Israel Medical Association Journal

Behçet’s disease (BD) is a systemic inflammatory disorder characterized by a protean clinical spectrum and an enigmatic pathogenesis. After being classified as an autoimmune disorder, spondyloarthritis and vasculitis, today BD is considered at the crossroad between autoimmune and auto-inflammatory syndromes. Many pathogenetic, clinical and therapeutic clues support this recent interpretation, enabling novel treatment choices such as interleukin (IL)-1 inhibition. Thus, in the last decade the IL-1 receptor antagonist anakinra and the anti-IL-1β monoclonal antibody canakinumab were increasingly administered in BD patients resistant to standard therapies, leading to interesting results and new intriguing pathogenetic implications. However, further studies are essential to both establish how the innate and acquired immune systems interact in BD patients and identify the best way of administering anti-IL-1 agents with regard to dosage, interval of administration and organ response.

Background: Balneotherapy is one of the most commonly used non-pharmacological approaches for osteoarthritis (OA). Recent data indicate that some biomarkers could be useful to predict OA progression and to assess therapeutic response.

Objectives: To evaluate the effects of mud-bath therapy on serum biomarkers in patients with knee OA. 

Methods: The study group comprised 103 patients with primary symptomatic bilateral knee OA who were randomly assigned to receive a cycle of mud-bath therapy over a period of 2 weeks or to continue their standard therapy alone. Clinical and biochemical parameters were assessed at baseline and after 2 weeks. Clinical assessments included global pain score on a Visual Analogue Scale (VAS) and the Western Ontario and McMaster Universities Index (WOMAC) subscores for knee OA. Cartilage oligomeric matrix protein (COMP), C-terminal cross-linked telopeptide type II collagen (CTX-II), myeloperoxidase (MPO) and high sensitivity C-reactive protein (hsCRP) serum levels were assessed by ELISA.

Results: At the end of mud-bath therapy we observed a statistically significant improvement in VAS and WOMAC subscores. Serum levels of COMP, MPO and hsCRP did not show any significant modification in both groups, while a significant increase (P < 0.001) in CTX-II serum levels was observed in the mud-bath group after the treatment.

Conclusions: A cycle of mud-bath therapy added to usual treatment had a beneficial effect on pain and function in patients with knee OA. The evaluation of serum biomarkers showed only a significant increase of CTX-II, perhaps due to an increase of cartilage turnover induced by thermal stress.

Behçet's disease (BD) is a multi-systemic disorder of unknown etiology characterized by relapsing oral-genital ulcers, uveitis, and involvement of the articular, gastrointestinal, neurologic, and vascular systems. The choice of treatment is based on the severity of systemic involvement, clinical presentation and the site affected, and includes corticosteroids, azathioprine, interferon, cyclophosphamide, methotrexate or tumor necrosis factor-alpha and interleukin-1 blockers. We present a case series of four refractory BD patients successfully treated with intravenous immunoglobulins (IVIG). All patients fulfilled International Study Group criteria. The patients’ mean age was 38.75 ± 12.09 years and mean disease duration 10.25 ± 8.5 years. Human leukocyte antigen B51 was positive in two of four patients. In addition to oral aphthosis, all patients suffered from genital ulcers and cutaneous BD-related manifestations; central nervous system involvement and arthralgia were found in two patients. Peripheral nervous system, gastrointestinal and eye involvement occurred in 25% of cases. In all patients, previously treated according to EULAR recommendations without reaching satisfactory results, IVIG induced immediate and sustained response over time without incurring any side effects. We propose IVIG administration as an additional effective and safe treatment option in patients with severe and resistant BD.

Background: Radiation exposure is a well-known risk factor for well-differentiated thyroid cancer (WDTC). However, disease characteristics, optimal treatment, time from exposure to disease appearance, and the effect on outcome of age at initial exposure have yet to be determined. 

Objectives: To identify the characteristics of radiation-induced thyroid carcinoma.

Methods: We retrieved the charts of all patients previously exposed to radiation who were diagnosed with WDTC between the years 1985 and 2013 in a tertiary referral center. 

Results: Forty-four patients were reviewed. Median time from radiation exposure to diagnosis was 23 years. These patients had higher rates of aerodigestive symptoms and distant metastases on presentation than seen in non-radiated patients. Patients who were exposed to radiation before age 15 years tended to develop the disease at a younger age but had a longer latency period (34.7 ± 15.3 vs. 16.3 ± 10 years, P < 0.001) and none had significantly higher rates of vocal cord palsy, hoarseness on presentation, or aggressive variants on histology compared to patients exposed to radiation at an older age. Disease-specific survival (DSS) was the same for both groups and were similar to that seen in the general population (95% 20 year DSS).

Conclusions: Radiation-induced thyroid cancer has a more aggressive presentation and the age at exposure affects the presentation of disease. Nonetheless, appropriate treatment leads to a favorable prognosis.

