Journal of Scleroderma and Related Disorders

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.

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.

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.

The overlapping of systemic sclerosis with hematologic malignancy has been described previously in the literature. This case report presents a patient with systemic sclerosis and multiple myeloma who had severe digital ischaemia that culminated in the amputation of several fingers.

A 65-year-old White female patient was diagnosed with limited systemic sclerosis in 2002, smouldering multiple myeloma IgG/kappa in 2017 and liver cirrhosis in 2018 due to autoimmune hepatitis. In 2021, she was admitted to the emergency room with dry ischaemia of all fingers and toes despite optimized therapy, associated with visual blurring. The diagnostic hypothesis was hyperviscosity syndrome associated with multiple myeloma reactivation. The patient underwent chemotherapy and despite initial laboratory improvement, 19 digits required amputation.

Although the association between systemic sclerosis and multiple myeloma is rare, it should be remembered in cases of significant worsening of Raynaud’s phenomenon. Causes unrelated to systemic sclerosis should also be considered in the presence of severe exacerbations in patients with other comorbidities.

Heart involvement is a common problem in systemic sclerosis. Recently, a definition of systemic sclerosis primary heart involvement had been proposed. Our aim was to establish consensus guidance on the screening, diagnosis and follow-up of systemic sclerosis primary heart involvement patients.

A systematic literature review was performed to investigate the tests used to evaluate heart involvement in systemic sclerosis. The extracted data were categorized into relevant domains (conventional radiology, electrocardiography, echocardiography, cardiac magnetic resonance imaging, laboratory, and others) and presented to experts and one patient research partner, who discussed the data and added their opinion. This led to the formulation of overarching principles and guidance statements, then reviewed and voted on for agreement. Consensus was attained when the mean agreement was ⩾7/10 and of ⩾70% of voters.

Among 2650 publications, 168 met eligibility criteria; the data extracted were discussed over three meetings. Seven overarching principles and 10 guidance points were created, revised and voted on. The consensus highlighted the importance of patient counseling, differential diagnosis and multidisciplinary team management, as well as defining screening and diagnostic approaches. The initial core evaluation should integrate history, physical examination, rest electrocardiography, trans-thoracic echocardiography and standard serum cardiac biomarkers. Further investigations should be individually tailored and decided through a multidisciplinary management. The overall mean agreement was 9.1/10, with mean 93% of experts voting above 7/10.

This consensus-based guidance on screening, diagnosis and follow-up of systemic sclerosis primary heart involvement provides a foundation for standard of care and future feasibility studies that are ongoing to support its application in clinical practice.

Juvenile systemic sclerosis is a rare childhood disease. Three disease activity indices have been published for adult patients with systemic sclerosis: the European Scleroderma Study Group Index, a modified version of the European Scleroderma Study Group Index and the revised European Scleroderma Trials and Research index. The objective of this study was to determine the feasibility and performance of the three disease activity indices in a prospectively followed cohort of patients with juvenile systemic sclerosis.

The analysis cohort was selected from the prospective international inception cohort enrolling juvenile systemic sclerosis patients. The correlation of the disease activity indices with the physicians’ and the patients’ global assessment of disease activity was determined. The disease activity indices were compared between patients with active and inactive disease. Sensitivity to change between 6- and 12-month follow-up was investigated by mixed models.

Eighty percent of the 70 patients had a diffuse cutaneous subtype. The revised European Scleroderma Trials and Research index was highly correlated with the physician-reported global disease activity/parents-reported global disease activity (r = 0.74/0.64), followed by the European Scleroderma Study Group activity index (r = 0.61/0.55) and the modified version of the European Scleroderma Study Group activity index (r = 0.51/0.43). The disease activity indices significantly differed between active and inactive patients. The disease activity indices showed sensitivity to change between 6- and 12-month follow-up among patients who improved or worsened according to the physician-reported global disease activity and the parents-reported global disease activity.

Overall, no disease activity score is superior to the other, and all three scores have limitations in the application in juvenile systemic sclerosis patients. Furthermore, research on the concept of disease activity and suitable scores to measure disease activity in patients with juvenile systemic sclerosis is necessary in future.

