Portuguese Recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

OBJECTIVE: To develop evidence-based recommendations for the non-pharmacological and pharmacological management of Raynaud's phenomenon (RP) and digital ulcers (DUs) in patients with systemic sclerosis and other immune-mediated connective tissue diseases (CTDs). METHODS: A task force comprising 21 rheumatologists, two surgeons (vascular and plastic), two nurses, and one patient representative was established. Following a systematic literature review performed to inform the recommendations, statements were formulated and discussed during two meetings (one online and one in-person). Levels of evidence, grades of recommendation (GoR), and level of agreement (LoA) were determined. RESULTS: Five overarching principles and 13 recommendations were developed. GoR ranged from A to D. The mean ± standard difference (SD) LoA with the overarching principles and recommendations ranged from 7.8±2.1 to 9.8±0.4. Briefly, the management of RP and DUs in patients with CTDs should be coordinated by a multidisciplinary team and based on shared decisions with patients. Nifedipine should be used as first-line therapy for RP and/or DUs. Sildenafil, tadalafil, and/or iloprost IV are second-line options for severe and/or refractory patients with RP and/or DUs. Sildenafil, tadalafil and/or Iloprost IV, should be prescribed for healing and prevention (also including bosentan) of DUs. In patients with RP and/or DUs, non-pharmacological interventions might be considered as add-ons, but there is limited quality and quantity of scientific evidence supporting their use. CONCLUSIONS: These recommendations will inform rheumatologists, specialist nurses, other healthcare professionals, and patients about a comprehensive and personalized management of RP and DUs. A research agenda was developed to address unmet needs, particularly for non-pharmacologic interventions.

The phenotype of mixed connective tissue disease patients having associated interstitial lung disease.

OBJECTIVE: We aimed to compare two matched populations of patients with MTCD with and without associated ILD and to identify predictive factors for ILD progression and severity. METHODS: This international multicenter retrospective study (14 tertiary hospitals), included MCTD patients who fulfilled at least one historical MCTD classification criteria. ILD was defined by the presence of typical chest high-resolution computed tomography (HRCT) abnormalities. Factors associated with ILD were assessed at baseline. Long-term progressive ILD was assessed in MCTD-ILD patients with multiple forced vital capacity (FVC) measurements. RESULTS: 300 patients with MCTD were included. Mean age at diagnosis was 39.7 ± 15.4 years and 191 (63.7%) were women. Mean follow-up was 7.8 ± 5.5 years. At baseline, we identified several factors associated with ILD presence: older age (p = 0.01), skin thickening (p = 0.03), upper gastro-intestinal (GI) symptoms (p<0.001), FVC <80% (p<0.0001), diffusing capacity for carbon monoxide <80% (p<0.0001), anti-topoisomerase antibodies (p = 0.01), SSA/Ro antibodies (p = 0.02), cryoglobulinemia (p = 0.04) and elevated C-reactive protein (p<0.001). Patients with MTCD-ILD were more likely to be treated with synthetic immunosuppressant agents (p<0.001) in particular mycophenolate mofetil (p = 0.03). Digital ulcers (DU) were identified as a risk factor for FVC decline >10%. During follow-up mortality was higher in the MTCD-ILD group (p<0.001). CONCLUSION: In this large international cohort of patients with MTCD, we identified different factors associated with ILD. Our findings also provide evidence that MCTD-ILD patients have increased mortality and that DU are associated with progressive lung disease.

Prognosis and long-term outcomes in type I cryoglobulinemia: A multicenter study of 168 patients.

Type I cryoglobulinemia (CG) accounts for 10%-15% of all cryoglobulinemias and are exclusively seen in clonal proliferative hematologic conditions. In this multicenter nationwide cohort study, we analyzed the prognosis and long-term outcomes of 168 patients with type I CG (93 (55.4%) IgM and 75 [44.6%] IgG). Five- and 10-year event-free survivals (EFS) were 26.5% (95% CI 18.2%-38.4%) and 20.8% (95% CI 13.1%-33.1%), respectively. In multivariable analysis, factors associated with poorer EFS were renal involvement (HR: 2.42, 95% CI 1.41-4.17, p = .001) and IgG type I CG (HR: 1.96, 95% CI 1.13-3.33, p = 0.016), regardless of underlying hematological disorders. IgG type I CG patients had higher cumulative incidence of relapse (94.6% [95% CI 57.8%-99.4%] vs. 56.6% [95% CI 36.6%-72.4%], p = .0002) and death at 10 years (35.8% [19.8%-64.6%] vs. 71.3% [54.0%-94.2%], p = .01) as compared to IgM CG, respectively. Overall, complete response of type I CG at 6 months was 38.7%, with no significant difference between Igs isotypes. In conclusion, renal involvement and IgG CG were identified as independent poor prognostic factors of type I CG.

