There are two major clinical subsets of scleroderma: (i) systemic sclerosis (SSc) is a complex systemic autoimmune disorder characterized by inflammation, vasculopathy, and excessive fibrosis of the skin and multiple internal organs and (ii) localized scleroderma (LoS), also known as morphea, is confined to the skin and/or subcutaneous tissues resulting in collagen deposition and subsequent fibrosis. SSc is rare but is associated with significant morbidity and mortality compared with other rheumatic diseases. Fatal outcomes in SSc often originate from organ complications of the disease, such as lung fibrosis, pulmonary artery hypertension (PAH), and scleroderma renal crisis (SRC). Current treatment modalities in SSc have focused on targeting vascular damage, fibrosis, and regulation of inflammation as well as autoimmune responses. Some drugs previously used in an attempt to suppress fibrosis, like D-penicillamine (D-Pen) or colchicine, have been disappointing in clinical practice despite anecdotal evidence of their advantages. Some canonical medications, including glucocorticoids, immunosuppressants, and vasodilators, have had some success in treating various manifestations in SSc patients. Increasing evidence suggests that some biologic agents targeting collagen, cytokines, and cell surface molecules might have promising therapeutic effects in SSc. In recent years, hematopoietic stem cell transplantation (HSCT), mostly autologous, has made great progress as a promising treatment option in severe and refractory SSc. Due to the complexity and heterogeneity of SSc, there are currently no optimal treatments for all aspects of the disease. As for LoS, local skin-targeted therapy is generally used, including topical application of glucocorticoids or other immunomodulatory ointments and ultraviolet (UV) irradiation. In addition, systemic immunosuppressants are also utilized in several forms of LoS. Here, we comprehensively discuss current treatment options for scleroderma, encompassing old, new, and future potential treatment options. In addition, we summarize data from new clinical trials that have the potential to modify the disease process and improve long-term outcomes in SSc.

Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune disease of unknown origin characterized by an uncontrolled inflammatory process resulting in fibrosis of the skin, internal organs and vasculopathy. Manifestations of SSc are heterogenous and can include pulmonary, cardiac, neural, renal, muscular, cutaneous and orofacial complications. Recent scientific advances have led to a better understanding of disease etiopathogenesis and the development of a new classification system. Therapeutic management is often multidisciplinary and targeted toward the affected organs. Oral health care providers (OHCPs) should be familiar with SSc, particularly as it relates to its impact on the orofacial region and modifications to delivery of oral health care for patients with this condition.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and uncontrolled cutaneous and internal organs fibrosis. Diagnosis of SSc in an early phase can be difficult because of a lack of typical symptoms. The delay in diagnosis and treatment of SSc may lead to uncontrolled progression of the disease, thus identification of possible early indicators of skin and organ involvement to prevent their further damage is necessary. The aim of this study is to review the latest biomarkers of organ involvement in SSc. In patients with lung fibrosis lung-epithelial-derived surfactant protein (SP-D), the glycoprotein Krebs von den Lungen-6 (KL-6), and chemokine ligands 2, 4 and 18 (CCL2, CXCL4, CCL18) are elevated, while in patients with skin fibrosis serum levels of heat shock protein 27 (Hsp27), interleukin 16 (IL-16), and IgG-galactosylation ratio are increased. Adiponectin concentration is inversely correlated with the intensity of cutaneous fibrosis. Skin gene profiling also seems very promising. In patients with heart involvement increased serum levels of brain natriuretic peptide (BNP) are present, as well as raised Midkine and Follistatin-like 3 (FSTL3) proteins, ratios of Cu/Se and ceruloplasmin(CP) /Circulating selenoprotein P(SELENOP) and higher whole blood viscosity level. Elevated calprotectin levels are found in individuals with gastrointestinal involvement. Increased levels of chemerin and ARA autoantibodies are associated with renal involvement, whereas high levels of adhesion molecules are found in patients with scleroderma renal crisis (SRC). Currently there are no biomarkers in use that can specifically identify the early involvement of organs.

