Israel Medical Association Journal

Inborn errors of immunity (IEI) encompass a rapidly growing spectrum of genetic disorders affecting immune development and function and resulting in susceptibility to infection, immune dysregulation, autoimmunity and malignancy.

The therapeutic approach to IEI has evolved considerably over recent decades. The cornerstones of management include antimicrobial prophylaxis, immunoglobulin replacement, and treatment of immune dysregulation and lymphoproliferative complications. For patients with severe IEI, hematopoietic stem cell transplantation offers potentially curative therapy, with early transplantation associated with improved outcomes in appropriately selected patients. The therapeutic landscape is expanding through the development of gene therapy and an increasing number of disease-specific, targeted treatments directed at defined molecular and immunological pathways.

These advances are shifting the paradigm from predominantly supportive management toward increasingly definitive and precision-based therapies. As therapeutic opportunities continue to evolve, broadening awareness of these advances across medical disciplines will be critical to ensuring that patients with IEI can benefit from the full range of available therapies and achieve the best possible outcomes.

Background: Diabetic foot (DF) is a dangerous complication of diabetes mellitus (DM). Modern treatment modalities and good organization of care can improve prognosis.

Objectives: To analyze results of DF treatment in a tertiary care setting and the degree of implementation of international guidelines in practice.

Methods: We conducted a retrospective analysis of 90 patients treated for DF ulcers/wounds in our center (May–December 2023). Thirty-five patients received only outpatient care. The median age was 65 (37–90) years, 96% had type 2 DM.

Results: Median wound duration was 29 (1–1461) days. Previous treatment was conducted by a family doctor in 30%, at a local wound clinic in 7%, by other medical specialists in 27%, or by the patient/relatives in 29%. At this stage off-loading devices were prescribed for 37%, and 35% were referred to a vascular surgeon. Limb ischemia occurred in 44 patients (49%), revascularization was conducted for 16 patients. At 6 months, healing rates were 48%. Minor or major amputation rates were 4% and 5%, respectively; 6% died, 29% stayed unhealed, and 8% were lost to follow-up. Multivariable analysis revealed independent predictors of non-healing (ethnic group and impossibility of revascularization) and of amputation (previous major amputation, presence of osteomyelitis, and white blood cell count).

Conclusions: To prevent diabetes-related amputations, healthcare professionals must prioritize preventive care, provide regular podiatry services for high-risk patients, ensure early specialist treatment for any foot ulcer, implement international guidelines at all levels of DF care, and increase the capacity of secondary wound clinics and access to revascularization.

Background: Proton pump inhibitors (PPIs) are a common and effective management strategy for eosinophilic esophagitis (EoE) leading to successful remission in most cases. However, there is uncertainty regarding the ideal follow-up pharmacological treatment to maintain remission. We performed a cost-effectiveness and quality-adjusted life year (QALY) analysis.

Objectives: To compare various approaches of pharmacologic treatments for EoE.

Methods: A Markov model was constructed to evaluate the cost-effectiveness and QALY of maintenance therapies for eosinophilic esophagitis, including PPI, topical corticosteroids (tCS), and no treatment strategy, with crossover in treatments for primary and secondary nonresponse. The primary outcomes were incremental cost-effectiveness and QALY at a 5-year time horizon.

Results: In the base-case scenario (5-year time horizon), the average costs were no treatment:₪ 73,075, PPI:₪ 81,455, and tCS:₪ 145,669 as maintenance therapy, with PPI being the dominant strategy (more effective/less costly), and a QALY of 45543, 4.5538, and 4.2283, respectively.

Conclusion: PPI was the most effective/least costly maintenance therapy. PPI is also the most cost-effective pharmacologic strategy. The relatively low adverse effects of this treatment, in addition to its effectiveness and low cost, make it an ideal choice following successful PPI induction treatment.

Background: Greater occipital nerve (GON) blocks are used in migraine management. While ultrasound-guided proximal GON blocks at the C2 level (GONC2) have been suggested to provide more sustained benefit, distal landmark-guided GON blocks are used due to their simplicity and accessibility.

