BACKGROUND: Systemic sclerosis (SSc) is a rare chronic autoimmune disease with heterogeneous manifestations. In the last decade, several clinical trials have been conducted to evaluate new treatment options for SSc. The purpose of this work is to update the recommendations of the Brazilian Society of Rheumatology in light of the new evidence available for the pharmacological management of SSc.
METHODS: A systematic review including randomized clinical trials (RCTs) for predefined questions that were elaborated according to the Patient/Population, Intervention, Comparison, and Outcomes (PICO) strategy was conducted. The rating of the available evidence was performed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. To become a recommendation, at least 75% agreement of the voting panel was needed.
RESULTS: Six recommendations were elaborated regarding the pharmacological treatment of Raynaud\'s phenomenon, the treatment (healing) and prevention of digital ulcers, skin involvement, interstitial lung disease (ILD) and gastrointestinal involvement in SSc patients based on results available from RCTs. New drugs, such as rituximab, were included as therapeutic options for skin involvement, and rituximab, tocilizumab and nintedanib were included as therapeutic options for ILD. Recommendations for the pharmacological treatment of scleroderma renal crisis and musculoskeletal involvement were elaborated based on the expert opinion of the voting panel, as no placebo-controlled RCTs were found.
CONCLUSIONS: These guidelines updated and incorporated new treatment options for the management of SSc based on evidence from the literature and expert opinion regarding SSc, providing support for decision-making in clinical practice.

Introduction Digital ischemia is alike any other visceral ischemic event leading to severe tissue damage ultimately causing necrosis of the involved extremity. It\'s like a preview of the upcoming systemic disorder and can present itself in any specialty and hence everyone, be it a physician or a surgeon must be primed toward how to proceed with a case of digital ischemia. In this case series, we present six such cases that presented with digital ischemic events either as a sole presentation or were followed by other systemic manifestations that led to their evaluation and ultimately the etiology behind it. Material and method Patients visiting Rheumatology OPD with complaints suggestive of digital ischemia were included in this study. All patients underwent thorough history taking and clinical examination to establish the cause of digital ischemia. Patients with probable infective, trauma, cardiac, and drug-induced causes and malignancies were excluded. As per probable autoimmune causes, patients underwent evaluation via antinuclear antibodies by immunofluorescence (ANA by IF), antiphospholipid antibodies like lupus anticoagulant (LAC), anticardiolipin antibodies (AcL) and anti Beta2GP1 antibodies, extractable nuclear antigens (ENA) and in cases of suspected vasculitis doppler ultrasound and angiography.  Results Six patients were identified as cases primarily presenting with digital ischemia or with a prior history of digital ischemia. Two patients were of the pediatric age group, one 16-year-old male presenting with acute arthritis and a history of digital ischemia one year back, and the other was a 12-year-old female with blackening of the second toe in her left foot with a history of similar complaints in the left great toe for which she underwent amputation of that toe. Other four cases were of the adult age group, with two cases of scleroderma, one with systemic lupus erythematosus, and one with Takayasu arteritis. All of these patients primarily presented to departments other than rheumatology. Conclusion Digital ischemia is a pan-specialty problem with the etiologies spreading across a vast spectrum of rheumatological disorders, many of which may present to different specialties initially, later discovered to be part of the systemic manifestation of autoimmune diseases. Hence, it becomes imperative to have a rheumatological perspective in these cases of digital ischemia which all specialities should be aware of, and timely referral may prevent permanent loss of the digits and in some cases the entire limb.