To date, scleroderma renal crisis (SRC) remains a life-threatening complication in patients affected by systemic sclerosis (SSc), with high morbidity and mortality. In the last few years, some studies have tried to more precisely identify predictors of SRC and clarify the role of previous drug exposure-in particular, angiotensin-converting enzyme (ACE) inhibitors and corticosteroids-in patients with SSc presenting other well-known risk factors for SRC. Different from the findings of previous reports, more recent findings suggest that the presence of chronic kidney disease, systemic arterial hypertension, and proteinuria might all be predictors of SRC. Moreover, because about 40 to 50% of SRC cases can present signs of microangiopathy, a recent study has proposed SSc thrombotic microangiopathy (SSc-TMA) as a clinically and pathophysiologically different entity from narrowly defined SRC. Even though such clear distinction may not always be applicable/feasible in clinical practice, it highlights that complement pathway dysregulation may play a key pathogenetic role in SRC presenting as TMA. Thus, plasma exchange may be considered in severe refractory cases. Nevertheless, ACE inhibitors and prompt achievement of blood pressure control (to rapidly improve ongoing renal ischemia) remain to date the cornerstone of SRC treatment. Here, we report the cases of three SSc patients with SRC followed at our rheumatology units. While describing these patients' risk factors, clinical presentation, and therapy, we aim to discuss the state of the art in SRC and highlight critical issues.

Fibrotic disease, which is implicated in almost half of all deaths worldwide, is the result of an uncontrolled wound healing response to injury in which tissue is replaced by deposition of excess extracellular matrix, leading to fibrosis and loss of organ function. A plethora of genome-wide association studies, microarrays, exome sequencing studies, DNA methylation arrays, next-generation sequencing, and profiling of noncoding RNAs have been performed in patient-derived fibrotic tissue, with the shared goal of utilizing genomics to identify the transcriptional networks and biological pathways underlying the development of fibrotic diseases. In this review, we discuss fibrosing disorders of the skin, liver, kidney, lung, and heart, systematically (1) characterizing the initial acute injury that drives unresolved inflammation, (2) identifying genomic studies that have defined the pathologic gene changes leading to excess matrix deposition and fibrogenesis, and (3) summarizing therapies targeting pro-fibrotic genes and networks identified in the genomic studies. Ultimately, successful bench-to-bedside translation of observations from genomic studies will result in the development of novel anti-fibrotic therapeutics that improve functional quality of life for patients and decrease mortality from fibrotic diseases.

A 40-year-old Japanese woman developed malignant-phase hypertension complicated by thrombotic microangiopathy, progressing to end-stage renal disease. Five years later, she was diagnosed with pulmonary arterial hypertension and interstitial pneumonia. Despite a lack of overt skin sclerosis, nucleolar staining in our indirect immunofluorescence analysis and nailfold capillaroscopy facilitated the diagnosis of anti-PM/Scl antibody-positive systemic sclerosis. We observed the persistent presence of anti-PM/Scl antibodies throughout the clinical course, suggesting that her kidney disease was scleroderma renal crisis. Anti-PM/Scl antibodies can be associated with multiple organ diseases. Careful attention to a patient's antinuclear antibody pattern and dermatological findings may help clarify the etiology of undiagnosed diseases.

Systemic sclerosis is a rare multisystem connective tissue disease. It predominantly affects women and poses a significant risk to mother and baby during pregnancy if not managed appropriately. The commonest manifestations are skin fibrosis and Raynaud's phenomenon. Subgroups of women have an increased risk of organ involvement, especially interstitial lung disease, pulmonary arterial hypertension and renal crises. Pregnancy increases the risk to the mother, especially those with established organ involvement, but also the development of new organ dysfunction; and risks to the fetus. Optimising these women prior to conception, along with careful management and surveillance during pregnancy, is vital for optimising pregnancy outcome. Women with scleroderma need to be managed in a specialised centre with coordinated care from the multi-disciplinary teams including physicians, obstetricians, anaesthetists, neonatologists and midwives. This review aims to describe the risks associated with systemic sclerosis and pregnancy, with management advice for physicians looking after pregnant women with this chronic condition.

