Fatigue is a common symptom in a large number of medical and psychological disorders including many rheumatologic illnesses. A frequent question for health care providers is related to whether reported fatigue is “in the mind” or “in the body” i.e. central or peripheral. If fatigue occurs at rest without any exertion this suggests psychological or central origins. If patients relate their fatigue mostly to physical activities including exercise then their symptoms can be considered peripheral. However, most fatiguing syndromes seem to depend on both peripheral and central mechanisms. Sometimes muscle biopsy with histochemistry may be necessary for the appropriate tissue diagnosis whereas serological tests generally provide little reliable information about the origin of muscle fatigue. Muscle function and peripheral fatigue can be quantified by contractile force and action potential measurements whereas validated questionnaires are frequently used for assessment of mental fatigue. Fatigue is a hallmark of many rheumatologic conditions including fibromyalgia, myalgic encephalitis/chronic fatigue syndrome, rheumatoid arthritis, systemic lupus, Sjogren’s syndrome and ankylosing spondylitis. Whereas many studies have focused on disease activity as a correlate to these patients’ fatigue it has become apparent that other factors including negative affect and pain are some of the most powerful predictors for fatigue. Conversely sleep problems, including insomnia seem to be less important for fatigue. There are several effective treatment strategies available for fatigued patients with rheumatologic disorders including pharmacological and non-pharmacological therapies
fibromyalgia; rheumatoid arthritis; systemic lupus; fatigue; inflammation; rheumatic
Patients with rheumatoid arthritis (RA) suffer significantly increased cardiovascular (CV) morbidity and mortality when compared to the general population. Both traditional CV risk factors and high levels of systemic inflammation have been linked to the increased CV risk in RA patients, but significant uncertainty remains regarding the mechanisms through which these factors contribute to CVD. In addition, ongoing questions remain regarding how best to identify RA patients at high risk for CVD, and what primary and secondary prevention strategies are effective at influencing CV outcome. The current review summarizes recent research in this field.
Rheumatoid arthritis; Cardiovascular disease; Atherosclerosis; Morbidity; Mortality; Risk factors; Inflammation; Therapy
Data now suggest that current strategies in the treatment of rheumatoid arthritis (RA) should focus on early identification and diagnosis, followed by early initiation of DMARD therapy. Initiation of treatment in early RA—ideally, less than 3–6 months after symptom onset—improves the success of achieving disease remission and reduces joint damage and disability. While the optimal treatment regimen in early RA is unclear, use of initial DMARD mono- or combination therapy with prompt escalation to achieve low disease activity or remission is an appropriate approach. Ultimately, the goal of RA management should be the prevention of inflammatory joint disease and, thereby, prevention of disability. To date, studies have shown that pharmacologic interventions can delay progression from undifferentiated inflammatory arthritis to classifiable RA. However, further investigation is needed to identify asymptomatic individuals at high risk for future RA and to intervene early enough in the pathogenesis of RA to prevent progression to clinical disease.
Rheumatoid arthritis; Early treatment; Prevention; Treatment; Strategies; Management; Therapy; DMARD; Joint damage; Autoimmunity
Macrophages play a central role in the pathogenesis of rheumatoid arthritis (RA). There is an imbalance of inflammatory and antiinflammatory macrophages in RA synovium. Although the polarization and heterogeneity of macrophages in RA have not been fully uncovered, the identity of macrophages in RA can potentially be defined by their products, including the co-stimulatory molecules, scavenger receptors, different cytokines/chemokines and receptors, and transcription factors. In the last decade, efforts to understand the polarization, apoptosis regulation, and novel signaling pathways in macrophages, as well as how distinct activated macrophages influence disease progression, have led to strategies that target macrophages with varied specificity and selectivity. Major targets that are related to macrophage development and apoptosis include TNF-α, IL-1, IL-6, GM-CSF, M-CSF, death receptor 5 (DR5), Fas, and others, as listed in Table 1. Combined data from clinical, preclinical, and animal studies of inhibitors of these targets have provided valuable insights into their roles in the disease progression and, subsequently, have led to the evolving therapeutic paradigms in RA. In this review, we propose that reestablishment of macrophage equilibrium by inhibiting the development of, and/or eliminating, the proinflammatory macrophages will be an effective therapeutic approach for RA and other autoimmune diseases.