The Health Assessment Questionnaire–Disability Index is an important outcome measure reflecting functional disability, but knowledge on its course over time in patients with systemic sclerosis is scarce. Therefore, we investigated the long-term course of the Health Assessment Questionnaire–Disability Index and its association with baseline characteristics in systemic sclerosis patients.

Systemic sclerosis patients, fulfilling the European League Against Rheumatism and the American College of Rheumatology 2013 criteria, were included from the Leiden Combined Care in Systemic Sclerosis cohort with annual assessments including the Scleroderma Health Assessment Questionnaire–Disability Index (range = 0–3). The course of the Health Assessment Questionnaire–Disability Index was evaluated over the total follow-up (baseline to last available Health Assessment Questionnaire–Disability Index) and between yearly visits. Based on a minimal clinical important difference of 0.22, courses were categorized into worsening, stable or improvement. The course of the Health Assessment Questionnaire–Disability Index over time was evaluated with linear mixed models. Baseline characteristics were compared between patients with a worsening or improvement of the Health Assessment Questionnaire–Disability Index over the total follow-up period with logistic regression analyses.

A total of 517 systemic sclerosis patients were included, with a median follow-up of 7 years (interquartile range = 4–9; 2649 visits) and a baseline Health Assessment Questionnaire–Disability Index of 0.625 (interquartile range = 0.125–1.25). On group level, the Health Assessment Questionnaire–Disability Index is stable with an annual increase of 0.019 (95% confidence interval = 0.011 to 0.027). Looking at subgroups, patients >65 years or who died/were physically unable to come during follow-up had a worse mean Health Assessment Questionnaire–Disability Index. In individual courses from baseline to the last follow-up, the proportions of patients with a clinically meaningful worsening, stable or improved Health Assessment Questionnaire–Disability Index were 35%, 42% and 23%, respectively. Patients with immunosuppressants (odds ratio = 0.5, 95% confidence interval = 0.3 to 0.9) or gastrointestinal involvement (odds ratio = 0.6, 95% confidence interval = 0.4 to 0.9) at baseline showed a reduced chance of worsening of the Health Assessment Questionnaire–Disability Index over the total follow-up period.

Over time, the average course of the Health Assessment Questionnaire–Disability Index was stable in systemic sclerosis patients. However, individual courses vary, with worsening occurring in one-third. Worsening occurred less often in individuals using immunosuppressants or with gastrointestinal involvement at baseline.

Systemic sclerosis (scleroderma) is an incurable inflammatory condition synonymous with unique nutrition needs. As rheumatologists are frequently responsible for managing the various organ manifestations, this study aimed to understand the service needs and nutritional concerns of rheumatologists involved in the care of adults with systemic sclerosis.

A 13-item online qualitative and quantitative survey was distributed via REDCap^® from January to March 2022 to rheumatologists who are members of the Australian Scleroderma Interest Group and consult patients with systemic sclerosis. Data were collected on rheumatologists’ demographics, and their views on symptoms observed, nutrition concerns and priorities, and preferred dietetic service provision for their patients. Data are reported as number (%).

Of 27 eligible rheumatologists, 17 (63%) completed the survey. All rheumatologists reported gastrointestinal symptoms in their patients (n = 17, 100%); predominantly reflux (n = 17, 100%) and dysphagia (n = 17, 100%). Weight loss was observed by the majority of rheumatologists (n = 15, 88%). Rheumatologists reported patients used food avoidance/special diets to manage symptoms (n = 12, 71%). Dietetic consultation was reported as potentially beneficial by all rheumatologists, with the preferred time being when symptoms increase or change (n = 15, 88%), and the preferred approaches being written resources (n = 15, 88%), face-to-face (n = 14, 82%) and telephone consultation (n = 14, 82%). Advice on gaining weight (n = 14, 82%) and systemic sclerosis symptom management (n = 13, 77%) were the most desired education topics reported.

Rheumatologists commonly observe gastrointestinal symptoms in patients with systemic sclerosis and report dietetics services would be advantageous in supporting their patients to gain weight and better manage their symptoms.

Several studies described the cross-sectional characteristics of systemic sclerosis patients and coexisting primary biliary cholangitis, but longitudinal prognostic data are lacking.

