Israel Medical Association Journal

Background: Serum ferritin is a sensitive inflammatory biomarker reflecting cell damage and oxidative stress in inflammatory rheumatic diseases. The use of ferritin for assessment of systemic sclerosis (SSc) activity, severity, and prognosis has not been fully elucidated.

Objectives: To assess the correlation between serum ferritin levels and SSc disease parameters, complications, and outcome.

Methods: Demographic, clinical, and laboratory data, including blood levels of ferritin, were collected from files of patients with SSc who were treated at the Rheumatology Institute at Rambam Health Care Campus from January 2004 to July 2021. The study compared SSc patients with elevated levels of ferritin to those with normal levels.

Results: We extracted data of 241 SSc patients (80% female, 60% with diffuse SSc, mean age 54 ± 15.4 years, mean disease duration 6.8 ± 4.5 years). During follow-up, 39% died. Elevated ferritin levels positively correlated with male sex; short disease duration; lung, heart, and kidney involvement; higher modified Rodnan skin score; anemia; elevated levels of creatinine kinase, C-reactive protein, creatinine, and troponin; reduced pulmonary function tests (forced vital capacity and diffusion capacity of the lung for carbon monoxide); and left ventricular ejection fraction. There were no correlations between ferritin levels and pulmonary hypertension or gastrointestinal involvement. Levels of ferritin negatively correlated with anti-centromere antibodies.

Conclusions: In SSc, ferritin can serve as a marker for ongoing systemic inflammation and prognosis, particularly in patients with lung and heart involvement. Further studies on serial ferritin measurement in the management of SSc patients are warranted.

Kidney involvement in systemic sclerosis (SSc) is common with altered kidney function present in approximately half of the patients [1]. Scleroderma renal crisis (SRC), the most severe kidney manifestation, occurs in about 20% of patients with this autoimmune disorder [1]. SRC mainly affects patients with the diffuse cutaneous systemic sclerosis (dcSSc) subtype of the disease, and particularly in those who are seropositive to anti RNA polymerase III antibodies [2]. In recent years, the prevalence of SRC has decreased following the initiation of medication therapy with angiotensin-converting-enzyme inhibitors (ACE-i). Previously, SRC mortality rates were as high as 78%. Contemporary studies in the post-ACE-i era suggest lower rates, with mortality rate ranging from 30% to 36% [3]. Nevertheless, progression to end-stage renal disease (ESRD) is evident and may require renal replacement therapies (RRTs). While renal transplant rates in SSc have increased, they constitute a small proportion of SSc-SRC patients (3–8%) and SSc-ESRD patients (4–17%).

In 2013, the idea of the hyperferritinemic syndrome was introduced to suggest the possible inflammatory properties of ferritin in contributing to the pathogenesis of four diseases, namely Still’s disease, macrophage activation syndrome (MAS), septic shock, and catastrophic antiphospholipid syndrome [1]. Based on this concept, ex vivo and in vitro studies were performed reporting the inflammatory properties of the heavy subunit of ferritin (FeH) in inducing the commitment of macrophages toward an inflammatory phenotype, production of pro-inflammatory cytokines, and the direct stimulation of NLRP3 and NF-kB pathway [2,4]. In addition, recent in vivo studies have established the pathogenic role of hyperferritinemia [4-6], mainly triggering a Still’s disease-like phenotype in a wild type murine model by the aberrant activation of immune cells and production of inflammatory mediators [5]. Moreover, the hyperferritinemic syndrome arena has seen many recent developments due to the rapid accrual of knowledge in coronavirus disease 2019 (COVID-19) [6,7]. Specifically, the appearance of hyperferritinemia is increasingly recognized to be associated with a more severe patient phenotype at higher risk of poor prognosis due to the appearance of the cytokine storm syndrome [8], which is a hyper-inflammatory state due to overwhelming massive release of inflammatory mediators and rapidly evolving to multiorgan failure [9].

