Current Rheumatology Reviews - Volume 3, Issue 1, 2007

The issue of immunization in patients with autoimmune disease has plagued rheumatologists for over 50 years. This has been confounded by a report from the World Health Organization recommending that individuals with autoimmune diseases should not receive allergy shots. Case reports have been published demonstrating instances whereby the development of a vasculitic or inflammatory process was temporally associated with a vaccine. It is indeed possible that immune suppressed patients exposed to a child who received a live vaccine are at an increased risk of developing that infection (although no case reports have ever been published in the rheumatic disease literature). Further, many patients observe a flare of their inflammatory process after receiving routine vaccinations. This could stem from their hypervigilance, coincidence or a true reaction. It is therefore a real pleasure to give the reader the opportunity to review the article by Valesini et al. in this issue of CRR, which addresses these important issues. The authors distill the subject based on numbers of patients, level of evidence based conclusions, study design, perception and practicality. In essence, the following guidelines apply: 1. Nearly all routine vaccinations are safe. 2. Rheumatic flares occur in less than 10% and are almost always transient. 3. Increased diligence is mandated if a live vaccine is given to a patient or family member, especially if one is immune suppressed. 4. The effectiveness of any given vaccination is usually 100% of what is seen in healthy controls, but may be less. Hopefully, the mitigations and concerns articulated by rheumatologists are mitigated by the thoughtful, thorough review in this issue.

Growth-plate cartilage and articular cartilage are virtually avascular tissues. Thus, chondrocytes must exist in extreme microenvironmental conditions, most prominently characterized by low oxygen tension. Diffusion distances for oxygen and nutrients between arteries and single chondrocytes range from 50 m to 3mm. Therefore, chondrocytes need specific strategies to adapt to these hostile conditions. Furthermore, they have to synthesize ATP in order to fulfill their main function, i.e. the synthesis of proteoglycans and type II collagen. In recent years increasing evidence for a pivotal role of the transcription factor hypoxia inducible factor-1 (HIF-1α) in cartilaginous tissues has been published. Murine growth-plates with functionally inactivated HIF-1α displayed great defects in their central areas caused by massive cell death. This very important observation points out that HIF-1α is absolutely necessary for chondrocytes to survive developmental hypoxia. Furthermore, it has been shown that HIF-1α has important functions for the regulation of anaerobic energy generation and matrix synthesis. Beside hypoxia, which seems to be more pronounced during osteoarthritis, other factors like pro-inflammatory mediators are able to activate HIF-1α in chondrocytes. Thus, an increasing dependence of OA chondrocytes on the adaptive functions of HIF-1 is reasonable to assume. In this review we will summarize the knowledge about HIF-1α for chondrocyte survival and matrix synthesis of growth-plate and articular cartilage during development and disease.

Recent studies on epigenetics, including DNA methylation and its regulatory enzymes, seem to contribute to elucidation of the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE), although the relationship between DNA methylation and SLE has long been the subject of investigation. To obtain a deeper understanding of the role of DNA methylation in the induction of SLE, we reviewed the relationship between DNA methylation and SLE based on findings reported in the literature and our own data. Various studies, including ours, have indicated the possible importance of DNA methylation, especially hypomethylation, in the etiology of SLE. These epigenetic studies may give us clues towards elucidation of the pathogenesis of SLE and development of new therapeutic strategies for this disease.

Inflammation in many autoimmune syndromes is modulated by the nervous system. This paper reviews important principles of neurogenic inflammation and findings of substance P overexpression in rheumatic diseases. Substance P is a key molecule in activating inflammation after antidromal axoplasmic transport and secretion at the nociceptor. We summarize the results from studies with rheumatoid arthritis, osteoarthritis, psoriatic arthritis, systemic lupus erythematodes, systemic sclerosis, vasculitides, Sjogren syndrome, vasculitides, reflex sympathetic dystrophy, gouty arthritis, fibromyalgia syndrome, chronic fatigue syndrome and degenerative vertebral spine disorders. Although substance P is associated with many of these diseases, selective receptor blockers have not been effective in therapy. In contrast, the nonselective antagonist capsaicin is beneficial in some conditions. We also discuss a novel therapeutic principle with selective serotonin antagonists that may induce a powerful downregulation of neurogenic inflammation.