Macrophage; Polarization; Rheumatoid arthritis; Therapy; Management; Reform; Removal; Joint recruitment; Inflammation; Depletion; TRAIL
Experimental models of rheumatoid arthritis (RA) have contributed immensely to our understanding of the pathogenesis as well as the treatment of this debilitating autoimmune disease. Significant progress has been made in the past few years in defining the role of newer cytokines and regulatory T cells, of inflammation-mediated bone and cartilage damage, and of the cholinergic anti-inflammatory pathway in modulating the disease process in arthritis. Furthermore, new therapeutic targets, including specific tyrosine kinases and proteasome subunits have been explored. These advances offer renewed optimism for continued improvements in the management of RA.
Osteoarthritis (OA) is one of the most common forms of degenerative joint disease and a major cause of pain and disability affecting the aging population. It is estimated that more than 20 million Americans and 35 to 40 million Europeans suffer from OA. Analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) are the only therapeutic treatment options for OA. Effective pharmacotherapy for OA, capable of restoring the original structure and function of damaged cartilage and other synovial tissue, is urgently needed, and research into such disease-modifying osteoarthritis drugs (DMOADs) is in progress. This is the first of three reviews focusing on OA therapeutics. This paper provides an overview of current research into potential structure-modifying drugs and more appropriately targeted pharmacological therapy. The challenges and opportunities in this area of research and development are reviewed, covering the most up-to-date initiatives, trends, and topics.
Osteoarthritis; Therapeutics; Pharmaceuticals; Pharmacological therapy; Analgesics; Non-steroidal anti-inflammatory drugs (NSAIDs); Bisphosphonates; Strontium ranelate; Inducible nitric oxide synthase (iNOS); Anti-MMP therapy; DMOADs; Biomarkers
Methotrexate (MTX) is one of the most commonly prescribed and most effective drugs for the treatment of rheumatoid arthritis (RA). Given the partial response of many patients and the side effect profile of the drug, there is considerable interest in identification of biomarkers to guide MTX therapy in RA. Upon entering cells, MTX is polyglutamated. Measuring methotrexate polyglutamates (MTX PGs) levels in circulating red blood cells (RBC) has been proposed as an objective measure that can help to optimize MTX therapy in RA. There is conflicting data with regard to the clinical utility of measurement of MTX PGs measurements as a predictor of the efficacy or toxicity of low-dose MTX effects in RA. Should large, randomized clinical trials of this assay show consistent, reproducible, long-term correlations between MTX PG levels and efficacy and toxicity, this test could become a prominent tool for clinicians to optimize the use of MTX in RA.
Rheumatoid Arthritis; Methotrexate; Polyglutamates
Juvenile idiopathic arthritis (JIA)-associated uveitis can be associated with vision-compromising complications such as cataracts, glaucoma, synechiae, and band keratopathy. Of these, cataracts are one of the most common sequelae of JIA-associated uveitis and can result in significant visual disability. Risk factors for cataracts include posterior synechiae and longstanding ocular inflammation. Prevention of cataract development is crucial through appropriate control of uveitis. However, not all preventive measures are successful, and further management consisting of medical and surgical techniques is often necessary. Various factors should be taken into consideration when deciding on cataract management, including timing of surgery and placement of an intraocular lens. Continued partnership between pediatric rheumatologists and pediatric ophthalmologists can help ensure favorable visual outcomes.
