Systemic Sclerosis: Evaluation and Treatment.

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with multi-organ involvement, fibrosis and vasculopathy. Treatment in SSc, including early diffuse cutaneous SSc (dcSSc) and the use of organ-specific therapies, has improved, as evident from randomized clinical trials. Treatments for early dcSSc include immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclophosphamide, rituximab and tocilizumab. Patients with rapidly progressive early dcSSc might be eligible for autologous haematopoietic stem cell transplantation, which can improve survival. Morbidity from interstitial lung disease and pulmonary arterial hypertension is improving with the use of proven therapies. Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-interstitial lung disease. Nintedanib and possibly perfinidone can be considered in SSc pulmonary fibrosis. Pulmonary arterial hypertension is frequently treated with initial combination therapy (for example, with phosphodiesterase5 inhibitors and endothelin receptor antagonists) and, if necessary, the addition of a prostacyclin analogue. Raynaud phenomenon and digital ulcers are treated with dihydropyridine calcium channel blockers (especially nifedipine), then phosphodiesterase5 inhibitors or intravenous iloprost. Bosentan can reduce the development of new digital ulcers. Trial data for other manifestations are mostly lacking. Research is needed to develop targeted and highly effective treatments, best practices for organ-specific screening and early intervention, and sensitive outcome measurements.

Effect of mycophenolate mofetil dose on antibody response following initial SARS-CoV-2 vaccination in patients with systemic sclerosis.

Background Second line treatment options for Systemic Sclerosis (SSc) are limited, and scarce data are available for choosing the order of treatment. Objectives The aim of this study is to update the SSc treatment algorithms obtained in 20121, based on SSc experts9 daily practice. Methods An initial survey was designed based on the 2012 algorithms. The survey asked experts whether they agreed with the 2012 algorithms or not, and which changes should be considered. The questionnaire was completed by 62 of 168 surveyed (67% response) between August and October 2016. Results For scleroderma renal crisis (SRC), there was 65% to 69% agreement with the previous algorithms (1st line angiotensin converting enzyme inhibitors [ACEI], 2nd and 3rd adding: calcium channel blockers [CCB] or angiotensin receptor blockers [ARB], and 4th alpha-blocker). In mild pulmonary arterial hypertension (PAH), only 45% of the experts agreed with the old algorithm. The majority suggested first phosphodiesterase 5 inhibitors (PDE5i) or endotelin receptor antagonists (ERA) plus PDE5i, then prostanoids. In severe PAH, 65% agreed with the preexistent scheme (1st prostanoids, 2nd ERA plus PDE5i, 3rd ERA plus prostanoids). For mild Raynaud9s phenomenon (RP) 66% agreed with the previous algorithm (1st CCB, 2nd adding PDE5i, 3rd ARB or switching to another CCB, 4th prostanoids). Regarding severe RP, 52% agreed with previous (1st CCB, 2nd adding PDE5i, 3rd ERA, 4th prostanoids). Conversely, 60% of the experts did not agree with the prior active digital ulcer (DU) treatment, suggesting 1st CCB, 2nd PDE5i, 3rd prostanoids. For interstitial lung disease (ILD), for induction only 24% agreed with the older proposal. Experts suggested 1st mofetil mycophenolate (MMF), 2nd intravenous (IV) cyclophosphamide (CYP), 3rd Rituximab. There was a 65% agreement on ILD maintenance (1st MMF, 2nd azathioprine [AZA], 3rd IV CYP, 4th oral CYP). For skin involvement, agreement for patients with a modified Rodnan skin score (mRSS) of 10 was 57% (1st methotrexate [MTX]), 2nd MMF); if the mRSS was 24, 32% suggested 1st MMF, 2nd MTX; and mRSS 32, 36% chose 1st MTX, 2nd MMF, 3rd IV CYP, 4th autologous stem cell transplantation (ASCT). In inflammatory arthritis 45% agreed with the previous algorithm, whereas others suggested 1st MTX, 2nd low dose steroids, 3rd hydroxychloroquine, 4th rituximab or tocilizumab. Conclusions There remains some disagreement for 2nd line treatment of SSc. Combination of PDE5i and ERA are prescribed now in mild PAH treatment. Prostanoids have been incorporated as 3rd line agents in active DU treatment. MMF is the new 1st line treatment for ILD induction and rituximab the 3rd. IV CYA and ASCT were recommended as 3rd and 4th line treatments in patients with severe skin involvement. Rituximab and tocilizumab have been incorporated into inflammatory arthritis treatment. This can guide therapy in SSc. References Walker KM, Pope J. Treatment of systemic sclerosis complications: what to use when first-line treatment fails–a consensus of systemic sclerosis experts. Semin Arthritis Rheum 2012;42(1):42–55. Disclosure of Interest None declared

Digital ulcers and cutaneous subsets of systemic sclerosis: Clinical, immunological, nailfold capillaroscopy, and survival differences in the Spanish RESCLE Registry.

