfully used, often in association. We treated six cases of AOSD with clarithromycin (CM) in combination with low-mild dose of GC and MTX. Four of them were not responsive to high-dose GC added to DMARDs, while two of them were treated with low-mild dose of GC added to CM from the beginning. CM, 500 mg b.i.d., was added to a mild-low dose of GC and to MTX. The dose of the drugs was reduced (and stopped where possible) following clinical and laboratory parameters. ACR criteria were used to assess clinical improvement. At 6 months 5 patients reached ACR 70% and could stop any therapy in 6–18 months; 1 continued chronic therapy with low-dose GC added to CM and MTX to maintain ACR 50%. CM can be a useful drug for the treatment of AOSD, even in patients not responsive to high-dose GC and DMARDs. No definitive conclusion can be drawn based on the present study.     

Alterations in the mucosa-associated bacterial composition in Crohn’s disease: a pilot study

Introduction

Changes in the intestinal bacterial composition seem to play a major role in the pathogenesis and in the clinical course of inflammatory bowel diseases (IBD), which consist of Crohn’s disease (CD), and ulcerative colitis (UC). Mutations in the NOD2 gene are the most important genetic risk factors for the development of CD. In this study, the association between mucosal biopsies and the mucosa-associated bacterial composition from CD and UC patients regarding their genetic risk factors (mutations in the NOD2 gene), their endoscopic activity, and their medical therapy (TNF-α blocking therapy) was examined.

Material and methods

Seventy biopsies from routine colonoscopies from 33 IBD patients (26 CD and 7 UC) were obtained. Disease activity and clinical characteristics were assessed. Seven different bacterial strains (Bacteroides fragilis, Escherichia coli, Prevotella melaninogenica, Clostridium coccoides, Clostridium difficile, Bifidobacterium bifidum, and Faecalibacterium prausnitzii) were quantified using real-time PCR. NOD2 genotyping from patients with CD was performed.

Results

Five of the 24 patients were positive for at least one mutation in the NOD2 gene. The bacterial composition was different in CD compared to UC, in macroscopic healthy compared to macroscopic inflamed biopsies, in NOD2 mutated compared to NOD2 wildtype patients, and in patients receiving TNF-α blocking therapy compared to patients without this treatment.

Conclusion

This study further characterizes the mucosa-associated bacteria in IBD patients. Different clinical situations lead to an altered mucosa-associated bacterial composition. The analyzed bacteria could be promising targets for cost-effective surveillance or therapies in IBD patients.

     

Castleman’s disease of the spleen

Castleman's disease(CD) is a rare lymphoproliferative disorder of unknown etiology.Clinically,it occurs as a localized(unicentric) disease or as a systemic(multicentric) disease.Unicentric Castleman's disease(UCD) presents as a solitary mass and primarily affects the mediastinal,retroperitoneal,and cervical lymph nodes.In contrast to multicentric CD,which involves peripheral lymphadenopathy and numerous systemic symptoms,UCD is not typically associated withgeneralized symptoms.Three main distinct histologic variants are recognized:hyaline-vascular type,plasma cell type,and mixed type.Extranodal CD is rare.Specifically,UCD exclusively in the spleen is extremely rare,with only 2 cases described in the literature to date.Here,we describe an asymptomatic 75-yearold man with a 5.7 cm × 4.5 cm sized heterogenous enhanced mass located in the spleen.He underwent surgical resection for diagnosis and treatment.A pathologic examination indicated the hyaline-vascular type of CD.In this patient,the preoperative diagnosis was difficult to determine,and therefore,invasive procedures were required.     

