Drug Survival on First Biologic Therapy Among Late-Onset Rheumatoid Arthritis Patients Compared to Early-Onset Patients: A Population-Based Cohort Study.

INTRODUCTION: Rheumatoid arthritis (RA) patients can be divided according to the age of disease onset and classified as late-onset RA ≥ 60 years old or early-onset RA < 60 years old. Current treatment guidelines do not stipulate any preference regarding the biologic that should be used first in the late-onset group. This study aims to compare the drug survival times on first biological treatment between late and early-onset RA patients. METHODS: This is a population based cohort study using the medical records of Leumit healthcare services. We included all eligible RA patients between 2000 and 2017. RA patients were divided into late- and early-onset RA groups and compared according to drug survival time on the first biological therapy. RESULTS: The final cohort included 3814 RA patients, 2807 (73.6%) of whom had early-onset RA. Overall, biologic disease-modifying anti-rheumatic drugs (bDMARDs) were used more often among early-onset compared to late-onset patients (16.9% vs. 7.8%, p < 0.001). Among early-onset patients, etanercept was associated with the longest drug survival time on the first biologic, and adalimumab and infliximab were associated with the longest drug survival times among late-onset patients. No differences were observed in drug survival times between late and early-onset patients on the first bDMARD, except for abatacept and golimumab with longer drug survival time among early-onset patients. CONCLUSION: Late-onset RA patients were treated with biologics to a lesser extent than early-onset patients, but no differences were observed in drug survival times at the first bDMARD between the two groups.

A very rare cause of blue finger: A case-based review.

Introduction: Cryofibrinogen is an abnormal, cold-insoluble protein composed of a combination of fibrinogen, fibrin, and fibronectin. Cryofibrinogenemia can be essential (e.g. primary) or secondary to various conditions. While low levels of cryofibrinogen can be seen in asymptomatic healthy individuals without evidence of clinical features typical of cryofibrinogenemia, cryofibrinogenemia associated with clinical features is considered very rare. The clinical features of cryofibrinogenemia ranges from skin manifestations, including Raynaud's phenomenon and livedo reticularis, to more severe organ-threatening manifestations such as tissue ischemia and gangrene. Case description: We report a case of a 48-year-old male who presented with blue finger and palpable purpura on his distal extremities. Laboratory workup was positive for anti-nuclear antibodies, anti-double-stranded DNA, anti-ribonucleoprotein, and rheumatoid factor, while antineutrophil cytoplasmic antibodies and cryoglobulins were negative. Testing for hypercoagulable states and infectious etiologies was unrevealing. Later, angiographic computed tomography showed multiple pulmonary embolisms and disruption of blood flow to the left fifth digit. As the aforementioned workup could not explain the presence of the thrombus by a thromboembolic cause, a search for an in situ cause other than antiphospholipid syndrome was initiated and concentrated mainly on cryofibrinogenemia. Blood samples collected using prewarmed anticoagulant containing tubes were sent to central lab familiar with performing the test. Two weeks later, a positive result for the presence of cryofibrinogen confirmed the diagnosis of cryofibrinogenemia. Due to the presence of multiple signs compatible with mixed connective tissue disease, he was diagnosed with cryofibrinogenemia secondary to mixed connective tissue disease, and treatment with prednisone, low-molecular-weight heparin, prostacyclin and hydroxychloroquine was initiaed with favorable outcome. Conclusion: Cryofibrinogenemia is a rare and underdiagnosed condition. Clinicians should be aware of this cryopathy especially in the cases of Raynaud's phenomenon and ischemic ulcers not explained by other causes. Precautions must be taken during the diagnostic process, and therapy should be given as soon as possible.

Biologic therapy is associated with malignancies among Israeli patients with rheumatoid arthritis: A population-based study.