Hydroxychloroquine (HCQ) is an antimalarial drug with immunomodulatory effects used to treat systemic lupus erythematosus (SLE) and scleroderma. The antiviral effects of HCQ have raised attention in the context of the COVID-19 pandemic, although safety is controversial. We examined linkages of national transplant registry data with pharmaceutical claims and Medicare billing claims to study HCQ use among Medicare-insured kidney transplant recipients with SLE or scleroderma (2008-2017; N = 1820). We compared three groups based on immunosuppression regimen 7 months-to-1 year post transplant: (a) tacrolimus (Tac) + mycophenolic acid (MPA) + prednisone (Pred) (referent group, 77.7%); (b) Tac + MPA + Pred + HCQ (16.5%); or (c) other immunosuppression + HCQ (5.7%). Compared to the referent group, recipients treated with other immunosuppression + HCQ had a 2-fold increased risk of abnormal ECG or QT prolongation (18.9% vs. 10.7%; aHR,1.12 1.963.42 , p = .02) and ventricular arrhythmias (15.2% vs. 11.4%; aHR,1.00 1.813.29 , p = .05) in the >1-to-3 years post-transplant. Tac + MPA + Pred + HCQ was associated with increased risk of ventricular arrhythmias (13.5% vs. 11.4%; aHR,1.02 1.542.31 , p = .04) and pancytopenia (35.9% vs. 31.4%; aHR,1.03 1.311.68 , p = .03) compared to triple immunosuppression without HCQ. However, HCQ-containing regimens were not associated with an increased risk of death or graft failure. HCQ may be used safely in selected kidney transplant recipients in addition to their maintenance immunosuppression, although attention to arrhythmias is warranted.

Systemic sclerosis (SSc) is a rare autoimmune disease that causes fibrosis in the skin and subcutaneous tissue, involving other organs such as the heart, lungs, kidneys, and gastrointestinal tract. Additionally, it can cause pulmonary arterial hypertension. Scleroderma renal crisis (SRC) is one of the most dreadful complications of SSc. SRC is a medical emergency that can present as a clinical picture of hypertensive encephalopathy. The pathophysiology involves an abrupt onset of moderate to severe hypertension that ranges from days to weeks; it is associated with an increase in plasma renin activity and acute kidney injury. It is known that by introducing angiotensin-converting enzyme inhibitors, the mortality decreases significantly in SRC. The renal biopsy plays an important role on the diagnosis and opportune treatment. We present a clinical case of SRC with a typical presentation of hypertensive emergency and acute kidney injury.

Systemic sclerosis (SSc) is a multisystem autoimmune and vascular disease resulting in fibrosis of various organs with unknown etiology. Accumulating evidence suggests that a common pathologic cascade across multiple organs and additional organ-specific pathologies underpin SSc development. The common pathologic cascade starts with vascular injury due to autoimmune attacks and unknown environmental factors. After that, dysregulated angiogenesis and defective vasculogenesis promote vascular structural abnormalities, such as capillary loss and arteriolar stenosis, while aberrantly activated endothelial cells facilitate the infiltration of circulating immune cells into perivascular areas of various organs. Arteriolar stenosis directly causes pulmonary arterial hypertension, scleroderma renal crisis and digital ulcers. Chronic inflammation persistently activates interstitial fibroblasts, leading to the irreversible fibrosis of multiple organs. The common pathologic cascade interacts with a variety of modifying factors in each organ, such as keratinocytes and adipocytes in the skin, esophageal stratified squamous epithelia and myenteric nerve system in gastrointestinal tract, vasospasm of arterioles in the heart and kidney, and microaspiration of gastric content in the lung. To better understand SSc pathogenesis and develop new disease-modifying therapies, it is quite important to understand the complex pathogenesis of SSc from the two distinct perspectives, namely the common pathologic cascade and additional organ-specific pathologies.

Since its first description around the year 2000, the local renin-angiotensin system (RAS) in skin has been subject of an increasing number of studies with many additions over the last two to three years. A focus of research has been investigations on the role of cutaneous angiotensin receptors and locally synthesised angiotensin II in wound healing, in dermatoses associated with skin fibrosis and in melanoma. This review will provide an introduction into the RAS with emphasis on information relevant for the cutaneous RAS. It will discuss the role of the RAS in skin physiology, followed by a detailed review of the existing literature addressing the role of local angiotensin II and angiotensin AT1 and AT2 receptors in wound healing and in various skin diseases such as hypertrophic scars/keloids, scleroderma, dystrophic epidermolysis bullosa, Dupuytren's disease, squamous cell carcinoma, melanoma and psoriasis. In a final section, the potential relevance of drugs, which interfere with the RAS, for future therapy of dermatological disorders is discussed. Collectively, research about the RAS in skin can currently be described as an area, which has gained increasing attention by basic researchers, thus resulting in a multitude of preclinical studies pointing to the potential relevance of components of the RAS as drug targets in dermatological diseases. With a few small clinical studies already performed successfully for indications such as hypertrophic scars and keloids, it can be said that the skin RAS is now in the critical phase of translation from preclinical evidence to clinical use.