Monostotic Paget’s disease of the tibia in Korea

The incidence of Pagets disease has been estimated to be about 3%, but it is extremely rare in Asia, especially in Korea. In addition, monostotic involvement seems to be far less frequent. In this report, we describe a case of monostotic Pagets disease localized in the right tibia.Abbreviations ALP alkaline phosphatase     

Crohn’s disease of the esophagus

Opinion statement Esophageal damage is an uncommon manifestation of Crohn’s disease. The diagnosis should be considered in patients who have other intestinal manifestations of Crohn’s disease and present with esophageal symptoms. Diagnosis should be based on history, known extraesophageal Crohn’s disease, endoscopic evaluation with biopsy, and exclusion of gastroesophageal reflux disease. Mild disease should be treated with acid suppression and a short course of steroids. 5-amino-salicylates are not likely to be effective due to drug release characteristics. Patients who have moderate to severe disease should be treated aggressively with acid suppression, a longer course of steroids, and consideration of immunosuppressive therapy with 6-mercaptopurine or azathioprine. Infliximab or other anti-tumor necrosis factor therapy also can be considered in refractory patients to try to prevent the complications of stricturing and fistula formation. In those patients who develop strictures of the esophagus, treatment with balloon dilatation of the stricture followed by injection of a long-acting steroid such as triamcinolone will help to alleviate symptoms. Surgery may be required for severe, refractory symptoms, but it has a high morbidity in this population.     

An attack of acute neuro-Behçet’s disease during the course of chronic progressive neuro-Behçet’s disease: report of two cases

A 29-year-old man and a 36-year-old man developed attacks of acute neuro-Behçet’s disease (NB) (right Horner’s syndrome and right hemiplegia and dysarthria, respectively) during the course of chronic progressive NB (acute on chronic). Although both patients recovered from acute NB after treatment with infliximab or corticosteroids, they continued to show manifestations of chronic progressive NB. It is suggested that acute NB and chronic progressive NB are different in their pathogenesis.     

Uncontrolled diabetes increases the risk of Alzheimer’s disease: a population-based cohort study

Aims/hypothesis  Diabetes has been related to Alzheimer’s disease with inconsistent findings. We aimed to clarify the association of diabetes with different dementing disorders taking into account glycaemic control, and to explore the link between glucose dysregulation and neurodegeneration. Methods  A dementia-free cohort (n = 1,248) aged ≥75 years was longitudinally examined to detect dementia, Alzheimer’s disease and vascular dementia (VaD) cases (Diagnostic and Statistical Manual of Mental Disorders, revised third edition [DSM-III-R] criteria). The Alzheimer’s disease diagnoses were subdivided into Alzheimer’s disease with stroke and Alzheimer’s disease without hypertension, heart disease and stroke. Diabetes was ascertained based on medical history, or hypoglycaemic medication use, or a random blood glucose level ≥11.0 mmol/l, which included undiagnosed diabetes when neither a history of diabetes nor hypoglycaemic drugs use was present. Uncontrolled diabetes was classified as a random blood glucose level ≥11.0 mmol/l in diabetic patients. Borderline diabetes was defined as a random blood glucose level of 7.8–11.0 mmol/l in diabetes-free individuals. Cox models were used to estimate HRs. Results  During the 9 year follow-up, 420 individuals developed dementia, including 47 with VaD and 320 with Alzheimer’s disease (of the 320 Alzheimer’s disease cases, 78 had previous, temporally unrelated stroke, and 137 had no major vascular comorbidities). Overall diabetes was only related to VaD (HR 3.21, 95% CI 1.20–8.63). Undiagnosed diabetes led to an HR of 3.29 (95% CI 1.20–9.01) for Alzheimer’s disease. Diabetic patients with random blood glucose levels <7.8 mmol/l showed no increased dementia risk. Uncontrolled and borderline diabetes were further associated with Alzheimer’s disease without vascular comorbidities. Conclusions/interpretation  Uncontrolled diabetes increases the risk of Alzheimer’s disease and VaD. Our findings suggest a direct link between glucose dysregulation and neurodegeneration.     

Persistent symptoms in patients with Crohn’s disease in remission: An exploratory study on the role of diet

Objectives: Patients with Crohn’s disease (CD) often report food hypersensitivities with gastrointestinal (GI) symptoms despite being in clinical remission. We aimed to identify the most frequent symptoms and dietary triggers in such patients, and also explored whether a strict elimination diet may reduce their GI symptoms.