UNASSIGNED: This study aimed to assess the effectiveness of iguratimod (IGU) as an alternative treatment for systemic sclerosis (SSc), especially in the prevention of ischemic digital ulcers (DUs).
UNASSIGNED: We constructed two cohorts from the Renji SSc registry. In the first cohort, SSc patients receiving IGU were observed prospectively with effectiveness and safety. In the second cohort, we picked up all the DU patients with at least a 3-month follow-up to investigate the prevention of IGU on ischemic DU.
UNASSIGNED: From 2017 to 2021, 182 SSc patients were enrolled in our SSc registry. A total of 23 patients received IGU. With a median follow-up of 61 weeks (IQR: 15-82 weeks), the drug persistence was 13/23. In total, 91.3% of the patients (21/23) became free of deterioration in the last visit with IGU. Of note, 10 patients withdrew from the study due to the following reasons: two patients withdrew due to deterioration, three due to incompliance, and five due to mild-to-moderate side effects. All the patients with side effects recovered fully after stopping IGU. Of note, 11 patients had ischemic DU, and 8 out of 11 (72.7%) patients had no new occurrence of DU during the follow-up. In the second cohort of 31 DU patients receiving a combination of vasoactive agents with a median follow-up of 47 weeks (IQR, 16-107 weeks), IGU treatment was protective of new DU occurrence (adjusted risk ratio = 0.25; 95% CI, 0.05-0.94; adjusted odds ratio = 0.07; and 95% CI, 0.01-0.49).
UNASSIGNED: Our study for the first time describes the potential of IGU possibly as an alternative treatment for SSc. To our surprise, this study provides a hint that IGU treatment can be used for the prevention of the occurrence of ischemic DU and merits further investigation.

OBJECTIVE: Semaphorin 3A (Sema3A) plays a regulatory role in immune responses. The aim of this study was to evaluate Sema3A levels in patients with systemic sclerosis (SSc), especially in major vascular involvements such as digital ulcer (DU), scleroderma renal crisis (SRC), pulmonary arterial hypertension (PAH), and to compare Sema3A level with SSc disease activity.
METHODS: In SSc patients, patients with DU, SRC, or PAH were grouped as major vascular involvements and those without as nonvascular, and Sema3A levels were compared between the groups and with a healthy control group. The Sema3A levels and acute phase reactants in SSc patients, as well as their association with the Valentini disease activity index and modified Rodnan skin score, were evaluated.
RESULTS: The Sema3A values (mean ± SD) were 57.60 ± 19.81 ng/mL in the control group (n = 31), 44.32 ± 5.87 ng/mL in patients with major vascular involvement SSc (n = 21), and 49.96 ± 14.00 ng/mL in the nonvascular SSc group (n = 35). When all SSc patients were examined as a single group, the mean Sema3A value was significantly lower than controls (P = .016). The SSc with major vascular involvement group had significantly lower Sema3A levels than SSc with nonmajor vascular involvement group (P = .04). No correlation was found between Sema3A, acute phase reactants, and disease activity scores. Also, no relationship was observed between Sema3A levels and diffuse (48.36 ± 11.47 ng/mL) or limited (47.43 ± 12.38 ng/mL) SSc types (P = .775).
CONCLUSIONS: Our study suggests that Sema3A may play a significant role in the pathogenesis of vasculopathy and can be used as a biomarker in SSc patients with vascular complications such as DU and PAH.

UNASSIGNED: The aim of the present systematic review and meta-analysis was to evaluate the therapeutic efficacy of bosentan, a dual endothelin receptor antagonist, for systemic sclerosis (SSc) patients with digital ulcers (DUs).
UNASSIGNED: A systematic search of MEDLINE, Embase, Web of Science, and Scopus was done using appropriate keywords till September 2021. Weighted mean difference (WMD) as the effect of therapeutic efficacy of bosentan on continuous outcomes was an estimate. Furthermore, the pooled prevalence of diffuse SSc and limited SSc was computed. Fixed or random effects models when appropriate were used for data synthesis.
UNASSIGNED: Totally, 469 patients, with a mean age ranging from 48.1 to 63.7 years, from 8 studies were included in the systematic review and meta-analysis. The pooled frequency of diffuse SSc and limited SSc was 56% (95% confidence interval [CI]: 39%, 73%) and 44% (95% CI: 27%, 61%). The pooled prevalence of new DUs following bosentan treatment was 21% (95% CI: 10%, 33%). The results of the meta-analysis showed a pooled mean decrease of WMD: -0.09 (95% CI: -0.020, 0.02, P = 0.10), WMD: -2.82 (95% CI: -5.91, 0.27, P = 0.07), and WMD: -6.65 (95% CI: -9.49, -3.82, P < 0.001) in mean SSc-Health Assessment Questionnaire, pain, and Rodnan score, respectively. Our meta-analysis also indicated a significant pooled decrease in the number of new DUs in SSc patients compared to placebo subjects (WMD: -0.89 [95% CI: -1.40, -0.37; P = 0.001]) and baseline values (WMD: -1.34 (95% CI: -1.95, -0.73; P < 0.001).
UNASSIGNED: Bosentan possibly is an efficacious treatment option for SSc-related DUs. Although further large-scale randomized clinical trials are required to confirm the preliminary finding and underlying mechanisms of action.