Juvenile idiopathic arthritis; Uveitis; Cataracts; Treatment; Prevention; Management; Glaucoma; Synechiae; Band keratopathy; Visual acuity; Visual impairment; Corticosteroids; Surgery; Intraocular lens
BAFF (B-cell–activating factor) is a critical survival factor for transitional and mature B cells and is a promising therapeutic target for systemic lupus erythematosus (SLE). In 2010–2011, two phase 3 clinical trials showed that the addition of the anti-BAFF antibody belimumab to standard-of-care therapy in patients with moderately active SLE results in a better outcome at 52 weeks than standard-of-care therapy alone. Belimumab has been US Food and Drug Administration approved for the treatment of SLE, and other drugs that target BAFF are now in various stages of clinical testing. This review describes the function of BAFF and its homolog APRIL (a proliferation-inducing ligand) and addresses the rationale for the treatment of SLE with BAFF/APRIL inhibitors.
Systemic lupus erythematosus; SLE; B cells; BAFF; APRIL; Belimumab; Atacicept; B-cell selection; Murine models; Inhibition; Clinical trials
The Hopkins lupus cohort is a longitudinal cohort study of over 2,000 systemic lupus erythematosus (SLE) patients, who are seen quarterly. This review covers ten important clinically-relevant studies of the cohort. These studies include the function of prednisone in atherosclerosis and thrombosis, the preventive function of hydroxychloroquine, new insights into rare neurological manifestations, and treatment of flares with bursts of steroids rather than maintenance steroids.
Systemic lupus erythematosus; SLE; Hopkins lupus cohort; Prednisone; Organ damage; Hydroxychloroquine; Thrombosis; Lupus nephritis; Lupus anticoagulant; Cardiovascular disease; Cognitive impairment; SLE myelitis; Small fiber neuropathy; Vitamin D; Flares
Our appreciation of the role of endoplasmic reticulum(ER) stress pathways in both skeletal muscle homeostasis and the progression of muscle diseases is gaining momentum. This review provides insight into ER stress mechanisms during physiologic and pathological disturbances in skeletal muscle. The role of ER stress in the response to dietary alterations and acute stressors, including its role in autoimmune and genetic muscle disorders, has been described. Recent studies identifying ER stress markers in diseased skeletal muscle are noted. The emerging evidence for ER–mitochondrial interplay in skeletal muscle and its importance during chronic ER stress in activation of both inflammatory and cell death pathways (autophagy, necrosis, and apoptosis) have been discussed. Thus, understanding the ER stress–related molecular pathways underlying physiologic and pathological phenotypes in healthy and diseased skeletal muscle should lead to novel therapeutic targets for muscle disease.
Skeletal muscle; Endoplasmic reticulum; Sarcoplasmic reticulum; Mitochondria; Myositis; ER stress; Autophagy; Necrosis; Apoptosis; Muscle disease
The seronegative spondyloarthopathies (SpA) share certain common articular and peri-articular features that differ from rheumatoid arthritis (RA) and other forms of inflammatory arthritis. These include the tendency of the SpAs to involve the axial skeleton in addition to the diarthrodial joints, and the prominent involvement of the extra-articular entheses (sites of ligamentous and tendon insertion), which are not common sites of primary pathology in RA and other inflammatory arthropathies. The differential anatomic sites of bone pathology in the SpAs in comparison to the other forms of arthritis suggest that the underlying pathogenic processes and cellular and molecular mechanisms that account for the peri-articular bone pathology involve different underlying disease mechanisms. This review will highlight the molecular and cellular processes that are involved in the pathogenesis of the skeletal pathology in the SpAs, and provide evidence that many of the factors involved in regulation of bone cell function exhibit potent immune-regulatory activity, providing support for the general concept of osteoimmunology.
