Israel Medical Association Journal

Background: Severe asthma affects up to 20,000 citizens of Israel. Novel biological therapies, which individually have been proven to reduce asthma morbidity in clinical trials, have become available in recent years. Comparative data among different drugs are scarce.

Objectives: To describe and compare the clinical outcomes of biological therapies in severe asthma patients treated at Shamir Medical Center.

Methods: We conducted a cohort study based on a review of cases treated with monoclonal antibodies for severe asthma at our center. Data were extracted for demographics, eosinophil count, lung function (FEV1), exacerbation rate, and median dose of oral prednisone. Between-drug comparison was conducted by repeated measures ANOVA.

Results: The cohort included 62 patients receiving biological therapy. All biologic drugs were found to reduce exacerbation rate [F(1, 2) = 40.4, P < 0.0001] and prednisone use [F(1, 4) = 16, P < 0.001] significantly. ANOVA revealed no difference of efficacy endpoints between the different drugs. Eosinophil count was significantly reduced post-biologic treatment in the anti-interleukin-5 agents (P < 0.001) but not under treatment with omalizumab and dupilumab.

Conclusions: All of the biological therapies were effective for improving clinical outcomes. None of the agents was clearly superior to any other. These data emphasize the need for severe asthma patients to be seen by pulmonary medicine specialists and offered, where appropriate, biological therapies.

Background: Behçet's disease is a multi-systemic chronic relapsing inflammatory disease, classified among the vasculitides. The heterogeneity of clinical manifestations challenges the disease management.

Objectives: To assess efficacy and safety of adalimumab in patients with active persistent Behçet's arthritis who did not respond to disease-modifying anti-rheumatic drugs and to assess the impact of treatment on the cytokine milieu.

Methods: Our cohort comprised 10 patients with active arthritis who received adalimumab in a 24-week investigator-initiated prospective open-label study. Patients who relapsed within 12 weeks following adalimumab discontinuation could enter a 3-year extension study. The patients underwent a comprehensive assessment including questionnaires and measurement of inflammatory cytokines, adalimumab serum levels, and anti-drug antibodies.

Results: A significant improvement was observed in arthritis, disease activity visual analogue scales, Behçet's disease current activity form, and interleukin-6 (IL-6) levels, but not in health assessment questionnaire and functional assessment of chronic illness therapy fatigue scale questionnaire. Resolution of oral and urogenital ulcers was achieved in all patients. Significant reduction of pain was reported by 40% of patients. The disease relapsed in 9 of 10 patients, within 2–6 weeks following adalimumab discontinuation. Of the 7 patients who continued the study, arthritis was resolved in 5. Two patients with high neutralizing antidrug antibodies titer relapsed.

Conclusions: Adalimumab treatment achieved a significant improvement in arthritis, mucocutaneous manifestations, and IL-6 levels in all study patients but only 40% reported significant pain reduction. The arthritis relapsed in 90% of patients following adalimumab discontinuation and long-term treatment was required.

Background: Although cross-reactions between Epstein-Barr virus (EBV) and human systemic lupus erythematosus (SLE) autoantigens occur, a complete analysis of the potential EBV peptide cross-reactome has not been performed.

Objectives: To analyze the whole EBV proteome searching for peptides common to SLE-related proteins and endowed with an immunological potential.

Methods: Fifty-one SLE-related proteins were analyzed for hexapeptide sharing with EBV proteome using publicly available databases.

Results: An extremely high number of hexapeptides are shared between 34 human SLE autoantigens and EBV proteins. The peptide sharing mostly occurs with complement components C4 and Interleukin-10 (IL-10).

Conclusion: This study thoroughly describes the EBV vs. SLE autoantigens peptide overlap and powerfully supports cross-reactivity as a major mechanism in EBV-associated SLE etiopathogenesis.

Background: Clinical research is needed to identify patients with axial spondyloarthritis (axSpA) who are more likely to be responsive to interleukin (IL)-17 inhibition.

Objectives: To evaluate short-term efficacy of secukinumab in the management of axSpA.

Method: Twenty-one patients (7 males, 14 females) with axSpA were consecutively treated with secukinumab. Laboratory and clinical assessments were based on erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Data were recorded at baseline and at a 3 month follow-up visit.