BACKGROUND: Systemic sclerosis (SSc) is a chronic systemic disease characterized by vascular damage, autoimmunity, and fibrosis in the skin and internal organs. In this study, we tried to determine the causes of severe infection in patients with SSc and to reveal the factors associated with severe infection.
METHODS: We retrospectively examined 214 SSc patients between January 2010 and August 2020. Forty-seven patients with at least one severe infection and 167 patients without severe infection were compared.
RESULTS: A total of 76 episodes of severe infections were detected in 47 (22%) patients. Common infections included pneumonia, infected digital ulcer, urinary tract infections, and osteomyelitis. Female patients had a higher frequency in the group without severe infection (91.6% vs. 80.9%, p = 0.035). Patients with severe infections had a higher frequency of digital ulcers (p < 0.001), cardiac (p = 0.002), and GIS involvement (p < 0.001). In multivariable analysis, digital ulcer presence (OR: 2.849 [1.356-5.898] (p = 0.006) and cardiac involvement (OR: 2.801 [1.248-6.285]) were associated with severe infection. Of the patients with severe infections, 34% had recurrent severe infections. There was no difference in demographic and clinical characteristics between patients with recurrent and nonrecurrent severe infections.
CONCLUSIONS: The presence of digital ulcer and cardiac involvement seem to be associated with a severe infection in patients with systemic sclerosis. In patients with cardiac involvement and digital ulcers, more careful attention may be required for the development of severe infections.

OBJECTIVE: Systemic sclerosis (SSc) is a disease characterized by diffuse sclerosis of skin and organs and small vessel vasculopathy. Despite it, large vessels can also be involved with ulnar artery vasculopathy, revealing as a more frequent feature of SSc. The aim of this paper is to assess the macrovascular involvement of SSc patients through an ultrasound (US) evaluation of radial and ulnar arteries.
METHODS: Radial and ulnar resistance indices (RIs) and peak systolic velocity (PV) (cm/s) together with clinical features of SSc patients were evaluated. Raynaud phenomenon (RP) and healthy control (HC) groups were used for comparison.
RESULTS: Forty-three SSc patients were evaluated. Twelve patients (28%) had ulnar artery occlusions (UAOs). In nine cases (75%), UAOs were bilateral. A high UAO prevalence (42%) was found in SSc patients with late nailfold-video-capillaroscopy (NVC) pattern (p = 0.0264). Patients with UAOs had digital ulcers (DUs) in 10 cases (83.3%). Radial and ulnar PVs were lower in SSc and RP patients than the HC group. Radial and ulnar RIs were higher in SSc and RP patients than the HC group. A decision tree analysis led to the classification of 70% of SSc patients with an ulnar RI > 0.82 and ulnar PV > 2.8 cm/s. The most influential variables on UAO development were interstitial lung disease (ILD) (p = 0.002) and NVC pattern (p = 0.002). A positive correlation was shown between modified Rodnan skin score (mRSS) and ILD (p = 0.283; r = 0.033), mRSS and DU (r = 0.344; p = 0.012) and DU and ILD (r = 0.303; p = 0.024). Male sex was associated with increased UAO frequency (p = 0.042).
CONCLUSIONS: UAO is a peculiar feature of severe SSc present in 28% of the cases, particularly associated with the presence of ILD and late NVC pattern. In 75% of the cases, UAOs are bilateral. DUs are very frequent in patients with UAOs (83%). The RI evaluated by US could be useful to distinguish SSc from HC patients. US could be a useful tool for assessing high-risk DU development in patients.