A 50-year-old Japanese woman with limited cutaneous-type SSc presented with severe gangrene in the fingertips of the hands and hypertension, tested positive for anti-PL-12 antibodies. She was diagnosed with acute heart failure owing to scleroderma renal crisis and pulmonary arterial hypertension. Therapeutic agents for pulmonary arterial hypertension were also effective for the digital gangrene. A 50-year-old Japanese woman received prednisolone treatment (2.5 mg/2 days) for systemic sclerosis (SSc) and interstitial pneumonia for approximately 15 years. She suddenly developed severe pain, cold sensation, and digital cyanosis and was treated with intravenous alprostadil (10 μg/day). Two days later, she presented with acute exacerbations of hepatic (aspartate aminotransferase, 4400 IU/L; alanine aminotransferase, 1997 IU/L), renal (creatinine, 2.14 mg/dl), and respiratory (blood oxygen saturation, 77% on room air) functions. Upon admission to the hospital, she presented with increased blood pressure (160/80 mmHg), and within a week developed severe gangrene in the second-to-fifth fingertips of the right hand and the second and fourth fingertips of the left hand (Figure 1A). A modified Rodnan skin score of 2, Raynaud's phenomenon, and nailfold bleeding were observed. Scleroderma was noted only in the extremities and was confirmed by histopathological examination of the forearm lesions. The patient tested positive for anti-nuclear (40×, cytoplasmic), aminoacyl-tRNA synthetase (ARS, 170 index), and PL-12 antibodies,1 but tested negative for anti-topoisomerase 1, centromere, RNA polymerase III, ribonucleoprotein, cardiolipin, anti-cardiolipin β2-glycoprotein I complex, lupus anticoagulant, and myeloperoxidase antineutrophil cytoplasmic antibodies. The findings from lung perfusion scintigraphy were normal. Computed tomography showed mild interstitial pneumonia. The trans-tricuspid pressure gradient (assessed by echocardiography), mean pulmonary arterial pressure, and levels of N-terminal prohormone of brain natriuretic peptide all showed marked elevation to 65 mmHg (normal, <35 mmHg), 50 mmHg (<25 mmHg), and 62,991 pg/ml, respectively. The patient was diagnosed with limited cutaneous-type SSc with anti-PL12 antibodies, acute heart failure, and congestive liver failure, owing to scleroderma renal crisis (SRC) and pulmonary arterial hypertension (PAH). The cardiac, renal, and hepatic functions of the patient improved after 5 days of treatment with continuous hemodiafiltration and a combination of an angiotensin-converting enzyme inhibitor and a Ca-channel antagonist. Endothelin receptor antagonist, phosphodiesterase-type 5 inhibitor, and selective prostacyclin receptor agonist were systemically administered (Figure 1B), and absolute ethanol and a sucrose povidone-iodine ointment were topically applied on the gangrenous fingertips. Seven months later, re-epithelialization in the fingertips was observed (Figure 1C). Anti-synthetase syndrome is often associated with the development of specific clinical symptoms, such as Raynaud's phenomenon, mechanic's hands, polyarthritis, interstitial pneumonia, and myositis.2 Anti-ARS antibodies, including anti-PL12 antibodies, are typically specific to polymyositis/dermatomyositis. The frequency of SSc in patients positive for anti-ARS antibodies is relatively low (3.6%).2 A few cases of SSc with anti-PL12 antibodies have been reported. However, there are no reported cases of this condition with digital gangrene, PAH, and SRC. Generally, SRC or PAH develops in SSc patients with anti-RNA polymerase III or anti-centromere antibodies, respectively.3, 4 Therapeutic agents for PAH are often effective for the concurrent treatment of digital ulcers and gangrene in patients with SSc.5 In this case, we prevented the progression of gangrene and achieved cure through a combination treatment with multiple anti-PAH agents. This approach may be useful for the treatment of patients with SSc who develop refractory digital ulcers and/or gangrene. Approval of the research protocol: N/A. Informed consent: Acquired. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A. The authors declare no conflicts of interest.