Osteoimmunology; Bone homeostasis; Spondyloarthritis; Ankylosing spondylitis; Psoriatic arthritis; Osteoclast; Osteoblast; Osteocyte; Bone remodeling; Inflammation; Cytokine; Bone morphogenic proteins; Wnt/βcatenin; Sclerostin
Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disorder that primarily affects children. Its hallmark is recurring episodes of sterile osteomyelitis. The clinical presentation is insidious onset of bone pain with or without fever. Laboratory studies typically reveal nonspecific evidence of inflammation. Radiologic imaging and histologic appearance resemble those of infectious osteomyelitis. There is a strong association with inflammatory disorders of the skin and intestinal tract in affected individuals and their close relatives, suggesting a shared pathophysiology and supporting a genetic component to disease susceptibility. Two genetic syndromes have CRMO as a prominent phenotype—Majeed syndrome and deficiency of the interleukin-1 receptor antagonist—and suggest that interleukin-1 may be a key cytokine in disease pathogenesis. This review briefly summarizes the main clinical and radiologic aspects of the disease and then focuses on genetics and pathophysiology and provides an update on treatment.
Chronic recurrent multifocal osteomyelitis; CRMO; DIRA; Osteomyelitis; Pathogenesis; Management; Bone pain; Bone disease; Children; Chronic nonbacterial osteomyelitis; CNO; SAPHO syndrome; Vertebrae; Sweet’s syndrome; Majeed syndrome; NSAIDs; Biphosphonates; Biologic agents
Congenital deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a spectrum of clinical phenotypes. All of these phenotypes are associated with marked overproduction of uric acid and related problems such as hyperuricemia, urate nephrolithiasis, tophi, and gout. The mildest phenotypes include only problems related to overproduction of uric acid. The most severe phenotype is known as Lesch-Nyhan disease, in which the phenotype also includes severe motor handicap, intellectual disability, and self-injurious behavior. In between these two extremes is a continuous spectrum of phenotypes with varying degrees of motor and cognitive handicap but no self-injurious behavior. The pathogenesis of overproduction of uric acid in HPRT deficiency is well-understood, and treatments are available to control it. The pathogenesis of the neurobehavioral problems is less well-understood, and effective treatments for them are lacking.
Inborn errors of metabolism; Uric acid; Lesch-Nyhan disease; Phenotypic spectrum; Gout; Nephrolithiasis; Treatment; Variants; Crystal arthritis
Important clinical advances in the treatment of systemic sclerosis have been made, yet fibrotic disease remains largely untreatable. Optimal design of clinical trials to test new therapeutics for fibrotic disease features has suffered from dual difficulties in patient selection and patient evaluation. Patient selection for entry into trials for treatment of interstitial lung disease and/or skin fibrosis is challenged by the natural history of the disease, which stabilizes in some patients while relentlessly progressing in others, and our lack of good clinical markers to distinguish between these trajectories. Patient evaluation is made difficult, particularly in skin disease, by the inherent difficulty in quantifying the extent of disease. Biomarkers hold the potential to solve many of these problems as surrogate outcome measures and as markers for disease progression. Identified biomarkers may have the potential to graduate to surrogate outcome singly or, more likely, in combination. Predictive biomarkers are still largely unknown.
Scleroderma; Systemic sclerosis; Surrogate outcomes; Subtypes; Biomarkers; Clinical trial; Disease status
Herbal remedies and dietary supplements have become an important area of research and clinical practice in orthopaedics and rheumatology. Understanding the risks and benefits of using herbal medicines in the treatment of arthritis, rheumatic diseases, and musculoskeletal complaints is a key priority of physicians and their patients. This review discusses the latest advances in the use of herbal medicines for treating osteoarthritis (OA) by focusing on the most significant trends and developments. This paper sets the scene by providing a brief introduction to ethnopharmacology, Ayurvedic medicine, and nutrigenomics before discussing the scientific and mechanistic rationale for targeting inflammatory signalling pathways in OA by use of herbal medicines. Special attention is drawn to the conceptual and practical difficulties associated with translating data from in-vitro experiments to in-vivo studies. Issues relating to the low bioavailability of active ingredients in herbal medicines are discussed, as also is the need for large-scale, randomized clinical trials.