Results: The study was comprised of 21 patients. Both BASDAI and ASDAS-CRP showed a statistically significant reduction between the baseline and the 3 month visit (P < 0.0001 and P = 0.0005, respectively). During the laboratory assessment, ESR showed a significant decrease (P = 0.008) while CRP improvement did not reach statistical significance (P = 0.213). No statistical significance was observed between patients treated with secukinumab 150 mg vs. 300 mg in BASDAI (P=0.99), ASDAS-CRP (P = 0.69), ESR (P = 0.54), and CRP (P = 0.56). No significant differences emerged between the BASDAI (P = 0.15), ASDAS-CRP (P = 0.09), and CRP (P = 0.15) rates in biologic-naïve patients and those previously failing tumor necrosis factor-α inhibition. Conversely, ESR decrease was significantly higher in the biologic-naïve subgroup (P = 0.01). No adverse events were reported.

Conclusions: Secukinumab has proven remarkable short-term effectiveness, regardless of the biologic treatment line. A dosage of 150 mg proved to be appropriate in the clinical and laboratory management of axSpA.

Background: Systemic CD11b+ cells have been associated with several cardiac diseases, such as chronic heart failure.

Objectives: To assess the levels of circulating CD11b+ cells and pro-inflammatory cytokines in cardiomyopathy induced by chronic adrenergic stimulation.

Methods: Male Lewis rats were injected with low doses of isoproterenol (isoprel) for 3 months. Cardiac parameters were tested by echocardiography. The percentage of CD11b+ cells was tested by flow cytometry. The levels of inflammatory cytokines in the sera were determined by an inflammation array, and the expression levels of cardiac interleukin-1 (IL-1) receptors were analyzed by real-time polymerase chain reactions. Cardiac fibrosis and inflammation were determined by histological analysis.

Results: Chronic isoprel administration resulted in increased heart rate, cardiac hypertrophy, elevated cardiac peri-vascular fibrosis, reduced fractional shortening, and increased heart weight per body weight ratio compared to control animals. This clinical presentation was associated with accumulation of CD11b+ cells in the spleen with no concomitant cardiac inflammation. Cardiac dysfunction was also associated with elevated sera levels of IL-1 alpha and over expression of cardiac IL-1 receptor type 2.

Conclusions: CD11b+ systemic levels and IL-1 signaling are associated with cardiomyopathy induced by chronic adrenergic stimulation. Further studies are needed to define the role of systemic immunomodulation in this cardiomyopathy.

 

Fevers recurring at a nearly predictable rate every 3–8 weeks are the signature symptom of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome, an acquired autoinflammatory disorder which recurs in association with at least one sign among aphthous stomatitis, pharyngitis, and/or cervical lymph node enlargement without clinical signs related to upper respiratory airways or other localized infections. The disease usually has a rather benign course, although it might relapse during adulthood after a spontaneous or treatment-induced resolution in childhood. The number of treatment choices currently available for PFAPA syndrome has grown in recent years, but data from clinical trials dedicated to this disorder are limited to small cohorts of patients or single case reports. The response of PFAPA patients to a single dose of corticosteroids is usually striking, while little data exist for treatment with cimetidine and colchicine. Preliminary interesting results have been published with regard to vitamin D supplementation in PFAPA syndrome, while inhibition of interleukin-1 might represent an intriguing treatment for PFAPA patients who have not responded to standard therapies. Tonsillectomy has been proven curative in many studies related to PFAPA syndrome, although the evidence of its efficacy is not widely shared by different specialists, including pediatricians, rheumatologists and otorhynolaryngologists.

Long-term extension studies and observational drug registers have revealed an increased risk of serious infections in patients treated with anti-tumor necrosis factor agents, particularly infliximab, etanercept and adalimumab. The same may be true for the newer biological drugs rituximab, tocilizumab and abatacept, although this has yet to be confirmed by long-term observational studies. We review the risk of tuberculosis, herpes zoster and other opportunistic infections, and the recommendations for screening for tuberculosis and hepatitis B and C infections in patients affected by rheumatoid arthritis, with the aim of informing patients and encouraging greater awareness among physicians.

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.