Methods: We assessed GI symptoms and dietary triggers in 16 patients with CD in clinical remission. Of these, 12 patients subsequently participated in a dietary intervention trial: two weeks on a habitual diet including wheat and dairy products followed by two weeks of a strict elimination diet. The severity of seven symptoms (overall symptoms, abdominal pain, bloating, abnormal feces, wind, fatigue, and musculoskeletal pain) was measured by using visual analog scales throughout the four weeks intervention period.

Main results: The most common symptoms were abdominal pain, wind, bloating, odorous wind/feces, and diarrhea. Dairy and wheat products were reported as the most frequent dietary symptom triggers. All symptoms improved (p?Conclusion: Our exploratory study suggests that dietary interventions such as an elimination diet may reduce GI symptoms in patients with CD in remission.     

Adult onset Still’s disease: a study of 14 cases

We studied the clinical profile, laboratory parameters, disease course, and outcomes of patients with adult onset Still’s disease (AOSD). A retrospective analysis of adult patients with Still’s disease diagnosed from 2000 to 2004 was carried out. Their clinical features and laboratory findings at presentation, disease course, and outcomes were analyzed. Data of 14 patients with Still’s disease were analyzed. The age at disease onset ranged from 16 to 59 years with a mean of 29.85, the male to female ratio being 9:5. The mean duration of illness from onset of symptoms to presentation was 14.5 months (range). The most common clinical manifestations were fever (n = 14), articular symptoms (n = 14), rash (n = 8), weight loss (n = 12), and sore throat (n = 5). Elevated ESR was present in all patients with a mean of 98.3 mm at 1 h. Hepatic enzymes were elevated in seven patients at disease onset. The mean duration of follow up was 19.14 months (range). Three patients progressed to chronic arthropathy. Cyclosporine led to dramatic recovery in five patients. Macrophage activation syndrome (MAS) was present in two patients, one after sulfasalazine therapy. One patient with MAS died. Still’s disease, although uncommon, has characteristic constellation of clinical and laboratory features and should be considered in the differential diagnosis of fever of unknown origin. Nonsteroidal anti-inflammatory drugs, steroids, and methotrexate may not be always effective, and cyclosporine is an effective drug in resistant cases. Sulfasalazine should be avoided in cases of AOSD.     

The incidence of Cushing’s disease: a nationwide Swedish study

Pituitary - Studies on the incidence of Cushing’s disease (CD) are few and usually limited by a small number of patients. The aim of this study was to assess the annual incidence in a...     

New horizons in the imaging of perianal Crohn’s disease: transperineal ultrasonography

Introduction: perianal disease, most commonly manifest as fistula or abscess formation, affects up to 40% of patients with crohn’s disease. perianal crohn’s disease is disabling, associated with poor outcomes, and represents a therapeutic challenge for physicians. correct diagnosis and classification of perianal disease is the first crucial step for appropriate multidisciplinary management.

Areas covered: A literature search was performed of the PubMed database using the terms ‘transperineal ultrasonography’, ‘transperineal ultrasound’, ‘perianal disease’, ‘perianal fistula’, ‘perianal abscess’, ‘magnetic resonance’, ‘endoanal ultrasonography’, ‘endoscopic ultrasound’ in combination with ‘Crohn’s disease’. A comprehensive review of the relative advantages and disadvantages of the various methods of evaluation of perianal Crohn’s disease is provided. A particular focus is placed on transperineal ultrasonography, including historical and technical factors, advantages and limitations, and its current role in practice. An algorithm for integration of transperineal ultrasound into the management of perianal Crohn’s disease into clinical practice is proposed, along with future areas research.

Expert commentary: Transperineal ultrasound is a simple, safe, cheap and reliable imaging technique for evaluation of perianal Crohn’s disease, which should be used more frequently in clinical practice.     

Crohn’s disease of the small intestine

Opinion statement  

Long-term incidence and characteristics of intestinal failure in Crohn’s disease: a multicenter study

Background

The aim of this study was to clarify the risk and characteristics of intestinal failure (IF) in patients with Crohn’s disease (CD).