BackgroundTreatment for many aspects of systemic sclerosis (SSc) lacks agreement.ObjectivesTo generate SSc treatment algorithms endorsed by high percentage of SSc experts.MethodsExperts from the Scleroderma Clinical Trials Consortium and the Canadian...

Predicting Mortality in Systemic Sclerosis

BackgroundSystemic sclerosis is a heterogenous immune-mediated connective tissue disease characterized by vasculopathy and progressive tissue and organ fibrosis. [1]ObjectivesOur aim was to determine characteristics of Finnish patients with systemic sclerosis...

Background: Systemic sclerosis (SSc) is a heterogeneous disease regarding its clinical expression, evolution and forms of presentation. In spite of the lack of a disease modifying therapy, there are effective treatment options to control complications such as pulmonary arterial hypertension (PAH), interstitial lung disease (ILD) or digital ulcers (DU). Early diagnosis is crucial and allows the physician to start these treatments as soon as possible. To know how and when we diagnose SSc and its clinical manifestations will help us to detect potential improvement areas. Objectives: To study the main clinical manifestations that lead to diagnosis of SSc, the delay of the diagnosis after the beginning of the first symptom, and to analyze the role of the different clinical features in the diagnosis. Methods: A retrospective and descriptive study was conducted, which included patients with SSc from our Rheumatology Department. Clinical data and specific autoantibodies profile (ACA, Scl-70, RNP) were recorded, paying special attention to the clinical manifestations that led to diagnosis. We classified them in eight categories: secondary Raynaud’s phenomenon (SRP), digital ischemia or DU, musculoskeletal symptoms, skin induration, ILD, PAH, specific autoantibodies detection, and others. The date of starting of Raynaud’s phenomenon (RP), of the first non-Raynaud symptom and the date when the diagnosis was established were registered. Analysis were conducted using STATA. Results: The sample included 149 patients with SSc, meeting the 2013 ACR/EULAR criteria. RP appeared several years prior to the diagnosis (median of 3 years, IQR 0-8), and typically before the first non-Raynaud symptom. 141 out of 149 patients (94,6%) presented RP prior to the diagnosis. However, SRP was the manifestation that led to diagnosis in only 42/149 patients (41,6%), followed by skin induration (18,1%) and DU (12,7%). Surprisingly, 30/149 patients (20,1%) were diagnosed after the appearance of severe complications such as DU, ILD or PHA. Most patients started symptoms related to SSc several years before diagnosis (details in Table 1). 40/48 patients (83%) that were diagnosed due to SRP, presented abnormalities in nailfold capillaroscopy as well as specific autoantibodies (Table 2). Presenting telangiectasia, calcinosis, ILD or PAH was not associated with an early diagnosis, nor was ACA, Scl-70 or RNP positivity. Conclusion: An early approach of RP with capillaroscopy and specific autoantibodies would avoid delays to SSc diagnosis, allowing a close follow-up and an early treatment if necessary. SSc must always be considered as a differential diagnosis in patients with DU, ILD or PAH. An adequate referral of patients from primary care physicians to rheumatologists, and a multidisciplinary approach with Vascular Surgery, Pneumology and Cardiology Units would advance the diagnosis of this complex and potentially severe disease. Disclosure of Interests: None declared