Somatostatin (somatotropin release inhibitory factor; SRIF) peptides are widely distributed in the mammalian body and, acting through a family of genetically homologous cell surface receptors (sst1-5), regulate cellular secretion and proliferation. Compelling evidence implicates SRIF peptides and peptidyl analogues in chronic inflammatory diseases such as rheumatoid arthritis (RA). SRIF membrane receptors exist on immune and synovial cells, thereby providing molecular targets on the principal participants in the RA pro-inflammatory cascade. Preclinical and clinical studies have shown that SRIF peptides and analogues are anti-inflammatory, however the cellular basis for this activity remains unclear. Since RA inflammation is propagated through cell-mediated immune responses which orchestrate the proinflammatory cytokine production by monocytes, macrophages and synovial fibroblasts, SRIF could provide a strategy for interrupting RA progression. SRIF and SRIF analogues reduce synoviocyte proliferation and suppress synovial cytokine production, thereby making SRIF analogues a potentially novel approach to RA treatment. This review summarizes our current knowledge of SRIF analogue therapies in RA.

Nodules are commonly found in patients with rheumatic diseases, most often in rheumatoid arthritis, but also in other conditions such as systemic lupus erythematosus (SLE). Rheumatoid nodulosis, however, is less frequent and not an established feature of SLE. We describe a patient with SLE and rheumatoid nodulosis, reviewing the literature and suggest that this manifestation falls into the spectrum of rhupus.

Although less than 1% of patients with the antiphospholipid syndrome (APS) develop the catastrophic variant, its potentially lethal outcome emphasizes its importance in clinical medicine today. However, the rarity of this variant makes it extraordinarily difficult to study in any systematic way. In order to put together all the published case reports as well as the new diagnosed cases from all over the world, an international registry of patients with catastrophic APS (“CAPS Registry”) was created in 2000 by the European Forum on Antiphospholipid Antibodies. Currently, it documents the entire clinical, laboratory and therapeutic data of more than 300 patients whose data has been fully registered. This registry can be freely consulted at the Internet (www.med.ub.es/MIMMUN/FORUM/CAPS.HTM) and it is expected that the periodical analysis of these data will allow us to increase our knowledge of this condition.

Rheumatic manifestations, in particular joint complaints, are frequent features in inflammatory bowel disease (IBD), with a prevalence varying from 10 to 35%. Their spectrum is almost wide, involving bone, tendons, entheses and joints. Joint manifestations may be seen as arthralgia and/or inflammatory arthropathies. These latter may in turn be found in three principal forms: the peripheral, the axial or spondylitis and that overlapping between these two varieties. Peripheral arthritis may be classified in oligoarticular (type I) and polyarticular (type II) forms. Oligoarthritis is the most frequent. Usually asymmetric, involving large joints of lower limbs, it is transient, commonly associated with IBD flares, and may disappear after few weeks, although in 10% of cases it may evolves to chronic arthritis. Type II arthritis is polyarticular and symmetric, involving hands and feet but also large joints. The prevalence is about 2-4% of IBD patients, its course is independent from IBD flares and usually evolves in chronic disease. Peripheral arthritis is classically nondeforming, non erosive, and seronegative for the rheumatoid factor. Axial involvement is equally frequent in both CD and UC and varies in different studies from 10 to 30% for sacroiliitis and from 3 to 10% for ankylosing spondylitis. Its course is independent from IBD state, the extension of IBD involvement and the occurrence of flares. The treatment of rheumatic manifestations in IBD is frequently problematic, due to the possibility of frequent side effects. Among drugs used for IBD, corticosteroids, also effective in joint complaints, may have osteopenic effects; sulfasalazine, sometimes able to control peripheral arthritis, is ineffective for the axial involvement. A potential gut toxicity is associated with the use of NSAIDs, which in some patients may induce asymptomatic lesions causing small gut bleeding and loss of proteins. Local injections with steroid may be used for tendonitis, monoarthritis or isolated sacroiliac inflammation. In patients with peripheral arthritis, especially when involving several joints and/or refractory to other therapies, disease modifying drugs for rheumatoid arthritis (DMARDs) should be used. Among these, methotrexate is also useful for CD while it seems inefficacious in UC. Cyclosporin, administrated alone or in association, may contain flares of steroid refractory UC. Azathioprine is commonly used to induce and maintain remission in refractory CD while its role on arthritis is marginal. Aminobisphosphonates seem effective for both axial and peripheral involvements and probably, it may represent a good option for the future in the management of enteropathic arthritis, because of their anti-osteopenic effect. Finally, the most promising opportunities derive from the recently introduced biologic agents, in particular anti-tumour necrosis factor (TNF) . Infliximab, a chimeric anti-TNFα monoclonal IgGI antibody, has largely demonstrated its efficacy in refractory CD and in all rheumatic manifestations. Other biologic agents are proposed, including the human anti-TNF monoclonal antibody adalimumab, antibodies to integrins (anti-α 4 β7), anti-ICAM-1 (intracellular adhesion molecule 1) and IL-10. Concerning the surgical options, the colectomy may be protective on type I peripheral arthritis but is not influent on the course of axial disease, while the surgery on small intestine usually do not prevent the appearance of peripheral arthritis. In the case of destructive arthritis, like coxitis, joint prosthesis may be necessary.