Osteoarthritis; Rheumatic diseases; Musculoskeletal complaints; Inflammation; Herbal medicine; Ethnopharmacology; Ayurvedic medicine; Nutrigenomics; Clinical trials; Articular cartilage; Synovium; Mesenchymal stem cell; Phytochemicals; Flavonoids; Catechins; Treatment
Cutaneous lupus erythematosus (CLE) is an autoimmune, inflammatory skin disease seen in patients with or without systemic lupus erythematosus (SLE). The management of CLE includes treatment and prevention of lesions, as well as routine assessment for systemic disease. Treatment options include both topical and systemic therapies. Topical therapies include corticosteroids and calcineurin inhibitors. Systemic therapies generally fall under one of three categories: antimalarials, immunomodulators, such as dapsone and thalidomide, and immunosuppressives, such as methotrexate and mycophenolate. Evidence for the treatment of CLE is limited by few prospective studies, as well as lack of a validated outcome measure up until recently. There is good evidence to support the use of topical steroids and calcineurin inhibitors, though most of these trials have not used placebo or vehicle controls. There have been no randomized placebo-controlled trials evaluating systemic therapies for the treatment of CLE.
cutaneous lupus erythematosus; topical steroids; topical calcineurin inhibitors; antimalarials; immunomodulators; immunosuppressives; Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)
Sarcoidosis affects the bone directly in only a minority of patients. Nonetheless, bone health should be considered in the management of all patients with sarcoidosis. Deficiency in vitamin D, an important contributor to bone health, has been linked to autoimmune disease incidence. Studies have shown that patients with sarcoidosis frequently have low levels of vitamin D-25 but may have normal or increased levels of vitamin D-1,25. In addition, granuloma formation has been linked to a failure of the innate immune system, which could be related to a deficiency in vitamin D, although this relationship has not been fully characterized. Furthermore, many patients with sarcoidosis are treated with corticosteroids, which are known to induce osteoporosis. Therefore, bone health may be impacted in several ways in sarcoidosis—by direct involvement with granulomas, vitamin D deficiency, or corticosteroid therapy.
Sarcoidosis; Bone health; Vitamin D; Calcium; Hypercalcemia; Bisphosphonates; Corticosteroids; Osteoporosis
Psoriatic arthritis (PsA) is characterized by focal bone erosions mediated by osteoclasts at the bone–pannus junction. The bulk of research over the past decade has centered on mechanisms that underlie osteoclastogenesis along with new insights into osteoimmunology; however, recent advances that focus on steps that lead to new bone formation are beginning to emerge. New revelations about bone formation may have direct relevance to PsA given the presence of enthesophytes, syndesmophytes, and bony ankylosis frequently observed in patients with this disorder. In this review, we discuss current developments in the pathogenesis of new bone formation, novel imaging approaches to study bone remodeling and highlight innovative approaches to study the effect of inflammation on bone. Lastly, we discuss promising therapies that target joint inflammation and osteitis with the potential to mediate pathologic bone formation.
Psoriatic arthritis; Ankylosing spondylitis; Osteoclastogenesis; Osteoblastogenesis; New bone formation; Bone biology; Imaging
Major scientific advances in basic science, pharmacology, and translational medicine have allowed the discovery of new molecular targets whose manipulation by new chemical entities has led to treatments for inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. Development of new agents for systemic lupus erythematosus (SLE) has lagged, however, because the protean manifestations of SLE present challenges for measuring therapeutic effects in a consistent manner. Composite end points combining several Disease Activity Indices (DAIs) are being used in ongoing global studies, but the uniform application of these complex DAIs across large numbers of clinical sites has proven difficult. We describe herein approaches that are being utilized to facilitate collection, review, and analysis of the clinical measures utilizing independent central adjudication committees.
Systemic lupus erythematosus; SLE; Data quality; Challenge; New agents; Therapy; Central adjudication committees; Disease Activity Index; Trials; Optimize