 

Background: Enoxaparin is frequently used as prophylaxis for deep venous thrombosis in critically ill patients. 

Objectives: To evaluate three enoxaparin prophylactic regimens in critical care patients with and without administration of a vasopressor.

Methods: Patients admitted to intensive care units (general and post-cardiothoracic surgery) without renal failure received, once daily, a subcutaneous fixed dose of 40 mg enoxaparin, a subcutaneous dose of 0.5 mg/kg enoxaparin, or an intravenous dose of 0.5 mg/kg enoxaparin. Over 5 days anti-activated factor X levels were collected before the daily administration and 4 hours after the injection.

Results: Overall, 16 patients received the subcutaneous fixed dose, 15 received the subcutaneous weight-based dosage, and 8 received the dose intravenously. Around two-fifths (38%) of the patients received vasopressors. There was no difference between anti-activated factor X levels regarding vasopressor administration. However, in all three groups the levels were outside the recommended range of 0.1 IU/ml and 0.3 IU/ml.

Conclusions: Although not influenced by vasopressor administration, the enoxaparin regimens resulted in blood activity levels outside the recommended range.

 

Background: Plain abdominal radiographs are still performed as a first imaging examination to evaluate abdominal pain in the emergency department (ED), despite uncertainty regarding their utility.

Objectives: To describe the frequency and outcomes of the use of plain abdominal radiographs in the diagnosis of patients presenting with acute non-traumatic abdominal pain in the ED of a medical center. 

Methods: We retrospectively reviewed the records of patients presenting to the ED with acute abdominal pain during a 6 month period. Further imaging (computed tomography, ultrasonography), when performed, was compared with the abdominal radiography. 

Results: Of 573 consecutive patients, 300 (52%) underwent abdominal radiography. Findings were normal in 88% (n=264), non-specific in 7.3% (n=22), and abnormal in 4.7% (n=14). For those with normal results, no further imaging was ordered for 43% (114/264). Of the 57% (150/264) who had follow-up imaging, 65% (98/150) showed abnormal findings. In 9 (3%) of the 300 patients, abdominal radiography identified bowel perforations and obstructions, and treatment was provided without the need for further radiologic examination.

Conclusions: The use of plain abdominal radiography is still common despite the high rate of false positive results. Efforts are needed to decrease the indiscriminate use of radiography in patients presenting with abdominal symptoms.

 

Background: Pain, fatigue and functional disability are common key outcomes in most rheumatologic disorders. While many studies have assessed the outcomes of specific disease states, few have compared the outcomes of various rheumatic diseases.

Objectives: To assess how the intensity and rating of pain, fatigue and functional disability vary among groups of patients with various rheumatic disorders receiving standard care. 

Methods: In a cross-sectional study conducted in a hospital-based rheumatology unit, standard clinical and laboratory data were obtained and all patients filled out questionnaires on pain, fatigue and daily function. The analysis concentrated on visual analogue scales (VAS) using specific statistical methods.

Results: A total of 618 visits of 383 patients with inflammatory as well as non-inflammatory rheumatic disorders were analyzed. Fibromyalgia patients had significantly higher VAS scores compared to all other groups. On the other hand, patients with polymyalgia rheumatica demonstrated significantly lower VAS scores compared to all other groups of patients. Patients with psoriatic arthritis also demonstrated relatively low VAS scores. VAS scores were lower in patients with inflammatory disorders as compared to patients with non-inflammatory disorders.

Conclusions: Our results suggest a spectrum of outcome intensity in various rheumatic disorders receiving standard care, ranging from fibromyalgia patients who report distinctive severity to patients with inflammatory disorders who are doing relatively well as compared to patients with non-inflammatory disorders. The findings emphasize the need to explore the underlying mechanisms of pain and fatigue in patients with non-inflammatory rheumatic disorders. 

 

Background: Gallbladder (GB) cancer is rare. Most cases are incidentally found in specimens after a cholecystectomy. Cholelithiasis is almost always present when this diagnosis is made. Obesity is a known risk factor for gallstone formation and thus may be related to GB cancer. 

Objectives: To highlight the importance of evaluation of the gallbladder before surgery, resection of the gallbladder whenever required, and screening the resected tissue for malignancy.

Methods: We retrospectively queried a prospectively maintained database of all bariatric procedures during the last 8 years for cases of concomitant laparoscopic sleeve gastrectomy (LSG) and laparoscopic cholecystectomy (LC). Pathologic reports of the gallbladders were reviewed. Demographic data and perioperative parameters were documented. 

Results: Of 2708 patients reviewed, 1721 (63.55%) were females and 987 (36.45%) males. Excluded were 145 (5.35%) who had a previous cholecystectomy. Of the remaining 2563, 180 (7.02%) had symptomatic gallbladder disease and underwent LSG with LC. Of these, two females (BMI 53 kg/m² and BMI 47 kg/m², both age 60) were found by histological examination to have adenocarcinoma in their GB specimens (1.11%). Both were reoperated, which included partial hepatectomy of the GB bed, resection of the cystic stump, lymph node dissection, and resection of the port sites. One patient is doing well, with no evidence of disease at a postoperative follow-up of 4 years. The second patient had recurrent disease with peritoneal spread and ascites 20 months post-surgery and died 18 months later. 