AIMS: To examine whether biologic disease-modifying anti-rheumatic drugs (bDMARDs) are associated with increased risk of malignancy among Israeli patients with rheumatoid arthritis (RA). METHODS: We identified RA patients meeting specified inclusion and exclusion criteria from the Leumit healthcare services database between the years 2000 and 2017. Data were collected regarding bDMARD and conventional DMARD consumption, types of malignancies, and their temporal relation to RA diagnosis. The association between baseline variables and occurrence of malignancies was examined by Cox regression. RESULTS: Among 4268 eligible RA patients, 688 (16.12%) were diagnosed with any malignancy. Melanoma skin cancer (MSC) was the most prevalent malignancy (148/688, 21.5%). The proportions out of all malignancies of MSC and non-melanoma skin cancer (NMSC) were higher after than before RA diagnosis (24.7% vs 19.1%, p = .025 and 24.7% vs 13.0%, p = .021, respectively). A higher proportion of RA patients diagnosed with malignancy used bDMARDs in comparison with RA patients who were malignancy-free (40.2% vs 17.5%, p < .001). After adjusting for demographic and clinical variables, bDMARDs were associated with an increased risk of malignancy (hazard ratio 1.42, 95% confidence interval 1.10-1.78). CONCLUSIONS: Biologic DMARDs are associated with increased risk of malignancy among Israeli RA patients, presumably contributed by MSC and NMSC. MSC was the most prevalent type of malignancy in this cohort and may indicate a predisposition state among Israeli RA patients.

Challenges in the Timely Diagnosis of Behcet's Disease.

Behcet's disease (BD) is a chronic, multi-systemic inflammatory disorder mainly characterized by recurrent oral and genital ulcers, skin lesions, and uveitis. As no pathognomonic laboratory test exists for BD, the diagnosis relies solely on clinical features. Over the years, great efforts have been invested in creating clinical diagnostic and classification criteria. The international study group criteria introduced in 1990 were the first true multinational set of criteria. Despite improving the ability to diagnose BD, these criteria still have limitations, including the inability to diagnose patients presenting without oral ulcers or presenting with rare manifestations of the disease. This led to the introduction of the international criteria for BD in 2013, which improved the sensitivity with minimal compromise on specificity. Despite the efforts made and as our understanding of the clinical manifestations of BD and genetic pathogenesis continue to evolve, efforts should be made to further enhance the currently accepted international classification criteria, perhaps by incorporating genetic testing (e.g., family history or HLA typing) as well as ethnic group-specific features.

Normotensive scleroderma renal crisis as the presenting symptom of systemic sclerosis sine scleroderma: A case report.

Scleroderma renal crisis is a rare but serious complication of systemic sclerosis. It is usually associated with marked hypertension and carries significant risk for morbidity and mortality. Its occurrence prior to the development of skin sclerosis is exceedingly rare. We report a case of a patient who presented with recurrent pericardial effusion and later tested positive for anti-nuclear and anti-topoisomerase antibodies. He later developed normotensive renal crisis as confirmed by kidney biopsy despite complete absence of skin involvement. To our knowledge, this is the first published case of a patient presenting with normotensive renal crisis without any skin involvement.

Cognitive Impairment in Anti-Phospholipid Syndrome and Anti-Phospholipid Antibody Carriers.

Cognitive impairment is frequently reported among anti-phospholipid syndrome (APS) patients as well as anti-phospholipid antibody (aPL) carriers, but it is less studied than other manifestations of this condition. Moreover, the exact prevalence of cognitive impairment in these patients has not been accurately determined, mainly due to inconsistency in the tools used to identify impairment, small sample sizes, and variability in the anti-phospholipid antibodies measured and positivity cutoffs. The notion of a direct pathogenic effect is supported by the observation that the higher the number of aPLs present and the higher the load of the specific antibody, the greater the risk of cognitive impairment. There is some evidence to suggest that besides the thrombotic process, inflammation-related pathways play a role in the pathogenesis of cognitive impairment in APS. The cornerstone treatments of APS are anti-coagulant and anti-thrombotic medications. These treatments have shown some favorable effects in reversing cognitive impairment, but solid evidence for the efficacy and safety of these treatments in the context of cognitive impairment is still lacking. In this article, we review the current knowledge regarding the epidemiology, pathophysiology, clinical associations, and treatment of cognitive impairment associated with APS and aPL positivity.

A Multimodal Messaging App (MAAN) for Adults With Autism Spectrum Disorder: Mixed Methods Evaluation Study.