Severe immune thrombocytopenia in two patients with systemic sclerosis.

Thrombocytopenia in the context of systemic sclerosis (SSc) is rare. It should primarily raise the possibility of scleroderma renal crisis. Immune thrombocytopenia (ITP) is another cause of low platelets that is common in systemic lupus erythematosus, but tremendously rare in patients with SSc. We herein report two cases of severe ITP in patients with SSc. The first case is a 29-year-old woman with very low platelet counts (2×109/L) that did not increase despite receiving corticosteroids, intravenous immunoglobulins (IVig), rituximab and romiplostim. Because of a symptomatic acute subdural haematoma, emergency splenectomy was performed and subsequently platelet counts normalised without neurological sequelae. The second case is a 66-year-old woman in whom self-limited mild epistaxis revealed low platelet counts (8×109/L). The patient did not improve after the use of IVig and corticosteroids. Secondarily rituximab and romiplostim normalised the platelet counts after 8 weeks. To the best of our knowledge this is the first reported case of severe ITP in a patient with diffuse cutaneous SSc and anti-topoisomerase antibodies.

Measurement Properties of Outcome Instruments for Large-Vessel Vasculitis: A Systematic Literature Review.

OBJECTIVE: To systematically review the measurement properties of outcome instruments used in large-vessel vasculitis (LVV). METHODS: MEDLINE, Embase, Cochrane, and Scopus databases were searched for studies published from inception to July 14, 2020, that addressed measurement properties of instruments used in giant cell arteritis (GCA) and Takayasu arteritis (TA). The measurement properties of the instruments identified were collected following the Outcome Measures in Rheumatology (OMERACT) and Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) frameworks. Instruments were grouped according to the following domains measured: disease activity/damage, organ function, and health-related quality of life (HRQOL)/health status. RESULTS: From 3534 articles identified, 13 met the predefined criteria. These studies addressed 12 instruments: 4 specific to TA, 2 designed for all types of systemic vasculitis, and 6 non-disease-specific instruments. No instruments specific to GCA were identified. Regarding TA, the Indian Takayasu Clinical Activity Score (ITAS) showed very good consistency, adequate reliability, but doubtful validity for disease activity. The Disease Extent Index-Takayasu (DEI-Tak) showed adequate construct validity but doubtful discriminating validity for disease activity/damage. Instruments, including the Vasculitis Damage Index and the Birmingham Vasculitis Activity Score, were poorly assessed for disease activity/damage. In total, 6 non-vasculitis-specific patient-reported outcome (PRO) instruments showed inadequate validity in GCA/TA. CONCLUSION: The measurement properties of 12 outcome instruments for LVV covering the OMERACT domains of disease activity/damage, organ function, and HRQOL were assessed. The ITAS and the DEI-Tak were the instruments with the most adequate measurement properties for disease activity/damage in TA. Disease activity/damage instruments specific to GCA, as well as validated PROs for both GCA and TA, are lacking.

Psychometric properties of outcome measurement instruments for ANCA-associated vasculitis: a systematic literature review.

OBJECTIVES: To systematically review the psychometric properties of outcome measurement instruments used in ANCA-associated vasculitis (AAV). METHODS: Medline, EMBASE, Cochrane, Scopus and Web of Science were searched from inception to 14 July 2020 for validation studies of instruments used in AAV. Following the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) and OMERACT frameworks, different psychometric properties (validity, reliability, responsiveness and feasibility) were summarized. Risk of bias was assessed according to the COSMIN checklist. RESULTS: From 2505 articles identified, 32 met the predefined selection criteria, providing information on 22 instruments assessing disease activity (n = 7), damage (n = 2), activity and damage (n = 1), health-related quality of life (HRQoL; n = 9) and function (n = 3). Most of the instruments were tested in AAV as a group or in granulomatosis with polyangiitis only.The BVAS, any version, the Vasculitis Damage Index (VDI) and the AAV-Patient-Reported Outcome (AAV-PRO) have been more extensively validated than the other instruments. BVAS for Wegener Granulomatosis (BVAS/WG) has been shown to be valid for measuring disease activity [correlation with Physician global assessment (r = 0.90)], reliability (inter-observer intraclass correlation coefficient = 0.97), responsiveness and feasibility. For damage, VDI was shown to be moderately valid (correlations with BVAS version 3 at 6 months r = 0.14, BVAS/WG at 1 year r = 0.40 and 5 years r = 0.20), and feasible. For HRQoL, AAV-PRO demonstrated validity (correlations of the six AAV-PRO domains with EQ-5D-5L: -0.78 to -0.55; discrimination between active disease and remission, P < 0.0001 for all comparisons). The overall performance of instruments assessing function was low-to-moderate. CONCLUSION: Among the 22 outcome measurement instruments used for AAV, BVAS (any version), VDI and AAV-PRO had the strongest psychometric properties.

