Israel Medical Association Journal

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: 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.

Background: Previous studies have demonstrated the utility of exercise hemodynamics during right heart catheterization (RHC) in the diagnosis of diastolic dysfunction (DD). Little data exists regarding exercise hemodynamics during RHC in symptomatic systemic sclerosis (SSc) patients. 

Objectives: To assess the added diagnostic value of using exercise hemodynamics during RHC in assessment of patients with symptomatic SSc.

Methods: We performed 22 RHCs in 17 SSc patients with dyspnea and/or pulmonary arterial hypertension (PAH). Exercise was performed in 15 RHCs using isotonic arm exercises while holding a 1 kg weight in each hand. Measurements of pulmonary arterial pressure (PAP), pulmonary arterial wedge pressure (PAWP), and cardiac output (CO) were taken at rest and during peak exercise. 

Results: Normal resting RHC (PAP 22 ± 3 mmHg, PAWP 11 ± 3 mmHg) was found in seven cases. Of these, exercise induced elevation in PAP was found in three (38 ± 7 mmHg), and exercise induced elevation in PAWP was found in four (24 ± 6 mmHg). Elevated resting PAP was found in 15 (41 ± 11 mmHg) with minor changes in exercise. Of the 22 RHCs, elevation of the PAWP was found in 11 (50%), half of which were in response to exercise. 

Conclusions: In symptomatic SSc patients, exercise hemodynamics provides important information on diastolic dysfunction that is not available with non-invasive testing. Findings on exercise RHC can explain patient symptoms in up to 50% of cases. Earlier and more accurate diagnosis of patient symptoms can aid in tailoring the correct therapy for each.

Systemic sclerosis (SSc) is characterized by extensive collagen deposition, microvasculopathy and autoantibodies. All three features can be promoted by activation of T cells and B cells. T cells are of Th2 type producing profibrotic cytokines IL-4 and IL-13 and inducing dendritic cell maturation that promotes Th2 response. B cells are overactivated and promote fibrosis by autoantibodies that activate fibroblasts or inhibit the degradation of extracellular matrix. They also promote fibrosis by cell-cell contact with fibroblasts or dendritic cells. B cells, through autoantibodies, may promote vasoconstriction and obliterative vasculopathy. They may also sustain activation of T cells by functioning as antigen-presenting cells. An immunoregulatory subset of B cells, namely IL-10-producing Bregs, is decreased in SSc. Finally, B cells have a critical role in animal models of SSc. All this evidence suggests an important role for B cells in the pathogenesis of SSc and makes B cells a potential target for therapeutic intervention in this disease. 

 

Systemic sclerosis (SSc) is a heterogeneous chronic autoimmune disease that it is very difficult to diagnose in the early phase, resulting in a critical delay in therapy which is often begun when internal organ involvement is already irreversible. The ACR or LeRoy criteria have a low sensitivity for the early phases; these criteria were replaced by the ACR/EULAR 2013 criteria which improved the disease classification. Therefore, the SSc diagnosis may be delayed for several years after the onset of Raynaud’s phenomenon (RP) and even after the onset of the first non-RP symptom. RP, antinuclear antibodies (ANA) positivity, and puffy fingers were recently indicated as “red flags” (by the VEDOSS project) – that is, the main elements for suspicion of SSc in the very early phase of the disease. Confirming the diagnosis requires further tests, particularly nailfold videocapillaroscopy and evaluation of specific disease antibodies (anti-centromere and anti-topoisomerase I). In this way, the VEDOSS project identified patients in the very early phase of disease enabling a ‘‘window of opportunity’’ whereby the physician can act with effective drugs to block or at least slow the progression of the disease. The principal challenge in the fight against SSc is to detect valid predictors of disease evolution in order to treat patients in the early stage of disease. While waiting to find valid predictors, a close follow-up of the patients with the VEDOSS red flags is essential, as is a close collaboration between rheumatologists and general practitioners in order to identify all potential SSc patients as soon as possible.

Background: Systemic sclerosis (SSc) is a chronic disease with prominent vasculopathy, inflammation, production of autoantibodies, and tissue fibrosis. Periodontitis is a chronic inflammatory oral condition manifesting as microbial infection, inflammation and destruction of the alveolar bone. In both conditions tumor necrosis factor-alpha (TNFα) and other pro-inflammatory cytokines play an important role in pathogenesis. 

Objectives: To assess the periodontal status in SSc patients and compare these parameters to TNFα level in gingival crevicular fluid (GCF) of SSc patients and healthy controls.

Methods: Twenty SSc patients and 20 controls underwent periodontal examination, including probing depth (PD), plaque index (PI), gingival index (GI), bleeding on probing (BOP), and measurement of TNFα levels in collected GCF. 

Results: SSc patients had a greater PD (3.74 ± 0.32 mm vs. 3.35 ± 0.31 mm, P > 0.003), GI (1.53 ± 0.34 vs. 1.12 ± 0.54, P > 0.049), and non-significantly higher BOP than controls. TNFα levels in GCF were higher in SSc patients (1.63 ± 0.36 vs. 1.15 ± 0.34 pg/ml, P = 0.001). Periodontitis parameters correlated with several SSc variables; PI in particular was higher in patients with longer disease duration, sclerodactyly, more severe skin involvement, and SSc activity score.

Conclusions: Patients with SSc have higher indices of periodontal inflammation and higher TNFα level in GCF than did healthy individuals. These changes probably reflect the complexity of factors that influence oral health in SSc. Common pathologic pathways may be responsible for the association between SSc and periodontitis, which requires further study.

 

Abstract

Background: Scleroderma lung disease (ILD-SSc) is treated mainly with cyclophosphamide (CYC). The effectiveness of CYC was judged after 12–24 months in most reports.

Objectives: To analyze the effect of monthly intravenous CYC on pulmonary function tests including forced vital capacity (FVC) and diffusing lung capacity (DLCO), as well as Rodnan skin score (mRSS), during long-term follow-up.

Methods: We retrospectively collected the data on 26 ILD-SSc patients who began CYC treatments before 2007. Changes in FVC, DLCO and mRSS before treatment, and at 1, 4 and 7 years after completion of at least six monthly intravenous CYC treatments for ILD-SSc were analyzed.

Results: Mean cumulative CYC dose was 8.91 ± 3.25 G. More than 30% reduction in FVC (0%, 8%, and 31% of patients), DLCO (15%, 23%, 31%), and mRSS (31%, 54%, 62%) at years 1, 4 and 7 was registered. During the years 0–4 and 4–7, annual changes in FVC, DLCO and mRSS were 3.2 vs. 0.42% (P < 0.040), 4.6 vs. 0.89% (P < 0.001), and 1.8 vs. 0.2 (P = 0.002). The greatest annual FVC and DLCO reduction over the first 4 years correlated with mortality (P = 0.022). There were no differences in the main variables regarding doses of CYC (< 6 G and > 6 G).

Conclusions: In patients with ILD-SSc, CYC stabilized the reduction of FVC during treatment, but this effect was not persistent. The vascular characteristic of ILD-SSc (DLCO) was not affected by CYC treatment. CYC rapidly improved the mRSS. This effect could be achieved with at least 6 G of CYC. Higher rates of annual reduction in FVC and DLCO in the first 4 years indicate the narrow window of opportunity and raise the question regarding ongoing immunosuppression following CYC infusions.