Outcomes in progressive systemic sclerosis treated with autologous hematopoietic stem cell transplantation compared with combination therapy.

OBJECTIVES: Autologous hematopoietic stem cell transplantation (AHSCT) has been shown to improve long-term survival for early diffuse progressive systemic sclerosis (SSc) compared with cyclophosphamide. Cyclophosphamide, however, does not provide a long-term benefit in SSc. The combination of mycophenolate mofetil (MMF) and rituximab is a potent alternative regimen. We aimed to retrospectively compare the outcomes of SSc patients who underwent AHSCT to patients who met the eligibility criteria for AHSCT but received upfront combination therapy with MMF and rituximab. METHODS: Repeated assessments of modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), and diffusing capacity (DLCO) values were conducted. Clinical improvement was defined as an mRSS decrease > 25% or an FVC increase > 10%. Event-free survival (EFS) was defined in the absence of persistent major organ failure or death. RESULTS: Twenty-one SSc patients in the combination therapy group were compared with sixteen in the AHSCT group. Age, sex and disease duration were similar between the two groups. Clinical improvement at 12 months was seen in 18 (86%) patients in the combination group compared with 13 (81%) in the AHSCT group (p= 0.7). The hazard ratio for EFS at 24 months favored the combination group (HR = 0.09, P= 0.04). During follow-up, both groups exhibited a significant and comparable reduction in mRSS and an increase in FVC values at each time interval up to 24 months. CONCLUSION: MMF and rituximab compared with AHSCT in SSc patients eligible for AHSCT resulted in similar skin and lung clinical improvement with a better safety profile at 24 months.

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.

Neurosarcoidosis: The Presentation, Diagnosis and Treatment Review of Two Cases.

Sarcoidosis is a chronic granulomatous disease of unknown cause characterized by the presence of non-caseating granulomas. The disease can affect any organ including the nervous system. Neurosarcoidosis occurs in about 5% patients with sarcoidosis. The clinical presentation of neurosarcoidosis is varied, and it can involve the brain, spinal cord and peripheral nervous system, separately or in different combinations. The diagnosis of neurosarcoidosis is challenging, as biopsies from the nervous system are not readily available. Anti-TNFα agents are becoming one of the cornerstone treatments for neurosarcoidosis. In this case-based review, we discuss two cases of neurosarcoidosis with different clinical presentations. The first patient presented with confusion, while the second presented with walking difficulty and neurogenic bladder. Both patients were treated with methylprednisolone pulse therapy with rapid, but non-complete, improvement. Therefore, infliximab was initiated in both cases with subsequent improvement in the clinical manifestations and imaging findings, emphasizing the effectiveness and safety of infliximab in cases of severe neurosarcoidosis. In conclusion, the goal of neurosarcoidosis management is to prevent organ system damage and minimize the toxic cumulative adverse effects of glucocorticoid use. In this case-based review we discuss the various presentations, the diagnosis and the treatment of neurosarcoidosis.

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.

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.

Immune-Mediated Disease Flares or New-Onset Disease in 27 Subjects Following mRNA/DNA SARS-CoV-2 Vaccination.

BACKGROUND: Infectious diseases and vaccines can occasionally cause new-onset or flare of immune-mediated diseases (IMDs). The adjuvanticity of the available SARS-CoV-2 vaccines is based on either TLR-7/8 or TLR-9 agonism, which is distinct from previous vaccines and is a common pathogenic mechanism in IMDs. METHODS: We evaluated IMD flares or new disease onset within 28-days of SARS-CoV-2 vaccination at five large tertiary centres in countries with early vaccination adoption, three in Israel, one in UK, and one in USA. We assessed the pattern of disease expression in terms of autoimmune, autoinflammatory, or mixed disease phenotype and organ system affected. We also evaluated outcomes. FINDINGS: 27 cases included 17 flares and 10 new onset IMDs. 23/27 received the BNT - 162b2 vaccine, 2/27 the mRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female. Among the 27 cases, 21 (78%) had at least one underlying autoimmune/rheumatic disease prior the vaccination. Among those patients with a flare or activation, four episodes occurred after receiving the second-dose and in one patient they occurred both after the first and the second-dose. In those patients with a new onset disease, two occurred after the second-dose and in one patient occurred both after the first (new onset) and second-dose (flare). For either dose, IMDs occurred on average 4 days later. Of the cases, 20/27 (75%) were mild to moderate in severity. Over 80% of cases had excellent resolution of inflammatory features, mostly with the use of corticosteroid therapy. Other immune-mediated conditions included idiopathic pericarditis (n = 2), neurosarcoidosis with small fiber neuropathy (n = 1), demyelination (n = 1), and myasthenia gravis (n = 2). In 22 cases (81.5%), the insurgence of Adverse event following immunization (AEFI)/IMD could not be explained based on the drug received by the patient. In 23 cases (85.2%), AEFI development could not be explained based on the underlying disease/co-morbidities. Only in one case (3.7%), the timing window of the insurgence of the side effect was considered not compatible with the time from vaccine to flare. INTERPRETATION: Despite the high population exposure in the regions served by these centers, IMDs flares or onset temporally-associated with SARS-CoV-2 vaccination appear rare. Most are moderate in severity and responsive to therapy although some severe flares occurred. FUNDING: none.

The impact of gender on the clinical presentation, management, and surgical outcomes of patients with native-joint septic arthritis.