The role of antifibrotic therapies in the treatment of systemic sclerosis-associated interstitial lung disease.

Systemic sclerosis (SSc) is a rare autoimmune condition with complex pathogenesis characterized by a heterogeneous presentation and different disease courses. Fibrosis of multiple organs including the lungs favored by inflammation and vasculopathy is the hallmark of SSc. SSc-associated interstitial lung disease (SSc-ILD) is common and can be associated with poor outcomes, this complication being the leading cause of death in recent series. Because of its huge heterogeneity, SSc-ILD management can be very challenging. Immunosuppressive therapy has long been used to prevent SSc-ILD progression with modest effects in clinical trials. However, thanks to a better understating of SSc pathogenesis, innovative therapies including antifibrotics are increasingly being developed. The achievement of the Safety and Efficacy of Nintedanib in Systemic SClerosIS (SENSCIS) trial has led to the approval by drug agencies of the first antifibrotic drug for SSc-ILD. In parallel, other antifibrotics are being investigated as possible beneficial therapies in SSc-ILD. An important unmet need remains to clarify the positioning of the various strategies, such as the added value of combination of immunosuppressants and antifibrotic therapies in patients at high risk of progression. Indeed, irreversible lung injury or self-perpetuated progression highlights the concept of a window of opportunity in SSc-ILD patients. Herewith, we provide an overview of the most significant clinical trials with antifibrotic drugs developed in recent years for the management of SSc-ILD and a viewpoint about their positioning in treatment algorithms.

An update on recent randomized clinical trials in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disorder characterized by a remarkable clinical heterogeneity and variable disease course. In this multifactorial condition, the interaction of several pathogenic pathways related to inflammation, vasculopathy and fibrosis promote organ damage. The understanding of the pathogenesis of SSc has improved in recent years leading to the identification of relevant therapeutic targets. Over the last few years, insightful clinical trials have been published and great progress has been made in developing effective therapeutic options. The positive results of the Safety and Efficacy of Nintedanib in Systemic SClerosIS (SENSCIS) trial have led to the approval by drug agencies of the first drug for SSc-related interstitial lung disease. However, the majority of clinical trials have focused on immunosuppressive therapy. Although benefit trends have been observed, outstanding results have not been achieved and to date no immunosuppressant has been approved in SSc. Clinical trial design has evolved regarding inclusion criteria with the aim to enrich for progressive patients. Endpoints have also been revised to better cover the fields of patients' feelings and functioning. Finally, background synthetic immunosuppressants have been allowed in some trials evaluating targeted therapies opening the door to combination therapies. Herewith, we provide an overview of the most significant clinical trials developed in recent years for the management of SSc.

Hepatitis C virus-related vasculitis.

Cryoglobulinemic vasculitis (CryoVas) is a small-to-medium vessel systemic vasculitis caused by the deposition of mixed cryoglobulins and immune complexes. Clinical spectrum of CryoVas ranges from mild symptoms to vasculitis involving multiple organs that may progress to more life-threatening ilness. Hepatitis C virus (HCV) chronic infection is the most frequent condition to be assessed in patients with CryoVas. The mortality rate among patients with HCV-associated CryoVas is 3× that of the general population, with a 63% 10-year survival rate. The recent advent of interferon-free direct-acting antivirals (DAAs), which have the potential to induce sustained virological response rates greater than 95%, has dramatically changed the management of chronic HCV infection and HCV-related CryoVas. B-cell depleting strategies, mainly with rituximab, are the main therapeutic option in severe and refractory cases of HCV-associated CryoVas. Despite the progress in the last years on the management of chronic HCV infection, there are still unmet needs regarding therapeutic management of severe and refractory HCV-associated CryoVas.

Emerging Molecular Targets for the Treatment of Refractory Sarcoidosis.