To describe the systemic sclerosis–primary biliary cholangitis phenotype, including baseline characteristics and outcomes.

We performed a multicentre the European Scleroderma Trials and Research Group study of systemic sclerosis patients with primary biliary cholangitis or with primary biliary cholangitis–specific antibodies, matched with systemic sclerosis controls free from hepatobiliary involvement matched for disease duration and cutaneous subset. Data were recorded at baseline and at the last available visit.

A total of 261 patients were enrolled (115 primary biliary cholangitis–systemic sclerosis, 161 systemic sclerosis). At baseline, systemic sclerosis–primary biliary cholangitis patients had a higher prevalence of anti-centromere antibodies (p = 0.0023) and a lower prevalence of complete absence of digital ulcers. The milder vascular involvement was confirmed at follow-up when crucial differences emerged in the percentage of patients experiencing digital ulcers; a significantly higher number of patients who never experienced digital ulcers were observed among primary biliary cholangitis–systemic sclerosis patients (p = 0.0015). Moreover, a greater incidence of pulmonary arterial hypertension (p < 0.001) and of conduction blocks (p = 0.0256) was observed in systemic sclerosis patients without primary biliary cholangitis. Patients with primary biliary cholangitis had higher levels of liver enzymes at baseline than systemic sclerosis patients; a significant decrease in liver enzymes was observed at follow-up. Out of 18 patients with cholangitis, one received a liver transplant at follow-up.

Our data show that systemic sclerosis–primary biliary cholangitis exhibit a mild systemic sclerosis and primary biliary cholangitis phenotype with outcomes being in general favourable.

Pulmonary hypertension is one of the leading causes of death in systemic sclerosis. Early detection and treatment of pulmonary hypertension in systemic sclerosis is crucial. Nailfold capillaroscopy microscopy, vascular autoantibodies AT1R and ETAR, and several candidate-biomarkers have the potential to serve as noninvasive tools to identify systemic sclerosis patients at risk for developing pulmonary hypertension. Here, we explore the classifying potential of nailfold capillaroscopy microscopy characteristics and serum levels of selected candidate-biomarkers in a sample of systemic sclerosis patients with and without different forms of pulmonary hypertension.

A total of 81 consecutive systemic sclerosis patients were included, 40 with systemic sclerosis pulmonary hypertension and 41 with no pulmonary hypertension. In each group, quantitative and qualitative nailfold capillaroscopy microscopy characteristics, vascular autoantibodies AT1R and ETAR, and serum levels of 24 soluble serum factors were determined. For evaluation of the nailfold capillaroscopy microscopy characteristics, linear regression analysis accounting for age, sex, and diffusing capacity of the lungs for carbon monoxide percentage predicted was used. Autoantibodies and soluble serum factor levels were compared using two-sample t test with equal variances.

No statistically significant differences were observed in quantitative or qualitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibody ETAR and AT1R titer between systemic sclerosis–pulmonary hypertension and systemic sclerosis–no pulmonary hypertension. In contrast, several serum levels of soluble factors differed between groups: Endostatin, sVCAM, and VEGFD were increased, and CXCL4, sVEGFR2, and PDGF-AB/BB were decreased in systemic sclerosis–pulmonary hypertension. Random forest classification identified Endostatin and CXCL4 as the most predictive classifiers to distinguish systemic sclerosispulmonary hypertension from systemic sclerosis-no pulmonary hypertension.

This study shows the potential for several soluble serum factors to distinguish systemic sclerosis-pulmonary hypertension from systemic sclerosis-no pulmonary hypertension. We found no classifying potential for qualitative or quantitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibodies.

To evaluate the clinical efficacy of thalidomide in patients with systemic sclerosis-associated interstitial lung disease.

Ninety-six systemic sclerosis-associated interstitial lung disease patients who received basic glucocorticoid treatment and admitted between 2016 and 2020 were included in this study, including 48 cases in the thalidomide group (combination of thalidomide and cyclophosphamide) and 48 cases in control group (cyclophosphamide monotherapy). Evaluation items included clinical symptoms, modified Rodnan skin score, pulmonary function test, chest high-resolution computed tomography scores, and adverse effects between two groups after 24 weeks of treatment.