Objectives: To evaluate distal GON blocks as an initial procedural approach for migraine; to assess the effect of subsequent proximal GONC2 blocks in patients who did not respond to an initial distal block.

Methods: We conducted a retrospective cohort study of adult migraine patients treated at a tertiary pain clinic between May 2022 and July 2023. Patients received either distal landmark-guided GON blocks or ultrasound-guided proximal GONC2 blocks as part of routine clinical care. Monthly migraine days (MMD) were assessed at baseline, 1 month, and 3 months following treatment.

Results: The cohort included 54 patients (27 distal, 27 GONC2). Baseline characteristics were comparable between groups. A significant overall effect of time on MMD was observed (P = 0.017). In the distal group, MMD decreased significantly at 1 month (P < 0.001) but not at 3 months. In the GONC2 group, MMD decreased significantly at both 1 month (P < 0.001) and 3 months (P = 0.001). No significant between-group differences were found at 1 month (P = 0.142) or 3 months (P = 0.509).

Conclusions: Distal GON blocks provide meaningful short-term reduction in migraine frequency and represent an effective, accessible initial interventional option. Proximal GONC2 blocks demonstrate sustained benefit and may be considered in selected patients. These findings support a pragmatic, stepwise approach to procedural migraine management.

Human T-cell Leukemia Virus (HTLV) was first described in 1980 as a retrovirus known by its ability to infect CD4 T cells or macrophages, leading to a chronic infection that may develop into adult T-cell leukemia/lymphoma (ATLL) and chronic progressive myelopathy known as HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [1]. Viral transmission occurs from unprotected sexual intercourse, vertical transmission, and contact with a contaminated blood sample. There is evidence of an association between HTLV-1 infection and rheumatic diseases [2,3].

From the first day of medical school, most physicians are indoctrinated with the concept that open communication with our patients is how medicine should be practiced. Regardless of our specialty, this forthright approach is thought to be the ideal. Whether it is taking a solid history, revealing a diagnosis, discussing therapeutic options and adverse events, discussing disease prognosis, or even conveying distressing information, this approach is the gold standard of management. We are communicating not only with the patient, but also with significant others such as family, partners, and friends; therefore, the physician must often repeat the message to different listeners. In the environment of medicine today in Canada and in many other places, is this situation ideal, and if so what is the cost?

In the setting of shortages, whether it is manpower, access to consultation or testing, therapeutic maneuvers, or blunt cost, what are the issues to consider when properly communicating with the patient? In this focus article, I do not offer new insights, just a perspective.

Background: Healthcare utilization in patients with psoriasis has been described from the perspective of psoriasis healthcare centers. Psoriasis healthcare utilization at the population level, including appointments with family physicians, impacts the overall financial expenditure.

Objectives: To describe the utilization of healthcare services in patients with psoriasis compared to the general non-psoriasis population.

Methods: We conducted a cross-sectional, population-based analysis of data from Clalit Health Services, the largest public health service provider in Israel, comparing the annual healthcare utilization and medication consumption of all Clalit members with psoriasis in 2023 with an age- and sex-matched group at a primary care clinic. We compared up to five non-psoriasis items.

Results: The study included 835,422 people (140,927 individuals with psoriasis and 694,671 without). Patients with psoriasis had more annual physician appointments than controls, and the meetings were longer. Patients with psoriasis took more sick leave and required more hospital admission compared to the control group. Tumor necrosis factor (TNF) inhibitors were prescribed much more often to patients with psoriasis than to the control group (3147 patients vs. 1857 in the matched control). More IL-17 blockers and IL-23 blockers were also prescribed more in the psoriasis group, although at a much lower level than the TNF inhibitors.

Conclusions: Patients with psoriasis used more healthcare services than the control group. Healthcare providers should allocate more resources to psoriasis care, both for primary care and at specialized psoriasis centers.