Sarcoidosis is a multisystem granulomatous disease of unknown origin that has variable clinical course and can affect nearly any organ. It has a chronic course in about 25% of patients. Corticosteroids (CS) are the cornerstone of therapy but their long-term use is associated with cumulative toxicity. Commonly used CS-sparing agents include methotrexate, cyclophosphamide, azathioprine, and mycophenolate mofetil. Twenty to forty percentage of sarcoidosis patients are refractory to these therapies or develop severe adverse events. Therefore, additional and targeted CS-sparing agents are needed for chronic sarcoidosis. Macrophage activation, interferon response, and formation of the granuloma are mainly mediated by T helper-1 responses. Different pro-inflammatory cytokines such as interleukin (IL)-8, IL-12, IL-6, and tumor necrosis factor-alpha (TNF-α) have been shown to be highly expressed in sarcoidosis-affected tissues. As a result of increased production of these cytokines, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is constitutively active in sarcoidosis. Several studies of biological agents that target TNF-α have reported their efficacy and appear today as a second line option in refractory sarcoidosis. Some case series report a positive effect of tocilizumab an anti-IL-6 monoclonal antibody in this setting. More recently, JAK inhibition appears as a new promising strategy. This review highlights key advances on the management of chronic refractory sarcoidosis. Novel therapeutic strategies and treatment agents to manage the disease are described.

Cryoglobulinemia after the era of chronic hepatitis C infection.

OBJECTIVES: Historically chronic hepatitis C virus (HCV) infection accounted for the majority of mixed cryoglobulinemia (MC). The advent of direct-acting antivirals (DAA) against HCV has dramatically changed the management and the prevalence of chronic HCV infection. We aimed to describe the spectrum of MC in the era of DAA agents. METHODS: We performed a longitudinal cohort study between 2011 and 2018 from a single-center French university hospital's database of 15 970 patients screened for MC. Epidemiological, clinical and immunological data of MC were recorded. We evaluated the incidence and evolution of MC before and after the era of DAA agents and compared HCV and non-HCV related MC. RESULTS: Among 742 patients who tested positive for cryoglobulin, 679 [mean age 55.5 years, 54.5% female and 381 (56.1%) with chronic HCV infection] patients with persistent MC were included in the study. 373 (54.9%) had type II and 306 (45.1%) type III cryoglobulin, and 139 (21.5%) had cryoglobulinemia vasculitis (CryoVas). The incidence of MC decreased steadily with 395 and 284 incident cases during 2011-2014 and 2015-2018, respectively. In 2011, the leading cause was chronic HCV infection (62.5% of all MC). Currently, autoimmune diseases [systemic lupus erythematosus (28.9%) and Sjögren's syndrome (10.7%)] are the main cause of MC. The incidence of CryoVas was similar between HCV-and non HCV-related MC. CONCLUSION: Direct-acting antivirals have dramatically changed the landscape and the incidence of MC.

Estrogens Counteract the Profibrotic Effects of TGF-ß and their Inhibition Exacerbates Experimental Dermal Fibrosis.

Systemic sclerosis primarily affects women. This sex bias raises the question on the role female hormones could play in the development of fibrosis, which is largely unknown. Our aim was to evaluate the effects of estrogens in the development of experimental dermal fibrosis, in the mouse models of bleomycin-induced dermal fibrosis and tight skin (Tsk-1) mice, and on the activation of dermal fibroblasts by transforming growth factor-ß (TGF-ß). Estrogen inhibition, obtained through gene inactivation for the estrogen receptor-αknockout or treatment with tamoxifen, exacerbated skin fibrosis in the bleomycin model and in the Tsk-1 mice. In the dermal fibroblasts, treatment with 17-ß-estradiol significantly decreased the stimulatory effects of TGF-ß on collagen synthesis and myofibroblast differentiation, decreased the activation of canonical TGF-ß signaling, and markedly reduced the expression of the TGF-ß target genes. Tamoxifen reversed the inhibitory effects of estrogens by restoring Smad2/3 phosphorylation and TGF-ß-induced collagen synthesis. Our results demonstrate a beneficial effect of estrogens in dermal fibrosis. Estrogens reduce the TGF-ß-dependent activation of dermal fibroblasts, and estrogen inhibition leads to a more severe experimental dermal fibrosis. These findings are consistent with the prominent development of systemic sclerosis in postmenopausal women and the greater severity of the disease in men.

Safety of combination therapy with two bDMARDs in patients with rheumatoid arthritis: A systematic review and meta-analysis.