BACKGROUND: Individuals with autism spectrum disorder (ASD) often exhibit difficulties in social and communication skills. For more than 30 years, specialists, parents, and caregivers have used techniques, such as applied behavioral analysis, augmentative and alternative communication, and the picture exchange communication system to support the social and communication skills of people with ASD. Even though there are many techniques devised to enhance communication, these techniques are not considered in existing social media apps for people with ASD. OBJECTIVE: This study aimed to investigate the effect of adding accessibility features, such as text-to-speech (TTS), speech-to-text (STT), and communication symbols (CS), to a messaging app (MAAN). We hypothesized that these accessibility features can enhance the social and communication skills of adults with ASD. We also hypothesized that usage of this app can reduce social loneliness in adults with ASD. METHODS: Semistructured interviews were conducted with 5 experts working in fields related to ASD to help design the app. Seven adults with ASD participated in the study for a period of 10 to 16 weeks. Data logs of participants' interactions with the app were collected. Additionally, 6 participants' parents and 1 caregiver were asked to complete a short version of the Social and Emotional Loneliness Scale for Adults (SELSA-S) questionnaire to compare pre-post study results. The Mobile Application Rating Scale: user version questionnaire was also used to evaluate the app's usability. Following the study, interviews were conducted with participants to discuss their experiences with the app. RESULTS: The SELSA-S questionnaire results showed no change in the family subscale; however, the social loneliness subscale showed a difference between prestudy and poststudy. The Wilcoxon signed-rank test indicated that poststudy SELSA-S results were statistically significantly higher than prestudy results (z=-2.047; P=.04). Point-biserial correlation indicated that the SELSA-S rate of change was strongly related to usage of the TTS feature (r=0.708; P=.04) and CS feature (r=-0.917; P=.002), and moderately related to usage of the STT feature (r=0.428; P=.17). Lastly, we adopted grounded theory to analyze the interview data, and the following 5 categories emerged: app support, feature relevance, user interface design, overall feedback, and recommendations. CONCLUSIONS: This study discusses the potential for improving the communication skills of adults with ASD through special features in mobile messaging apps. The developed app aims to support the inclusion and independent life of adults with ASD. The study results showed the importance of using TTS, STT, and CS features to enhance social and communication skills, as well as reduce social loneliness in adults with ASD.

Factors associated with drug survival on first biologic therapy in patients with rheumatoid arthritis: a population-based cohort study.

Lack of sufficient head-to-head trials comparing biologic disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA), makes the choice of the first bDMARD a matter of rheumatologist's preference. Longer drug survival on the first bDMARD usually correlates with early remission. We aimed to identify factors associated with longer drug survival. We conducted a population-based retrospective longitudinal cohort study. We identified RA patients using the relevant International Classification of Disease 9th codes. "True" RA patients were defined as patients fulfilling, additionally, at least one of the following: receiving conventional DMARDs (cDMARDs), being positive for rheumatoid factor or anti-cyclic citrullinated peptide, or being diagnosed by a rheumatologist. We compared drug survival times and identified factors associated with longer drug survival. We identified 4268 true RA patients between the years of 2000-2017. 820 patients (19.2%) received at least one bDMARD. The most commonly prescribed bDMARDs were etanercept (352, 42.9%), adalimumab (143, 17.4%), infliximab (142, 17.3%) and tocilizumab (58, 7.1%). Infliximab was associated with the longest drug survival (47.1 months ± 46.3) while golimumab was associated with the shortest drug survival (14.9 months ± 15.1). Male gender [hazard ratio (HR) = 0.76, 95% confidence interval (CI), 0.63-0.86, p = 0.001], concurrent conventional DMARDs use (HR = 0.79, 95% CI 0.68 - 0.98, p = .031) and initiating bDMARD therapy in earlier calendric years (HR = 1.12, 95% CI 1.10 -1.18, p = 0.0001) were associated with longer drug survival. Male gender, concomitant cDMARDs and initiating biologic therapy at earlier calendric years are associated with longer drug survival.

Efficacy and safety of culture-expanded, mesenchymal stem/stromal cells for the treatment of knee osteoarthritis: a systematic review protocol.

BACKGROUND: Osteoarthritis is a progressive multifactorial condition of the musculoskeletal system with major symptoms including pain, loss of function, damage of articular cartilage and other tissues in the affected area. Knee osteoarthritis imposes major individual and social burden, especially with the cost and complexity of surgical interventions. Mesenchymal stem/stromal cells have been indicated as a treatment for degenerative musculoskeletal conditions given their capacity to differentiate into tissues of the musculoskeletal system. METHODS: A systematic search will be conducted in Medline, Embase, Cochrane Library, Scopus and relevant trial databases of English, Japanese, Korean, German, French, Italian, Spanish and Portuguese language papers published or in press to June 2018, with no restrictions on publication year applied. References will be screened and assessed for eligibility by two independent reviewers as per PRISMA guidelines. Cohort, cross-sectional or case controlled studies will be included for the analysis. Data extraction will be conducted using a predefined template and quality of evidence assessed. Statistical summaries and meta-analyses will be performed as necessary. DISCUSSION: Results will be published in relevant peer-reviewed scientific journals and presented at national or international conferences by the investigators. TRIAL REGISTRATION: The protocol was registered on the PROSPERO international prospective register of systematic reviews prior to commencement, CRD42018091763 .