Until recently the possibility of healing of erosive changes in RA has been neglected. When evaluating the radiographic course within clinical studies, a reduction of the radiographic score indicating improvement was not allowed since repair of erosions was considered to be impossible. During the last 3 decades several case reports and case series have been published demonstrating convincingly that healing of erosions of RA patients really occurs. In addition, a subcommittee on healing of the OMERACT imaging committee undertook to confirm the existence of repair by performing several studies: different experts had to evaluate erosions on radiographs of the same patients taken at two different time points demonstrating deterioration or improvement. Blinded to the sequence of the films they agreed which film was better or worse and which erosion was greater or smaller. Since 50% of the films showing improvement were taken at the second time point, that study confirmed that healing really exists. Owing to several special features healing could be diagnosed without knowing the sequence of the films in one study, not convincingly so in another study. Among different features indicating healing on radiographs the following can be distinguished with relative certainty: “re-cortication”, meaning the re-appearance of a cortical plate that had been destroyed; “filling-in”, meaning filling of an erosion with new bone; “restoration”, meaning complete normalisation of the shape of the joint and the trabecular structure of the subchondral bone. The best agreement between observers concerns erosion size. Radiographic evaluation blinded to the sequence of the films in trials with biologics resulted in negative scores exceeding the measurement error of the scoring method in a certain percentage of patients, again supporting the existence of healing. As healing only occurs in an individual joint after the inflammatory process has been quiet in that joint for several months, healing could be utilized as an outcome measure in addition to the slowing or arrest of progression. This article gives an overview over the history and present knowledge of radiographic signs of erosion healing.

Since the first identification of self-reactive antibodies in systemic lupus erythematosus and other systemic autoimmune rheumatic diseases, many autoantibodies have been identified as useful probes in molecular and cell biology and as diagnostic and prognostic biomarkers in clinical immunology. Among the autoantigens, double-stranded desoxoribonucleic acid (dsDNA), the Smith antigen (Sm), ribonucleoproteins (RNP), Scl-70 (topoisomerase I), proliferating cell nuclear antigen (PCNA), and others were described as serologic hallmarks in the diagnosis of systemic autoimmune rheumatic diseases. Despite these advances in identifying autoantibody markers, a number of challenges and controversies persist concerning their origin, clinical usefulness and relevance. These include the association between anti-ribosomal P antibodies and clinical features in systemic lupus erythematosus, the disease specificity of several autoantibodies (i.e. chromatin, Jo-1, alpha-fodrin, topo I and CENP), the relationship between the SS-A/Ro52 and SS-A/Ro60 autoantibody system(s) and the detection of anti-RNP/Sm and anti-fibrillarin antibodies.

The development of rheumatic diseases after immunization has been reported in the medical literature but a causal relationship has not been established. Infections remain an important cause of morbidity and mortality in patients with rheumatic diseases who may be immunodepressed for immunological dysfunctions or immunosuppressed due to the pharmacologic therapy. Although vaccines against infectious diseases are considered the standard way in preventive medicine, it is still a controversial issue among rheumatologists whether or not patients with rheumatic disorders should undergo vaccination. In recent decades increased numbers of studies on influenza and pneumococcal vaccines administered to patients with systemic lupus erythematosus have proven their safety. These vaccinations, generally immunogenic (i.e. able to induce a protective level of specific antibodies), may not induce an adequate response in patients receiving immunosuppressive therapy. The safety and the immunogenity of Tetanus toxoid, and HBV vaccinations in SLE patients are not completely defined so far. Considering the few available studies, influenza, pneumococcal, and HBV vaccines seem to be safe and immunogenic in patients with rheumatoid arthritis. The effect of TNFα blocking therapies on human immune responses to vaccination is discussed. We also review existing knowledge on vaccination in patients with Sjogren's syndrome and in children with rheumatic disorders, discussing risks and benefits.