Background: Patients with systemic sclerosis (SSc) are at increased risk for autoimmune thyroid diseases, but information regarding thyroid nodules and cancer in SSc is scarce.

Objectives: To evaluate the thyroid gland in patients with SSc at a single Israeli center.

Methods: Thyroid workup was conducted in consecutive SSc patients: thyroid-stimulating hormone (TSH), free thyroxine (fT4), anti-thyroid peroxidase, and anti-thyroglobulin antibodies, as well as thyroid ultrasound and fine needle aspiration (FNA) when appropriate.

Results: Fifty patients, mean age 51.3 ± 13.5 years (44 women) were evaluated. Ten were previously diagnosed with thyroid disease. Median TSH level was 2.0 (normal range 0.23–4 mIU/l) and median fT4 level was 1.0 (normal range 0.8–2.0 ng/dL). Among the 40 thyroid disorder-naive patients, 3 had subclinical hypothyroidism and 5 had positive anti-thyroid antibodies; 22 (44%) had 1–6 thyroid nodules, which were ≥ 1 cm in 12 (24%). Accordingly, six patients underwent FNA, and five were diagnosed as colloid nodules and one as papillary carcinoma.

Conclusions: New cases of clinically significant autoimmune thyroid disease were not detected in our cohort of patients with SSc. Nevertheless, almost half had thyroid nodules. The clinical significance of these findings and their relation to thyroid cancer remains to be determined.

Background: Systemic sclerosis (SSc) is a connective tissue disease that may affect the heart and the autonomic nervous system (ANS). There is little knowledge regarding the degree of ANS involvement in SSc patients with unknown cardiac disease.

Objectives: To evaluate cardiac and pupillary autonomic functions in patients before cardiac involvement has emerged.

Methods: The study comprised 19 patients with SSc and 29 healthy controls. Heart rate variability (HRV) analysis for time and frequency domains, as well as deep breathing test and Ewing maneuvers, were performed in all patients. Automated pupillometry for the evaluation of pupillary diameter and pupillary light reflex was completed in 8 SSc patients and 21 controls.

Results: Both groups had similar characteristics, except for medications that were more commonly or solely prescribed for SSc patients. Compared with control subjects, the SSc patients had significantly lower HRV parameters of NN50 (15.8 ± 24.4 vs. 33.9 ± 33.1, P = 0.03), pNN50 (4.9 ± 7.4% vs.10.8 ± 10.8%, P = 0.03), and triangular index (11.7 ± 3.4 vs. 15.7 ± 5.8, P = 0.02). Abnormal adaptive responses in heart rate changes were recorded during deep breathing tests and Ewing maneuvers. There was no significant difference in any of the pupillometric indices or other HRV parameters within groups.

Conclusions: SSc patients may manifest cardiac autonomic dysfunction, while their autonomic pupillary function is seemingly spared. The role of certain medications, the significance of differential organ involvement, as well as the prognostic value of our findings should be evaluated in future studies

Surgical interventions in patients with systemic sclerosis (SSc), in particular plastic procedures, might cause undesired consequences. Notably, liposuction seems to possess greater risk as adipose tissue has been shown to play an important role in treating wounds and ulcers in patients with SSc. While anticentromere antibodies were found to be correlated with vasculopathy in SSc, patients with SSc and anticentromere antibodies might be more vulnerable to surgical wound complications following liposuction. A 46-year-old female patient, who had been diagnosed with SSc at the age of 31 years, had antinuclear as well as anticentromere antibodies. She underwent abdominoplasty with liposuction and developed severe skin necrosis of the abdomen following the procedure and at the site of liposuction. The correlation with anticentromere and the role of liposuction in skin necrosis in SSc are presented.

Background: Autologous hematological stem cell transplantation (HSCT) is a novel therapy for systemic sclerosis (SSc) that has been validated in three randomized controlled trials.

Objectives: To report the first Israeli experience with HSCT for progressive SSc and review the current literature.