RATIONALE, AIMS AND OBJECTIVES: Approximately 20 000 cases of septic arthritis (SA) occur in the U.S. yearly. We examined whether gender-related differences exist in the presentation, management, and outcomes of patients with native joint septic arthritis (NJSA). METHODS: This was a retrospective study of medical files of patients aged 18 years and older admitted between 1998 and 2015 to a single tertiary care hospital and diagnosed with NJSA. All study subjects had positive synovial fluid or blood cultures and each was managed surgically. Patients' charts were reviewed for demographics, comorbidities, clinical presentations, microbiology profiles, management, and outcomes. Cases of osteomyelitis, septic bursitis, prosthetic joint, and culture-negative SA were excluded. RESULTS: Of 324 NJSA patients, those who were female (n = 130; 40.1%) were significantly older at presentation than males (mean age: 63.6 vs 58.3; P = .006). Prior joint pathology was more common amongst females, including osteoarthritis (20.8% vs 12.9%; P = .04) and rheumatoid arthritis (10% vs 3.6%; P = .03). Female patients had a higher frequency of hip involvement (17.7% vs 10.8%; P = .05). No differences were observed in clinical presentations, culture results, medical management, or outcomes between genders. CONCLUSIONS: Compared to men, women with NJSA presented at an older age and had more prior joint pathology and a higher frequency of hip involvement. These differences, however, had no significant impact on the clinical presentation, medical management, or outcomes of NJSA.

The association between serum magnesium levels and community-acquired pneumonia 30-day mortality.

BACKGROUND: Community acquired pneumonia (CAP) is a common illness affecting hundreds of millions worldwide. Few studies have investigated the relationship between serum magnesium levels and outcomes of these patients. We aimed to study the association between serum magnesium levels and 30-day mortality among patients with CAP. METHODS: Retrospective overview of patients hospitalized with CAP between January 1, 2010 and December 31, 2016. Participants were analyzed retrospectively in order to identify the risk factors for a primary endpoint of 30-day mortality. Normal levels of magnesium levels in our laboratory varies between 1.35 and 2.4 mg/dl. RESULTS: 3851 patients were included in our cohort. Age > 75 years, blood urea nitrogen (BUN) > 20 mg/dl, hypoalbuminemia, and abnormal levels of magnesium were all associated with increased risk of 30-day mortality. Normal magnesium levels were associated with the lowest mortality rate (14.7%). Notably, within the normal levels, high normal magnesium levels (2-2.4 mg/dl) were correlated with higher mortality rates (30.3%) as compared to levels that ranged between 1.35-2 mg/dl (12.9%). Hypomagnesemia and hypermagnesemia were both associated with excess of 30-day mortality, 18.4 and 50%, respectively. CONCLUSION: Hypomagnesemia and hypermagnesemia on admission were associated with an increased rate of 30-day mortality among adult patients hospitalized with CAP. Interestingly, magnesium levels within the upper normal limits were associated with higher mortality.

Diffuse Large B Cell Lymphoma Mimicking Granulomatosis with Polyangiitis.

In a patient with systemic multiorgan disease with overlapping features, the differential diagnosis included infectious diseases, malignancies, and systemic autoimmune or inflammatory diseases. We present an unusual case of a young male with B cell lymphoma who presented with symptoms mimicking systemic vasculitis and review the existing literature.

Serum inorganic phosphorus levels predict 30-day mortality in patients with community acquired pneumonia.

BACKGROUND: Community acquired pneumonia is a major cause of morbidity and mortality. The association between serum phosphorus levels on admission and the outcome of patients with community acquired pneumonia has not been widely examined. We aimed to investigate the prognostic value of serum phosphorus levels on admission on the 30- day mortality. METHODS: The cohort included patients of 18 years old or older who were diagnosed with community acquired pneumonia between 2006 and 2012. Patients were retrospectively analyzed to identify risk factors for a primary endpoint of 30-day mortality. Binary logistic regression analysis was used for the calculation of the odds ratios (OR) and p values in bivariate and multivariate analysis to identify association between patients' characteristic and 30-day mortality. RESULTS: The cohort included 3894 patients. In multivariate regression analysis, variables associated with increased risk of 30-day mortality included: age >80 years, increased CURB-65 score, RDW >15, hypernatremia >150 mmol/l, hypoalbuminemia <2 gr/dl and abnormal levels of phosphorus. Levels of <1.5 mg/dl and >4.5 mg/dl were significantly associated with excess 30-day mortality, 38 % (OR 2.9, CI 1.8-4.9, P = 0.001) and 39 % (OR 3.4, CI 2.7-4.2, P = 0.001), respectively. Phosphorus levels within the upper normal limits (4-4.5 mg/dl) were associated with higher mortality rates compared to levels between 1.5-3.5 mg/dl, the reference group, 24 % (OR 1.9, CI 1.5-2.4, P = 0.001). CONCLUSIONS: Abnormal phosphorus levels on admission are associated with increased mortality rates among patients hospitalized with Community acquired pneumonia.

[SYNCOPE CAUSED BY INTRA-OCULAR TIMOLOL].

INTRODUCTION: Timolol eye-drops are commonly used for the treatment of glaucoma. Despite being topically applied, some systemic absorption occurs with the resulting adverse reactions related to its beta-adrenoreceptor blocking activity CASE PRESENTATION: We report the case of a 68 years old healthy male who was admitted to our department for further workup following two episodes of syncope. Medical history taking revealed that the episodes of syncope occurred soon after beginning treatment with intra-ocular timolol for glaucoma. An electrocardiogram demonstrated a sinus bradycardia rhythm and a prolonged PR interval, consistent with the negative effects of a beta adrenergic receptor antagonist on the heart's electrical generation and conduction system. DISCUSSION: This case demonstrates the potential for dangerous systemic side effects of a topically-applied medication. It also highlights the importance of thorough medical history taking in the evaluation of syncope, including inquiry regarding the use of all, especially new, medications. CONCLUSION: Detailed medical history taking can help in avoiding the performance of an expensive and unnecessary workup.