Conclusions: GB cancer is a rare finding in cholecystectomy specimens. The incidence of this entity might be higher in obese older females owing to the higher incidence of cholelithiasis in these patients. 

 

Background: The practice of administering intravenous contrast to children varies by institution depending on their routine. 

Objectives: To assess the necessity of routine contrast administration in brain magnetic resonance imaging (MRI) of pediatric outpatients referred for chronic headache workups. 

Methods: We conducted a retrospective review of consecutive pediatric brain MRI examinations performed during January and February 2014 in 30 pediatric outpatients referred for evaluation of chronic headache. Independent review was performed by two board-certified neuroradiologists. The raters reviewed each MRI first as a non-contrast examination (without seeing the post-contrast images) and then with post-contrast images. 

Results: No abnormalities were found in six patients. One patient had an indeterminate finding of a tubular cerebellar lesion requiring follow-up. In the remaining patients (n=23), the findings were subclinical and included: mucosal thickening in the paranasal sinuses in 9 patients, cystic changes of the pineal gland in 8 (size 2–9 mm), small developmental venous anomalies in 6, non-specific FLAIR hyperintensities in 4, opacification of the mastoids in 2, and telangiectasia in 1 patient. The subclinical cases that were missed on pre-contrast images were: one small developmental venous anomaly, one telangiectasia and one small pineal cyst, none of which hold clinical significance. All kappa inter-rater and intra-rater agreement scores resulted in values above 0.75, excellent agreement according to Fleiss guidelines.

Conclusions: There seems to be little reason to medically justify large-scale use of routine IV contrast administration to evaluate a brain MRI of pediatric patients referred for chronic headache. 

 

Background: Evidence suggests that prolonged bisphosphonate (BP) treatment predisposes to atypical fractures (AF), but the etiology has yet to be determined. Addressing causality begins with case identification, which requires radiological adjudication. However, many trials based their case findings on coded diagnoses. 

Objectives: To investigate the feasibility of case findings by the coding system and the reproducibility of radiological evaluations in two hospitals in Israel, and to compare BP exposure of AF patients to a control group with typical (intertrochanteric of femoral neck) fractures. 

Methods: Diagnostic databases from 2007–2010 were reviewed and admission X-rays of patients were examined in two steps by two radiologists. Fractures were classified as atypical or not atypical according to published criteria. A 2:1 control group was created. Ambulatory drug acquisition was reviewed. 

Results: Of the 198 patients who fulfilled the search criteria, 38 were classified by initial radiological opinion as AF. Subsequent radiological opinion judged 16 as not atypical. Of the AF patients, 80% were exposed to BP. Of those, 81% continued to receive BP treatment for 2.4 years after AF. Only one AF patient was discharged with suspected AF diagnosis. In the control group, 27% were exposed to BP prior to fracture (P < 0.001). 

Conclusions: Thorough radiological revision is mandatory for proper classification of AF, and even when performed there is significant inconsistency in interpretation. Conclusions drawn from trials based solely on coded diagnoses lead to significant bias. BP exposure was significantly higher in the AF group. Caregiver unawareness of AF leads to improper management. 

 

Background: Several studies have identified associations between low vitamin D concentrations and risk of upper respiratory infections (URI). T lymphocytes have a major anti-viral role, are affected by vitamin D metabolism, and may mediate the link between vitamin D and URIs. Competitive swimmers have a relatively high rate of URIs, alongside a high prevalence of low vitamin D concentration. 

Objectives: To examine the associations linking T cell receptor excision circles (TREC, markers of thymus activity), circulating 25(OH)D concentrations and the effect of vitamin D supplementation, and URI symptoms in young competitive swimmers.

Methods: We tested 82 adolescent swimmers for serum 25(OH)D and TREC concentrations and found that 55 had vitamin D insufficiency. Randomized supplementation of either vitamin D3 or placebo was given for 12 winter weeks. URI symptoms were recorded weekly. The associations between TREC copy numbers, vitamin D and URI burden were examined.

Results: TREC concentrations decreased with the participants’ age (r = -0.346, P = 0.003), with no significant between-gender difference. TREC concentrations did not materially differ among subjects with normal, insufficient or deficient vitamin D status, and were not affected by vitamin D supplementation. No significant correlations were found between TREC levels or their changes during the study period, and mean URI severity or duration. 

Conclusions: Thymus activity, represented by higher TREC levels, was not related to vitamin D concentrations or status, and was not affected by vitamin D supplementation in adolescent swimmers. TREC concentrations were not associated with URI severity or duration in this population.