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UNASSIGNED: Severe digital ischemia, including digital ulcers and gangrene, is considered rare in patients with antisynthetase antibodies. This study aimed to elucidate the clinical features of antisynthetase-positive patients complicated with digital ulcers and/or gangrene using a systematic literature review and case series in a single-center cohort.
UNASSIGNED: A systematic literature review was conducted to identify reports describing antisynthetase-positive cases with digital ulcers and/or gangrene. Our cohort of consecutive patients with antisynthetase antibodies was stratified by the history of severe digital ischemia. Demographic and clinical features and outcomes in patients with severe digital ischemia identified in the systematic literature review and our cohort were compared with those in patients without severe digital ischemia in our cohort.
UNASSIGNED: The systematic literature review revealed 12 antisynthetase-positive patients with severe digital ischemia from one case series and eight case reports. Seven (7%) of 100 patients with antisynthetase antibodies in our cohort had a record of severe digital ischemia. Severe digital ischemia was often found at presentation and was associated with the classification of systemic sclerosis with or without myositis overlap. Clinical features associated with severe digital ischemia in antisynthetase-positive patients included Raynaud\'s phenomenon (p < 0.001), digital pitting scars (p = 0.001), and nailfold capillary abnormality (p = 0.02). Outcomes of severe digital ischemia were generally favorable with vasodilators.
UNASSIGNED: Severe digital ischemia is an overlooked complication in antisynthetase-positive patients. Antisynthetase antibodies should be measured in patients presenting with digital ulcers or gangrene, especially in those with systemic sclerosis phenotype and features associated with antisynthetase antibodies in the absence of systemic sclerosis-specific autoantibodies.

UNASSIGNED: Ischemic digital ulcers (DUs) are frequent and severe complications of systemic sclerosis (SSc). Treatment options for SSc-related digital vasculopathy are based on aggressive vasodilation, with the objective to improve blood flow in ischemic areas. Intravenous prostanoids are recommended to treat active DUs. However, the level of evidence for the duration of 5 days is low. Therefore, the aim of this study was to determine whether prolonging the infusion beyond 5 days increases the rate of healing of active DUs in SSc.
UNASSIGNED: This is an observational longitudinal retrospective bicenter study from 2000 to 2017. The objective was to compare the healing rate and time (defined by a healing of at least 50% of DUs) between two durations of iloprost administration: 5 days or less, or more than 5 days.
UNASSIGNED: Forty-one patients, with a mean age of 47 ± 15 years at diagnosis and 32 (78%) females have been included. Systemic sclerosis was diffuse in 10 (24%) cases and 13 (32%) had an interstitial lung disease. A total of 243 iloprost infusions for DUs were performed: 140 infusions for 5 days or less, and 103 infusions for more than 5 days (prolonged duration). Patients with active DUs which received >5 days of iloprost had higher modified Rodnan skin scale at the time of iloprost infusion (median 33 vs. 15; p < 0.05), more interstitial lung disease (44 vs. 27%; p < 0.05), more anti-topoisomerase I antibody positivity (59 vs. 44%; p < 0.05), and received more previous cyclophosphamide therapy (48 vs. 19%; p < 0.05). While the number of active DUs before iloprost infusion was not significantly different among those who received ≤5 days and >5 days of iloprost, the time to healing after iloprost infusion significantly decreased in SSc patients who received >5 days iloprost infusion: 48 [7-392] vs. 91 [9-365] days (p < 0.05). The proportion of SSc patients with healed DUs tended to increase in patients with >5 days iloprost infusion (log rank = 0.06). The number of patients with complete DU healing at day 90 was significantly increased in SSc who received >5 days of iloprost: 53 (51%) vs. 52 (37%) (p < 0.05). In addition, the time to healing was not significantly associated with the use of calcium channel blockers, endothelin receptor antagonists or a combination of PDE-5 inhibitors.
UNASSIGNED: Prolonging duration of iloprost >5 days could improve the healing rate and the time to healing of SSc-related DUs. Prospective randomized studies are needed to confirm these data and define the optimal duration of iloprost therapy.