Uncontrolled hypercoagulation and inflammation (thromboinflammation), which are both independent and closely related and amplifying each other pathological processes, form the basis for pathogenesis of a wide range of diseases and complications, including immuno-inflammatory (autoimmune) rheumatic diseases, with the development of potentially fatal injuries of internal organs. Thrombotic microangiopathy is one of the most prominent prototypes of thromboinflammatory pathological conditions. The close link between environmental factors, hemostasis genetic defects and the complement system, inflammation and autoimmunity as pathogenetic mechanisms of microthrombosis draws particular attention to studying thrombotic microangiopathy in immuno-inflammatory rheumatic diseases, primarily systemic lupus erythematosus, antiphospholipid syndrome and scleroderma renal crisis. In future, these studies may be important for expanding the idea of the role of autoimmune mechanisms in pathogenesis of critical hemostasis disorders in human diseases, and for developing new approaches to therapy. Recently, special attention has been paid to the treatment of systemic lupus erythematosus and antiphospholipid syndrome with eculizumab, which is humanized monoclonal IgG2/4k antibody that blocks the complement component C5a and the membrane attack complex (C5b-9) formation, and which is registered for the treatment of atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, as well as severe forms of myasthenia gravis and neuromyelitis optica. Further studies in this direction will create prerequisites for improving the prognosis not only in patients with orphan disorders, but also for widespread human diseases.

You are consulted to evaluate a 56-year-old woman with known Raynaud's phenomenon, finger swelling of several; months' duration, and new hypertension with a blood pressure of 160/100 mm/Hg. She also reports progressive shortness of breath. Physical examination reveals telangiectasias, sclerodactyly, and proximal skin sclerosis (thick shiny skin on the chest and upper arms), and bibasilar crackles are found on chest examination. Laboratory tests reveal evidence of microangiopathic hemolytic anemia, thrombocytopenia, and elevation of the serum creatinine level (previously normal), and chest computed tomography shows evidence of ground-glass opacification in both lower lung fields.

The kidney is frequently involved by autoimmune rheumatic diseases. The renal manifestations may be variable, ranging from asymptomatic proteinuria and microscopic haematuria to nephrotic syndrome and rapidly progressive glomerulonephritis or vasculitis. In a number of cases the kidney involvement is related to the treatment of the original disease and may represent a major cause of morbidity and mortality. Thus, it is important for nephrologists and rheumatologists to remember that dysfunction of the kidney may be part of the primary systemic disorder or consequence of its pharmacotherapy. In the first part of this review we will analyse the kidney involvement in four autoimmune connective tissue diseases: systemic lupus erythematosus, Sjögren syndrome, polymyositis/dermatomyositis, and systemic sclerosis. Renal disease is common in lupus and is a main cause of morbidity and mortality. About 10% of patients with Sjögren syndrome may present interstitial nephritis or, more rarely, glomerulonephritis. Myoglobinuria and acute kidney injury is a frequent complication of polymyositis. Renal disease is one of the most serious complications of systemic sclerosis and may present with a dramatic renal crisis, characterized by malignant hypertension, oligo-anuria, and microangiopathic thrombocytopenic anaemia.

Eosinophilic fasciitis (EF) is a rare connective tissue disease characterized by increased peripheral blood eosinophils and diffuse fasciitis, generalized morphea (GM) is a subtype of localized scleroderma, and IgA nephropathy is a chronic glomerulonephritis caused by abnormal deposition of IgA in the mesangial area of the glomeruli. We describe a 49-year-old male patient with hard skin, cutaneous hyperpigmentation, and proteinuria. The patient had suffered from a long disease course of hard skin, while urine protein was newly detected. Finally, the clinical presentation and physical examination, limb MRI, skin biopsy, and renal biopsy confirmed the diagnosis of eosinophilic fasciitis associated with generalized morphea and IgA nephropathy. This case is the first report of EF associated with GM and IgA nephropathy.