Background: Although the epidemiology of Creutzfeldt-Jakob disease (CJD) in Israel has been studied extensively, it is unknown whether its incidence is mainly a result of vertical transmission due to the high penetrance of the E200K mutation in patients with familial CJD (f-CJD) compared to sporadic CJD (s-CJD), or whether there are other yet undiscovered contributing factors.

Objectives: To conduct an age-period-cohort (APC) analysis of Creutzfeldt-Jakob disease in Israel.

Methods: In this APC analysis, we used a web-based statistical tool to identify whether patient age, period of birth, and cohort had any effect on incidence trends of s-CJD and f-CJD.

Results: APC analysis demonstrated no significant shifts in net drift, indicating the absence of any overall trend of changes over time. Cohort analysis revealed that individuals affected by either s-CJD or f-CJD who were mostly born in Israel in the second half of the 20th century exhibited the same risk as those born mainly in Libya at the beginning of 20th century. There were no changes in risk of s-CJD and f-CJD between 1985 and 2019.

Conclusions: The incidence rates of s-CJD and f-CJD in Israel have remained unchanged, indicating that the probability of a future increase in the incidence is negligible.

Background: Vitamin B6 is an essential cofactor in amino acid metabolism. Its deficiency is linked to neuropathy, anemia, and cardiovascular risk. Deficiency is common among hemodialysis patients due to dialytic losses and restrictive diets; however, data related to high-flux (HF) dialysis membranes and Mediterranean dietary patterns are scarce.

Objectives: To assess the prevalence and determinants of deficiency in unsupplemented Israeli hemodialysis patients.

Methods: This retrospective chart review, utilizing a cross-sectional design, was conducted in August 2024. We included 27 chronic hemodialysis patients not receiving vitamin B6 supplementation, representing the available unsupplemented cohort from a unit of approximately 150 patients. Vitamin B6 status was assessed by measuring plasma pyridoxal-5'-phosphate (PLP); deficiency < 20 ng/ml. Clinical and nutritional parameters were evaluated to identify deficiency.

Results: Vitamin B6 deficiency was noted in 63% of patients (median PLP 18 ng/ml, interquartile range 13–23). The cohort was 67% male, median age 74 years. All patients were treated with HF dialyzers. No significant correlations were found between PLP levels and nutritional indices or laboratory markers. A non-significant trend was observed between older age and lower PLP levels (r = -0.35, P = 0.098).

Conclusions: Vitamin B6 deficiency was common among Israeli hemodialysis patients treated with HF dialyzers, despite a presumed Mediterranean diet. It was not associated with nutritional status, suggesting dialysis-related losses, potentially augmented by high-flux membranes, may outweigh intake. Given the high prevalence of deficiency and low cost, routine low-dose vitamin B6 supplementation may be warranted, particularly in older patients.

Background: Elbow range of motion (ROM) is commonly assessed during initial evaluation and follow-up. While goniometry is considered the current gold standard, previous studies have raised concerns regarding its user dependence and measurement consistency.

Objective: To evaluate whether smartphone application-based elbow ROM measurements are comparable to visual estimation and goniometry in patients following elbow trauma.

Methods: We conducted a prospective cohort study of 18 patients with elbow injuries. Demographic and medical data were collected. Maximal flexion-extension active ROM was measured by goniometry, smartphone application, and visual estimation by orthopedic surgeons. Measurements were compared to determine agreement and accuracy among different modalities.

Results: Eighteen patients with elbow injuries were included. Inter-rater reliability was good to excellent across all rater groups (intraclass correlation coefficient 0.78–0.93). Using paired t-tests with Bonferroni correction, only one attending surgeon showed a significant underestimation of extension compared to goniometry (16.9° vs. 22.5°, P < 0.05). No significant differences were found for residents, other attendings, or smartphone measurements in either extension or flexion (P > 0.05). Bland-Altman analysis revealed modest mean bias within ± 6° for all methods, although limits of agreement were wide (up to ± 20–30°). Smartphone-based measurements demonstrated significantly higher and less variable Pearson correlation coefficients with goniometry compared to surgeon visual estimations (0.91–0.95 vs. 0.81–0.93, P < 0.05).