OBJECTIVES: We performed a systematic review and meta-analysis of the current literature to assess the safety of combining two biologic disease-modifying antirheumatic drugs (bDMARDs) in the treatment of rheumatoid arthritis (RA). METHODS: We systematically searched for controlled studies evaluating safety in patients with RA treated with two bDMARDs independently of dose-regimen. Databases used were MEDLINE (via Pubmed), EMBase, Cochrane Library, Scopus, ClinicalTrials.gov, and the WHO International Clinical Trials Registry platform. A meta-analysis was performed between groups on combination therapy and patients on single therapy using random effects model calculating odds ratio (OR) as well as 95% confidence interval (CI). The primary outcome was the rate of serious adverse events (SAEs). RESULTS: Six studies with a total of 623 patients (410 on combination therapy and 213 on single therapy) were included. Median follow-up was 9.5 months (range 6-12 months). There was a significant increase in SAEs in the combination group (14.9 vs 6.0%, OR 2.51, 95% CI 1.29-4.89, I2 0%) as well as in total adverse events (94.6 vs 89.1%, OR 2.07, 95% CI 1.11-3.86, I2 0%). When performing subgroup analysis in patients receiving only full-dose of both bDMARDs there was a significant increase in serious infections (6.7 vs 0.6%, OR 5.58, 95% CI 1.25-24.90, I2 0%) and the risk of SAEs remained significantly higher (17.1 vs 6.2%, OR 2.72, 95% CI 1.30-5.69, I2 0%). CONCLUSION: Our findings suggest that combination therapy with two bDMARDs in RA appears to increase the risk of SAEs during the first twelve months of treatment.

T-cell costimulation blockade is effective in experimental digestive and lung tissue fibrosis.

BACKGROUND: We aimed to investigate the efficacy of abatacept in preclinical mouse models of digestive involvement, pulmonary fibrosis, and related pulmonary hypertension (PH), mimicking internal organ involvement in systemic sclerosis (SSc). METHODS: Abatacept has been evaluated in the chronic graft-versus-host disease (cGvHD) mouse model (abatacept 1 mg/mL for 6 weeks), characterized by liver and intestinal fibrosis and in the Fra-2 mouse model (1 mg/mL or 10 mg/mL for 4 weeks), characterized by interstitial lung disease (ILD) and pulmonary vascular remodeling leading to PH. RESULTS: In the cGvHD model, abatacept significantly decreased liver transaminase levels and markedly improved colon inflammation. In the Fra-2 model, abatacept alleviated ILD, with a significant reduction in lung density on chest microcomputed tomography (CT), fibrosis histological score, and lung biochemical markers. Moreover, abatacept reversed PH in Fra-2 mice by improving vessel remodeling and related cardiac hemodynamic impairment. Abatacept significantly reduced fibrogenic marker levels, T-cell proliferation, and M1/M2 macrophage infiltration in lesional lungs of Fra-2 mice. CONCLUSION: Abatacept improves digestive involvement, prevents lung fibrosis, and attenuates PH. These findings suggest that abatacept might be an appealing therapeutic approach beyond skin fibrosis for organ involvement in SSc.

Targeting Costimulatory Pathways in Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune T-cell disease that is characterized by pathological fibrosis of the skin and internal organs. SSc is considered a prototype condition for studying the links between autoimmunity and fibrosis. Costimulatory pathways such as CD28/CTLA-4, ICOS-B7RP1, CD70-CD27, CD40-CD154, or OX40-OX40L play an essential role in the modulation of T-cell and inflammatory immune responses. A growing body of evidence suggests that T-cell costimulation signals might be implicated in the pathogenesis of SSc. CD28, CTLA-4, ICOS, and OX40L are overexpressed in patients with SSc, particularly in patients with cutaneous diffuse forms. In pre-clinical models of SSc, T-cell costimulation blockade with abatacept (CTLA-4-Ig) prevented and induced the regression of inflammation-driven dermal fibrosis, improved digestive involvement, prevented lung fibrosis, and attenuated pulmonary hypertension in complementary models of SSc. Likewise, potent anti-fibrotic effects were seen with the blockade of OX40L by reducing the infiltration of inflammatory cells into lesional tissues leading to decreased fibroblast activation. Concerning clinical effects, a preliminary observational study suggested some effectiveness of abatacept on inflammatory joint involvement, whereas clinical improvement of skin fibrosis was observed in a small placebo-controlled randomized trial. Currently there is one ongoing phase II clinical trial assessing the efficacy of abatacept in SSc (ASSET trial, NCT02161406). Overall, given the lack of available effective agents and the known toxic effects of immunosuppressive agents approved for use in SSc, costimulatory pathways offer the advantage of a targeted approach to costimulatory signals and potentially a better safety profile.