Alternatives to Biologics in Management of Knee Osteoarthritis: A Systematic Review.

BACKGROUND: Knee osteoarthritis (KOA) is a common condition encountered by physicians. KOA is addressed by a wide array of modalities including a number of nonbiological treatments. METHODS: PubMed, ISI Web of Science, and SPORTDiscus were searched for level 1 to 4 studies published from inception to August 2017. RESULTS: A total of 18 studies were evaluated and results demonstrated moderate supporting evidence for prolotherapy and limited evidence for botulinum toxin type A, sodium bicarbonate and calcium gluconate, and low-molecular weight fraction of 5% human serum albumin. Evidence for local anesthetic agents was conflicting. CONCLUSION: There is moderate supportive evidence for the effectiveness of prolotherapy in improving pain and function in both, short-term and long-term. Limited supporting evidence found for botulinum toxin type A, sodium bicarbonate and calcium gluconate, and low-molecular weight fraction of 5% human serum albumin in improving pain and function. There is conflicting evidence for the use of local anesthetic agents in patients with KOA.

Associations of Peritoneal Glucose Load With Male Sexual Dysfunction and Depression in Peritoneal Dialysis Patients.

This cross-sectional study examined possible associations of peritoneal glucose load with male sexual dysfunction and depression in peritoneal dialysis patients. Compared to patients with peritoneal glucose load ≤3 g/kg per day, those with load >3 g/kg per day had higher Beck Depression Inventory scores, (18.9 ± 5.4 vs. 11.4 ± 5.8, P = 0.002) and lower International Index of Erectile Function scores, serum total testosterone and DHEA [(15.4 ± 6.4 vs. 45.1 ± 20.7, P < 0.001), (8.5 ± 3.0 vs. 13.9 ± 3.2, P < 0.001), (113.9 ± 58.8 vs. 280.2 ± 128.3, P < 0.001); respectively)]. Of participants with peritoneal glucose load >3 g/kg per day, 84.6% had mild to moderate erectile dysfunction and 92.3% had abnormal Beck Depression Inventory scores. Peritoneal glucose load inversely correlated with International Index of Erectile Function scores (P < 0.001), total serum testosterone (P = 0.002) and serum DHEA (P = 0.001); and directly with Beck Depression Inventory scores (P < 0.001) and serum estradiol (P < 0.001). This study demonstrated higher prevalence of sexual dysfunction, depression and sex hormone disturbances in male peritoneal dialysis patients receiving higher peritoneal glucose load.

Does Ramadan Fasting Affect Hydration Status and Kidney Function in CKD Patients?

BACKGROUND/AIMS: This study is the first of its kind to examine the impact of the Ramadan fasting on hydration status, plasma brain natriuretic peptide (BNP) levels, and kidney function in chronic kidney disease (CKD) patient. METHODS: This prospective cohort study included 2 groups of patients with CKD grades 2-4: thirty-one Muslim patients who fasted the month of Ramadan (fasting group) and 26 Muslim patients who did not fast (control group). One week before the Ramadan fast, in the last week of the month of Ramadan (4 weeks), and 4 weeks after the end of the Ramadan month (8 weeks), hydration status and blood analysis of urea, creatinine and BNP levels were measured. RESULTS: Among fasting patients, serum urea levels increased significantly (p = 0.024) during the last week of fasting and returned to basal levels at 4 weeks after the end of the Ramadan month, the estimated glomerular filtration rate did not change significantly at the end of fasting (p = 0.411), the hydration status indices and plasma BNP levels were significantly decreased after fasting (p ≤ 0.021) but returned to basal values 4 weeks thereafter. CONCLUSIONS: Patients with CKD grades 2-4 can fast throughout the month of Ramadan with no significant deterioration of renal functions and with a reasonable degree of safety.

Does whey protein supplementation affect blood pressure in hypoalbuminemic peritoneal dialysis patients?