Conclusions: Smartphone-based elbow ROM measurements were statistically comparable to goniometry and demonstrated superior correlation and accuracy relative to clinical visual assessments. These findings support the integration of smartphone tools in the clinical setting.

Immunoglobulin E-mediated cow's milk allergy (IgE-CMA) is the most common food allergy in infancy. Recent evidence suggests that early infant feeding practices, particularly the pattern of cow's milk formula (CMF) exposure during the first days and months of life, may influence the risk of developing IgE-CMA. Studies indicate that transient CMF supplementation followed by prolonged avoidance is associated with an increased risk of IgE-CMA, whereas continued regular CMF consumption after initial exposure may reduce this risk. This review summarizes the current evidence regarding IgE-CMA prevention, discusses the limitations of the available data, presents the recommendations of the Israeli Association of Allergy and Clinical Immunology, and highlights key unanswered questions requiring further research.

Inborn errors of immunity (IEI) result from pathogenic germline variants. These disorders are clinically characterized by increased susceptibility to infections and immune dysregulation, often leading to reduced survival [1]. By linking specific monogenic defects to immune phenotypes, IEI serve as experiments of nature that provide powerful models for dissecting human immunology [2]. The International Union of Immunological Societies (IUIS) currently classifies IEI into 10 major categories with overlapping phenotypes [3]: combined T- and B-cell immunodeficiencies, combined immunodeficiencies with syndromic features, predominantly antibody deficiencies, diseases of immune dysregulation, congenital defects of phagocytes, defects in intrinsic and innate immunity, autoinflammatory diseases, complement deficiencies, bone marrow failure, and phenocopies of IEIs. The recent 2024 IUIS update was designed to serve clinicians and researchers and to inform the design of targeted sequencing panels that facilitate the genetic diagnosis of IEI. It lists 508 genes underlying 559 conditions [3]. Of note, molecular, cellular, and clinical investigations of IEI have transformed our understanding of disease pathogenesis and enabled effective targeted therapies.

The field of inborn errors of immunity (IEI), previously known as primary immune deficiencies, includes susceptibility to infections, autoimmunity, uncontrolled inflammation and malignancy is rapidly expanding. Novel scientific discoveries together with artificial intelligence and machine learning are transformed into advances in the diagnosis and treatment of affected patients. These changes require adjustments in the knowledge, skills and attitudes of health care providers, and particularly expert clinicians managing patients with IEI. In this perspective, we highlighted some of the educational needs that should be adapted to ensure that the next generation of physicians provide best care for those affected by IEI.

STING-associated vasculopathy with onset in infancy (SAVI) is a rare monogenic type I interferonopathy that may present with heterogeneous clinical manifestations and mimic common inflammatory disorders of childhood. We report the first familial case of SAVI in Israel, affecting a father and daughter carrying an identical pathogenic gain-of-function TMEM173 variant. The daughter initially presented with features fulfilling criteria for rheumatoid factor-positive juvenile idiopathic arthritis (JIA), later developing growth failure and progressive interstitial lung disease. In contrast, the father developed adolescent-onset inflammatory arthritis, subsequently lung disease, and a severe infectious neurological complication during treatment. This case highlights marked intrafamilial phenotypic variability, the diagnostic challenges posed by atypical inflammatory arthritis and the importance of genetic testing in treatment-refractory or systemic disease. Our findings underscore both the benefits and limitations of JAK inhibition in SAVI, particularly with respect to pulmonary disease and growth outcomes.

Inborn errors of immunity represent a heterogeneous group of disorders with variable clinical manifestations. Within this group of disorders, severe combined immunodeficiency (SCID) is the most profound disorder, where affected infants present clinically early in life, and have almost uniformly fatal outcome unless hematopoietic stem cell transplantation (HSCT) is performed. Gene therapy or enzyme replacement therapy are options in some specific SCID forms [1]. The estimated incidence of SCID in the United States is 1 in 58,000 live births, while in Israel the incidence is as high as 1 in 29,000 live births. This higher rate is due to a high rate of consanguineous marriages in certain communities [2].