Current Rheumatology Reports

The microvascular involvement in systemic sclerosis (SSc) is characterized by endothelial damage and smooth muscle cell migration in the intima. The vascular pathologic modifications in SSc are strikingly similar to those of atherosclerosis. SSc also is characterized by an accelerated macrovascular disease. The gene encoding for angiotensinconverting enzyme (ACE) is a 21-kb, 26-exon gene, localized on chromosome 17 (17q23). Polymorphic sites are an insertion/deletion (I/D) that consists of three genotypes: DD and II homozygotes, and ID heterozygote. ACE gene polymorphisms have been linked to vascular disorders (coronary artery disease, hypertension, cerebrovascular disease, hypertrophic cardiomyopathy, and diabetic or nondiabetic nephropathy). In particular, the possession of ACE D allele was associated with an increased risk of developing malignant vascular injury. ACE D allele frequency of the I/D polymorphism was associated with an increased risk of SSc, suggesting a genetic contribution to the disease. The discrepancy between the high prevalence of D allele and reduced ACE plasma levels in SSc demonstrate the lack of knowledge on the regulation and function of renin-angiotensin system in SSc.

Janus kinase–signal transducers and activators of transcription cell signaling proteins (JAK-STATs) play a key regulatory role in functioning of several inflammatory cytokines. JAK-STAT signaling proteins are the key regulators of the cytokine/cytokine receptor system involved in the pathogenesis of various autoimmune disease including spondyloarthritis (SpA). This article mainly highlights the JAK-STAT signaling system, its association with the relevant cytokine/cytokine-receptor system, and its regulatory role in pathogenesis of SpA. Also, we have briefly addressed the principle for the use JAKi in SpA and the current status of use of JAK inhibitors (JAKi) in SpA. Recent developments with newer JAK molecules as well as other molecules beyond JAK inhibitors are now an exciting field for the development of novel therapies for autoimmune diseases and various malignant conditions. In this article, we have provided a special emphasis on how various cell signaling systems beyond JAK/STAT pathway are relevant to SpA and have provided a comprehensive review on this upcoming field in respect to the novel TYK2 inhibitors, RORγT inhibitors, mTOR inhibitors, NGF inhibitors, and various STAT kinase inhibitors. SpA are a group of autoimmune diseases with multifactorial etiologies. SpA is linked with genetic predisposition, environmental risk factors, and the immune system-mediated systemic inflammation. Here, we have provided the regulatory role of JAK/STAT pathway and other intracellular signaling system in the pathogenesis of SpA and its therapeutic relevance.

Type I interferons (IFNαβ) induce the expression of hundreds of genes; thus, it is unsurprising that the initiation, transmission, and resolution of the IFNαβ-mediated immune response is tightly controlled. Mutations that alter nucleic acid processing and recognition, ablate IFNαβ-specific negative feedback mechanisms, or result in dysfunction of the proteasome system can all induce pathogenic IFNαβ signalling and are the focus of this review. Recent advances have delineated the precise cytoplasmic mechanisms that facilitate self-DNA to be recognised by cGAS and self-RNA to be recognised by RIG-I or MDA-5. This helps clarify interferonopathies associated with mutations in genes which code for DNase-II and ADAR1, among others. Similarly, loss of function mutations in Pol α, which lowers the presence of antagonistic ligands in the cytosol, or gain of function mutations in RIG-I and MDA-5, result in increased propensity for receptor activation and therefore IFNαβ induction. As the aetiology of monogenic autoinflammatory diseases are uncovered, novel and sometimes unsuspected molecular interactions and signalling pathways are being defined. This review covers developments that have come to light over the past 3 years, with reference to the study of interferonopathies.

The authors noted significant study limitations to the studies of TCA including lack of trials using standard antidepressant doses, short study duration, lack of adequate measures of mood disorder, and small sample sizes. The authors suggest double-blind, placebo-controlled, parallel-group studies of sufficient sample size and adequate duration. In addition, if agents with antidepressant activities are studied, adequate assessment of mood disorders is critical. Standardized outcome measures, including physical functioning and quality of life, should be included.

The idiopathic inflammatory myopathies (IIMs) represent a heterogeneous group of disorders characterized by mononuclear cell infiltration of muscle and varying degrees of muscle dysfunction. To better understand the pathogenesis of these diseases, investigators have devised a number of infectious, genetic, and antigen-induced animal models that replicate different aspects of muscle involvement. Although the underlying heterogeneity of disorders encompassed by IIM precludes development of a single unifying model, several recently developed experimental systems have provided tremendous insight regarding the contributions of both immune- and non–immune-mediated disease pathways in various subsets of IIM. In turn, by elucidating the pathogenic roles of such disparate factors as endoplasmic reticulum stress and innate immune signaling, these models have established the foundation for more novel, targeted therapeutic intervention.

Not all fractures heal well. One method that has been used to improve fracture healing is low-intensity pulsed ultrasound (LIPUS). LIPUS has been US Food and Drug Administration approved for several years, and some preclinical and clinical evidence indicates that fracture healing can be improved by this technique, which appears to be generally safe. There are several suggested mechanisms of action of LIPUS. Clinical studies generally support its usefulness in accelerating fracture healing. A less-established modality is whole body vibration (WBV), which appears to stimulate bone and muscle growth while suppressing adipogenesis in animal studies. Early studies in humans, including some in children with disabilities, suggest that WBV holds promise as a technique for reducing fracture risk. The exact place of WBV in preventing fracture remains to be established.

Systemic vasculitis can affect practically any structure in or around the eye. Although the ocular presentations of vasculitic disease are highly variable and may be quite subtle, it is important for physicians to understand some of the basic concepts, critical findings, and potential significance of ocular signs and symptoms. In addition to preserving sight, awareness of specific ocular syndromes may afford a critical clue to undiagnosed or newly active systemic vasculitis. A brief discussion of the most common ocular syndromes seen in systemic vascular disease is presented, with special attention given to the signs that may be appreciated by non-ophthalmologists. Recent concepts of ocular immunologic therapy are also reviewed, especially as they relate to the use of systemic immunomodulating drugs, because care of these patients often requires close cooperation between ophthalmologists, primary care physicians, and rheumatologists.

Magnetic resonance imaging (MRI) has become an increasingly important imaging technique in osteoarthritis (OA) research, and is widely used in the ongoing endeavor to understand the pathogenesis of OA and to develop structure and disease-modifying OA drugs. MRI offers semiquantitative, quantitative and compositional evaluation of knee OA, and enables visualization of tissues that are not seen by radiography, including but not limited to cartilage, meniscus, bone marrow lesions, synovitis, and muscles. It is now recognized that contrast-enhanced MRI enables more accurate evaluation of synovitis than MRI without contrast. Because of its ability to visualize multiple pain-related tissue pathology in three dimensions, MRI is the best modality for imaging of OA.