To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients. A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools. Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 non-pharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk. The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by widespread fibrosis affecting the skin, internal organs, and vasculature. However, there are currently no systemic, disease-modifying therapies available for the treatment of the overall condition, and the outcomes remain poor. Studies into disease pathogenesis have identified several pathways that are dysregulated in SSc, and novel targeted therapies are currently being developed. In this special issue, we invited authors to submit original research articles, review articles, or case reports/case series describing preclinical, translational, or clinical studies related to new therapies for SSc. A set of papers in this special issue focuses on identification of new therapeutic targets in preclinical and translational studies. V. J. Moulin's paper is a review article describing the role of apoptosis in the initiation and maintenance of disease in SSc, through effects on the immune system, vascular damage, and fibroblast proliferation. This report discusses potential therapies targeting apoptosis and the Fas/FasL pathway that could be investigated in patients with SSc. Other paper describes vascular changes in the bleomycin-induced mouse model of SSc. The authors discuss the use of this mouse model to investigate targeting fibrosis, apoptosis, and cellular adhesion molecules for the treatment of vascular disease in SSc. The paper by T. Radstake et al. reviews the evidence that hypoxia contributes to the pathogenesis of SSc, with a focus on the role of hypoxia inducible factor (HIF)-1 alpha in the vasculopathy, immune dysregulation, and fibrosis in SSc. This paper summarizes potential therapeutic interventions to bypass the dysfunctional hypoxic pathway in SSc. The paper by R. De Vries et al. describes an original research study evaluating the accumulation of advanced glycation end products (AGE) in the skin of patients with SSc compared with controls using a technique called skin autofluorescence. Although this study did not find a significant difference in AGE accumulation in SSc skin compared with control samples, use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in the SSc patients may have confounded the results. The paper by E. G. Kroon et al. is an original research article evaluating the expression of Types I and III interferons (IFNs) and interferon-stimulated genes (ISG) in peripheral blood mononuclear cells from SSc patients compared with controls. This study confirmed the increased basal expression of Type I IFNs and the ISG 2′5′OAS in SSc, but found no induction of Type III IFNs. This paper provides further evidence that targeting the IFN pathway may be useful in the treatment of SSc. The paper by S. M. Violette et al. reviews the preclinical data supporting the role of the integrin αvβ6 in the activation of fibrosis via the transforming growth factor (TGF)-β pathway. This paper summarizes in vivo evidence of the utility of blocking αvβ6 for the treatment of lung fibrosis and provides rationale for pursuing this therapeutic approach in patients with SSc-associated interstitial lung disease. Another set of articles includes reviews of novel therapies that are currently being evaluated for the treatment of SSc. The paper by M. Anderson et al. reviews the role of interleukin-6 (IL-6) in SSc, summarizing evidence of effects on B cells, inflammation, fibrogenesis, and endothelial cell activation. The paper reviews the rationale for ongoing clinical trials of agents blocking IL-6 transsignaling for the treatment of SSc. The paper by S.-N. Liossis et al. reviews the published literature supporting the role of B cells in SSc, summarizing data from animal models and human studies. The authors then review the results of four clinical trials assessing the effects of B cell depletion with rituximab therapy on skin disease and lung function in patients with SSc. The paper by R. F. Spiera and J. Gordon reviews the preclinical and clinical studies of tyrosine kinase inhibitors, with a focus on experience with imatinib, in the treatment of SSc and related fibrotic conditions. The authors conclude that interpretation of the results from the completed proof-of-concept studies is difficult due to the small size and heterogeneity of the populations studied and the open-label designs. The review article by K. Phillips et al. describes published studies investigating the utility of phosphodiesterase-5 inhibitors (PDE-5-I) in the treatment of Raynaud's phenomenon (RP) and/or digital ulcers (DU), detailing results of studies using sildenafil, vardenafil, and tadalafil. The authors also list the ongoing clinical studies of PDE-5-I for RP and DU. The paper by D. F. Fiorentino et al. reviews the role of endothelin-1 in the pathogenesis of SSc-associated vascular disease and summarizes the published reports evaluating the use of endothelin receptor antagonists in the treatment of RP and DU. One of the sets in this special issue includes two articles describing rare clinical manifestations of SSc, gastric antral vascular ectasias and primary biliary cirrhosis, and management strategies for these entities. The paper B. Markewitz et al. is a case series describing the tolerability and efficacy of naltrexone for the treatment of pruritus and gastrointestinal symptoms in three patients with SSc. The paper by K. Nikolov and M. Baleva reviews the rationale for using intravenous immunoglobulins (IVIG) in the treatment of SSc. The authors also summarize the published case reports and series supporting the potential efficacy of IVIG in the treatment of skin sclerosis in SSc. In summary, this special issue provides an interesting compilation of articles addressing potential emerging therapies for the treatment of SSc, including information gleaned from preclinical, translational, and clinical studies. We, the guest editors, hope readers find that the manuscripts included herein offer a comprehensive summary of the current status of drug development and promising therapies for SSc. Lorinda Chung Oliver Distler Laura Hummers Eswar Krishnan Virginia Steen

Raynaud's Phenomenon: A Brush Up!

FRI0478 Update on Lung Transplantation in Systemic Sclerosis in Spain

BackgroundCombined Care in Systemic Sclerosis (CCISS) is a prospective cohort of patients referred to Leiden University Medical Center for Raynaud’s Phenomenon (RP), a suspicion of systemic sclerosis (SSc) or a...

Tackling systemic sclerosis from all angles.