OBJECTIVE: Hypertension and hypoalbuminemia are common risk factors for cardiovascular complications in peritoneal dialysis (PD) patients. Data are limited regarding the effects of whey protein consumption on blood pressure in this population. The aim of the present study was to examine if whey protein supplementation for 12 weeks to hypoalbuminemic PD patients affects their blood pressure. PATIENTS AND METHODS: This prospective randomized study included 36 stable PD patients with serum albumin levels <3.8 g/dL. During 12 weeks, 18 patients were instructed to consume 1.2 g/kg/day of protein and an additional whey protein supplement at a dose of 25% of the instructed daily protein (whey protein group). Eighteen patients were instructed to consume protein in the amount of 1.2 g/kg/day and an additional 25%, without whey protein supplementation (control group). RESULTS: Compared to the control group, in the whey protein group, serum albumin levels, oncotic pressure, and dialysate ultrafiltration significantly increased (3.55±0.14 to 4.08±0.15 g/dL, P<0.001; 21.81±2.03 to 24.06±1.54 mmHg, P<0.001; 927.8±120.3 to 1,125.0±125.1 mL/day, P<0.001; respectively) and were significantly higher after 12 weeks (4.08±0.15 vs 3.41±0.49 g/dL, P<0.001; 24.06±1.54 vs 22.71±1.77 mmHg, P=0.010; 1,125.0±125.1 vs 930.6±352.8 mL/day, P=0.017; respectively) in the whey protein group compared to the control group. Fluid overload, the extracellular to intracellular ratio and mean arterial pressure (MAP) significantly decreased (2.46±1.08 to 1.52±0.33, P<0.001; 1.080±0.142 to 0.954±0.124, P<0.001; 102.6±3.80 to 99.83±3.85, P=0.018; respectively) and were significantly lower in the whey protein group after 12 weeks (1.52±0.33 vs 2.23±0.73, P<0.001, 0.954±0.124 vs 1.048±0.111, P=0.002; 99.83±3.85 vs 102.8±3.93, P=0.018; respectively). CONCLUSION: Whey protein supplementation for 12 weeks decreased MAP in hypoalbuminemic PD patients.

The relationship between oxidized serum albumin and blood pressure in hypoalbuminemic peritoneal dialysis patients.

BACKGROUND: Oxidative stress produces molecular modifications of serum albumin that disturb its biological functions and interfere with its detection by the bromocresol green assay (BCG). Oxidative stress, inflammation, and hypoalbuminemia are common peritoneal dialysis (PD). This study aimed to evaluate the relationship between serum albumin, oxidized serum albumin (OSA), oncotic pressure, and blood pressure in hypoalbuminemic PD patients. METHODS: Twenty-four PD patients with serum albumin levels <3.5 g/dl enrolled in the study. Data were compared between participants with the mean arterial pressure (MAP) <105 mmHg (n = 12) and MAP ≥ 105 mmHg (n = 12). RESULTS: Serum albumin levels were ≤3.0 g/dl and similar in both groups (p = 0.298). The calculated OSA and oncotic pressure were significantly higher in patients with MAP ≥ 105 mmHg than in those with MAP < 105 mmHg. MAP was positively and marginally correlated with serum albumin levels (measured by BCG) (r = 0.34, p = 0.05), and positively and significantly correlated with the calculated OSA and oncotic pressure (r = 0.44, p = 0.015, r = 0.58, p = 0.002; respectively). The oncotic pressure was positively correlated with the calculated OSA (r = 0.47, p = 0.011). CONCLUSION: OSA, undetectable by the commonly used BCG, may contribute to higher blood pressure in hypoalbuminemic PD patients.

The effectiveness of prolotherapy in treating knee osteoarthritis in adults: a systematic review.

Introduction: Osteoarthritis (OA) often leads to symptoms such as pain, stiffness and decreased function. OA is treated with a wide range of modalities, both conservatively and surgically. Prolotherapy has been used to treat various musculoskeletal problems and has shown some promise. Sources of data: Searches of the electronic databases, PubMed, ISI web of science, PEDro and SPORTDiscus, were conducted for all Level 1-4 studies published from inception through to December 2016. Areas of agreement: Ten studies were evaluated and results show significant improvement in scores for pain, function and range of motion, both in the short term and long term. Patient satisfaction was also high in these patients (82%). Areas of controversy: Meta-analysis was not possible due to heterogeneity of outcome measures and populations. Growing points: Moderate evidence suggests that prolotherapy is safe and can help achieve significant symptomatic control in individuals with OA. Areas for developing research: Future research should focus on larger sample size, standardization of treatment protocol and basic science evidence.