Review Articles in 2008

Clinical trials in rheumatology, similar to other areas of research, are associated with a plethora of ethical issues. Relevant issues, depending on the type of trial (for example, early phase trials, prevention trials and postmarketing studies), are outlined in this article, along with issues related to the selection of control arms for clinical trials, the selection of relevant outcome measures and some of the challenges in obtaining informed consent.

Biologic agents that target tumor necrosis factor represent an attractive approach to the treatment of vasculitic diseases, especially those associated with granuloma formation. Available data on the use of these agents for individual vasculitic diseases, and the potential to apply these data to the care of vasculitis patients in clinical practice are discussed in this Review.

Although osteoarthritis is the most common form of joint disease, an effective treatment for this disease is lacking. In this Review, the authors outline the potential use of strategies based on mesenchymal stem cells, which can differentiate into cells of the chondrogenic lineage, in the regeneration and maintenance of damaged articular cartilage.

Signaling from Toll-like receptor (TLR) molecules induces the expression of several molecules that are involved in both innate and adaptive immunity. Targeting TLRs, their co-receptors or their downstream adaptors might be a more selective therapeutic approach for rheumatoid arthritis or systemic lupus erythematosus than inhibiting more global signals, such as nuclear factor κB, as outlined in this Review.

New, noninvasive imaging techniques that can determine various components of bone strength are being developed to assess the risk of fracture in patients with osteoporosis. These techniques, which include three-dimensional assessments of bone density, geometry and microarchitecture, and integrated measurements of bone strength by engineering analyses, are outlined in this article.

Drugs that inhibit tumor necrosis factor (TNF) provide considerable benefit in treatment of rheumatoid arthritis (RA); however, there is an unmet medical need for alternative therapies with higher clinical benefit and lower safety risk and cost. The potential to treat RA by targeting TNF-converting enzyme, which promotes the release of soluble TNF from its membrane-bound precursor, is outlined in this Review.

Several randomized controlled trials have investigated the effects of a number of drugs on the reduction of fracture risk in women with postmenopausal osteoporosis. Meanwhile, algorithms have become available to identify women at the highest risk of fractures. In this context, this article outlines patient- and drug-related determinants that contribute to the clinical decision about initiating and choosing drug therapy for the prevention of fractures.

Cyclophosphamide is an important therapy for patients with severe rheumatic diseases; it is, however, responsible for gonadal toxicity. There are a number of interventions aimed at reducing this toxicity, including estrogen-containing oral contraceptives, hormone agonists and antagonists of gonadal receptors in females, and testosterone therapy and storage of gametes for male patients. These strategies are outlined in this article.

Early-onset systemic lupus erythematosus (SLE) is thought to be associated with an increased risk to cardiovascular health as well as a severe disease phenotype. As outlined in this article, inflammatory and immune abnormalities that are intrinsic to SLE, primary dyslipidemias and secondary effects of treatments such as corticosteroids, might all contribute to premature atherosclerosis.

Several different surgical treatment options are available to patients with rheumatoid arthritis, with the aims of restoring function and quality of life, preventing joint deterioration, relieving pain, and correcting deformity, as discussed in this article. In addition, a number of factors and specialists should be involved in deciding if and when to proceed with surgical intervention.

A major source of genetic heterogeneity is derived from single base-pair alterations in the DNA sequence. The presence of these single-nucleotide polymorphisms can be measured and analyzed, and can potentially be used, therefore, to investigate genetic heterogeneity, to identify disease-associated variants and, in the future, to develop tailored clinical approaches for individual patients with rheumatic diseases.

Autoimmune inflammatory myopathies are a heterogeneous group of chronic inflammatory muscle diseases that result in progressive inflammatory muscle damage and weakness. As discussed in this Review, damage-induced enhancement of autoantigen expression and adjuvant activity might contribute to pathogenic mechanisms in these diseases.

The detection of antiphospholipid antibodies is important to confirm the occurrence of antiphospholipid syndrome, but current assays fail to convincingly correlate the presence of these antibodies with the incidence of thrombosis, a characteristic of the disease. De Laat and colleagues outline newly developed assays to detect antiphospholipid antibodies, the correlation of these assays with clinical symptoms, and potential pathogenic mechanisms to explain the occurrence of these symptoms.

Hematopoietic stem cells (HSCs) can self-renew and potentially differentiate into all types of hematopoietic and immune-system cells. HSC transplantation for the treatment of autoimmune diseases aims to ablate and reset the dysregulated immune system. There are several critical issues, however, such as optimal patient selection and conditioning regimens, to consider before this technique can be more widely applied to the treatment of patients with immune-mediated disease.

Metalloproteinases are thought to be involved in the pathological destruction of joint tissues in rheumatoid arthritis and osteoarthritis; however, matrix metalloproteinase inhibitors failed to effectively treat disease in early clinical trials. It is now clear that more-specific inhibition of these enzymes is required for the success of this therapeutic approach.

Various factors, such as physical, socio-cultural and psychological deficiencies, are important in the development and maintenance of chronic pain. The multidimensionality of pain creates a challenge for patients and physicians in its management and treatment but, as outlined in this article, multidisciplinary pain programs represent the best therapeutic option for patients suffering from this condition.

Patients with rheumatoid arthritis or systemic lupus erythematosus have an increased burden of cardiovascular disease, which is incompletely explained by traditional risk factors. Circulating levels of macrophage migration inhibitory factor are increased in these patients, which, together with other evidence, has lead to this cytokine being considered as a possible link between these inflammatory diseases and atherosclerosis.

Tendinopathy, although common, is difficult to treat, and most currently available treatments are not effective or evidence-based. As outlined in this Review, the molecular pathology of the tendon is being elucidated and could lead to the identification of novel therapeutic agents for the treatment of chronic tendinopathies.

Synoviolin is involved in endoplasmic reticulum (ER)-associated degradation (ERAD), a process that reduces the burden caused by unfolded proteins on the ER. Synoviolin is overexpressed in synovial cells in patients with rheumatoid arthritis; this overexpression causes a hyper-ERAD state, which might result in the autonomous proliferation and aberrant protein production observed in rheumatoid synovial cells.

Systematic reviews, with or without meta-analyses, offer an objective appraisal of the available evidence compared with traditional narrative reviews. In this Review, Dr Finckh and Dr Tramèr examine the analytical strengths of and the main problems encountered by both systematic reviews and meta-analyses, focusing on how to best assess the validity of each for the practicing clinician.