Remarkable improvements in several aspects were found in the thalidomide group, including modified Rodnan skin score, expiratory dyspnea score, cough visual analog scale score, total ground-glass opacity score, and total interstitial lung disease score. Compared to the control group, improvements in the thalidomide group were found, such as significantly decreased cough visual analog scale score and expectoration; increased number of platelets; improved pulmonary fibrosis (p = 0.056), and reduced carbon monoxide diffusing capacity (p = 0.053). There were no statistically significant differences in the expiratory dyspnea score and predicted forced vital capacity between the two groups. Patients who experienced at least one adverse event in the control group and thalidomide group were 33.3% and 64.6% (p = 0.002); while those with serious adverse events were 8.3% versus 12.5% (p = 0.504). Venous thrombosis was found in one case in the thalidomide group.

Thalidomide combined with cyclophosphamide can improve the symptoms of cough and expectoration in patients with systemic sclerosis-associated interstitial lung disease, and may slightly delay the progression of pulmonary fibrosis, but with the possibility of an increased risk of adverse events.

Autologous haematopoietic stem cell transplantation improves event-free survival and lung function and reduces skin thickening in patients with progressive diffuse cutaneous systemic sclerosis. Anti-thymocyte globulin is a key lymphoablative constituent of conditioning protocols and is administered in a weight-based dosage. However, whether anti-thymocyte globulin exposure contributes to response to autologous haematopoietic stem cell transplantation and lymphocyte reconstitution in diffuse cutaneous systemic sclerosis patients is unknown. We aimed to explore the relationship between anti-thymocyte globulin exposure, lymphocyte reconstitution and treatment response in diffuse cutaneous systemic sclerosis patients undergoing autologous haematopoietic stem cell transplantation.

A retrospective cohort of 15 diffuse cutaneous systemic sclerosis patients undergoing autologous haematopoietic stem cell transplantation was performed. Clinical characteristics and routine laboratory results were retrieved from electronic medical records. Anti-thymocyte globulin concentrations were measured in cryopreserved plasma samples at four time points (day 1 and week 1, 2 and 4) after stem cell reinfusion. Anti-thymocyte globulin exposure was estimated using a validated population pharmacokinetic model.

During a median follow-up of 45 months (interquartile range 19–66), 11 (73%) patients had a treatment response, and 4 (27%) were non-responders. Although all patients received the same weight-based anti-thymocyte globulin dosage, 7.5 mg/kg divided over 3 days, anti-thymocyte globulin exposure varied. Anti-thymocyte globulin exposure was higher in responders than in non-responders (163 AU*day/mL (interquartile range 153–183) and 137 AU*day/mL (interquartile range 101–149), respectively, p = .026). Anti-thymocyte globulin exposure was not correlated with lymphocyte reconstitution or infection rate.

Weight-based dosing of anti-thymocyte globulin results in variable anti-thymocyte globulin exposure and treatment response across individuals.

How support and informational needs of people with systemic sclerosis (SSc) may differ by time since diagnosis is not known. Our objective was to determine if informational and support needs of recently diagnosed individuals with systemic sclerosis differ from people diagnosed for longer periods of time.

The North American Scleroderma Support Group Members survey included 30 items on reasons for attending support groups. Respondents were classified by time since diagnosis of 0–3 years, 4–9 years or 10+ years. Survey item responses were dichotomized into Not Important or Somewhat Important versus Important or Very Important. We conducted Chi-square tests with Hochberg’s Sequential Method to identify item differences by time since diagnosis.

A total of 175 respondents completed the survey. Most support needs were rated as Important or Very Important by respondents, regardless of disease duration, particularly needs related to interpersonal and social support (10 items; median 81%) and learning about disease treatment and management strategies (11 items; median 82%). Discussing other aspects of living with systemic sclerosis (e.g. spirituality, discussing disease with family and friends) was rated lower (9 items; 44%). Respondents with 0–3 years since diagnosis were the highest on 29 of 30 items. Respondents with 0–3 years since diagnosis were significantly higher on items related to discussing medical care and 4 items on other aspects (spirituality, talking with family and friends, financial issues, sexual issues).

People with systemic sclerosis have a wide range of information and support needs, regardless of their disease duration, but people with recent diagnoses have greater needs.