Methods: Five SSc patients who were evaluated in our department and were treated by HSCT were included. Medical records were evaluated retrospectively. Demographic, clinical, and laboratory data were recorded. Continuous data are presented as the mean ± standard deviation. Categorical variables are presented as frequencies and percentages.

Results: Five SSc patients were treated with HSCT. Four patients were adults (mean age 53 ± 12 years) and one was a 12-year-old pediatric patient. All patients were female. HSCT was initiated 1.4 ± 0.8 years after diagnosis. Two patients were RNA POLIII positive, two were anti-topoisomerase 1 positive, and one only antinuclear antibodies positive. All patients had skin and lung involvement. The mean modified Rodnan Skin Score was 29 ± 4.7 before HSCT, which improved to 10.4 ± 9.6 after HSCT. The forced vital capacity improved from 68 ± 13% to 90 ± 28%. Diffusing capacity of the lungs for carbon monoxide increased by 6%. Among severe adverse events were cyclophosphamide-related congestive heart failure, antithymocyte globulin-related capillary leak syndrome, and scleroderma renal crisis. All symptoms completely resolved with treatment without sequela. No treatment related mortality was recorded.

Conclusions: HSCT is an important step in the treatment of progressive SSc in Israel. Careful patient selection reduces treatment related morbidity and mortality.

Microvascular damage, clinically expressed by Raynaud’s phenomenon, is generally the first symptom of the disease and the injured vascular cells, both endothelial and perivascular, may transdifferentiate to myofibroblasts, thus leading to collagen deposition in the tissue and consequent fibrosis. Systemic sclerosis (SSc, scleroderma) is complex disease characterized by autoimmunity, vasculopathy, and fibrosis. It has been shown that microvascular damage may be the first symptom of SSc. Injured endothelial cells and pericytes may transdifferentiate into myofibroblasts, the cells responsible for fibrosis and collagen deposition in the tissue. Based on these factors, the process of myofibroblast generation may link two pivotal events of SSc: microvascular damage and fibrosis. Understanding the development, differentiation, and function of myofibroblasts is therefore crucial to individuate early pathogenetic events and develop new therapeutic target for SSc, a condition in which no disease-modifying agents are available. The aim of this review was to discuss the possible origins of myofibroblasts in SSc, highlighting the process of endothelial mesenchymal transition and pericytes to myofibroblast transition and to show how these events may contribute to pathogenesis of the disease.

Background: The aggregation of autoimmune diseases in relatives (AID-R) of patients with systemic sclerosis (SSc) has been reported.

Objectives: To analyze the prevalence of autoimmune diseases in SSc relatives and to compare their features to those of SSc patients without AID-R (controls).

Methods: A case-control analysis compared SSc patients with AID-R to those without AID-R (25 patients) with similar disease duration.

Results: Among 322 patients, 25 (7.7%; 21 females, 41.4 ± 15.6 years of age, disease duration 11 ± 8.6 years) had AID-R (21 had a first-degree relative, 4 had a second-degree relative, and 2 had both). Fourteen patients (56%) and five controls (20%) had an additional autoimmune disease (P < 0.009). Diffuse SSc (48% vs. 24%) and arthritis (72% vs. 28%) were more frequent among the patients with AID-R than the controls (P < 0.05). No significant differences were found regarding lung, heart, vascular, and digestive system involvement. The mean number of additional autoimmune diseases was 0.84 ± 0.94 in AID-R vs. 0.24 ± 0.52 in controls (P < 0.038). The mean number of autoantibodies was 2.8 ± 1.5 and 2.2 ± 0.9 (P < 0.047). Five patients died during follow-up, four of whom had AID-R. Relatives of SSc patients had diverse autoimmune diseases; the prevalence of SSc in scleroderma relatives was 1.86% (2 in first-degree and 6 in second-degree relatives). SSc patients with AID-R had an obvious tendency to polyautoimmunity.

Conclusion: A precise family history is an important clue in prognosis and prediction of autoimmune diseases in SSc patients and their relatives.