Methods

The present study was a retrospective study in 12 hospitals. CD patients who underwent initial surgery at any of the 12 hospitals between 1970 and 2009 were collected (n = 1,703). Those who developed IF were reviewed (n = 68), and the cumulative risk of IF was analyzed by the Kaplan–Meier method. In addition, IF patients who underwent initial surgery at other hospitals and were then treated at any of the 12 hospitals were also reviewed (n = 33). Thus, a total of 101 IF patients were collected, and the cumulative risk of IF-related death was analyzed.

Results

The cumulative risk of IF after the initial surgery was 0.8 % (5 years), 3.6 % (10 years), 6.1 % (15 years), and 8.5 % (20 years). In CD patients with IF, mean age at initial surgery, IF occurrence, and present age at the time of the study were 28.2, 38.2, and 46.1 years, respectively. The mean number of surgeries per patient was 3.3. The mean length of the remnant small bowel was 163 cm. Twelve IF patients (12 %) had died and the cumulative risk of IF-related death by the time from the occurrence of IF was 1.1 % (3 years), 3.7 % (5 years), 6.5 % (7 years), and 8.9 % (10 years).

Conclusion

The occurrence of IF and IF-related death in CD patients is not rare over the long term. There is a pressing need to develop strategies for the prevention and management of IF.     

Anal ulcerations in Crohn’s disease: Natural history in the era of biological therapy

BackgroundThe natural history of anal ulcerations in Crohn’s disease remains unknown.AimsTo assess the long-term outcomes of anorectal ulcerations.MethodsData from consecutive patients with perineal Crohn’s disease were prospectively recorded. The data of patients with anal ulceration were extracted.ResultsAnal ulcerations were observed in 154 of 282 patients (54.6%), and 77 cases involved cavitating ulcerations. The cumulative healing rates were 47%, 70% and 82% at 1, 2 and 3 years, respectively. Patients with a primary fistula phenotype had a shorter median time to healing of their anal ulceration (28 [13–83] weeks) than those with a stricture (81 [28–135] weeks) or those with isolated ulceration (74 [31–181] weeks) (p = 0.004). Among patients with ulcerations but no fistula at referral (n = 67), only 4 (6%) developed de novo abscesses and/or fistula during follow-up. There was no benefit associated with introducing or optimising biologics, nor with combining immunosuppressants and biologics.ConclusionAnal ulceration in Crohn’s disease usually requires a long time to achieve sustained healing. Determining the impact of biologics on healing rates will require dedicated randomised trials although it does not show a significant healing benefit in the present study.     

Cardiovascular involvement in Crohn’s disease in the absence of ankylosing spondylitis

We describe a patient who had aortic regurgitation associated with Crohn’s disease in the absence of ankylosing spondylitis. Aortitis and aortic insufficiency are fairly uncommon in Crohn’s disease. The patient required aortic valve replacement because of severely uncoated cusps secondary to inflammation of the aortic wall and aortic valve. There was a saccular formation just above the right non-coronary commissure. This sac was closed with a pericardial patch. Pledgeted sutures were used for implantation of the prosthetic valve to avoid periprosthetic leakage. The right coronary ostium had narrowed due to aortic wall thickening. A right internal thoracic artery to right coronary artery bypass was done since there was no necessity for proximal anastomosis.     

Politics,culture, and the legitimacy of disease: the case of Buerger’s disease

Thromboangiitis obliterans (TAO) or Buerger’s disease is a rare form of vasculitis with distinctive clinical and pathological features that carries significant morbidity, often leading to amputation, and is strongly associated with tobacco smoking. Despite its distinctive clinicopathological characteristics, the existence of TAO as an entity sui generis was challenged for many years as it languished in relative obscurity. Then, as societal attitudes towards smoking changed, TAO not only became accepted as a disease entity, it quite literally became a poster child to illustrate the ills of smoking. Herein, we examine the history of TAO to illustrate the power of societal attitudes and politics in shaping medicine.