Current Rheumatology Reviews - Volume 4, Issue 1, 2008

As a medical student in the 1970s, we were told about a mysterious entity characterized by relapsing fevers, arthritis and abdominal pain in young patients termed Familial Mediterranean Fever. Cloning of the MEFV gene on chromosome 16p13.3 in 1997 was a major step forward in our understanding of the disease. MEFV encodes pyrin, which plays a role in the regulation of the inflammasome which results in the production of pro-inflammatory cytokines, especially interleukin- 1β. Although case reports of other febrile, relapsing rheumatic related conditions in children were published, the last 5 years has represented a quantum leap in our classification, categorization and understanding of the etiopathogenesis of these disorders. There are now 9 closely related diseases, which are now temed “Autoinflammatory Diseases”. Gattorno and colleagues nicely review that these 9 diseases fall into four general categories: periodic recurrent fevers, cryopyrinopathies, granulomatous disorders and pyogeneic disorders [1]. Although quite rare, advances in this area are now moving at warp speed and investigators now are now nailing down the mutations responsible for these disorders and for the first time are able to manage them. The most exciting recent breakthroughs concern cryopyrin-associated periodic syndrome, or CAPS (not to be mistaken for catastrophic antiphospholipid syndrome). Consisting of Muckle- Wells syndrome, familial cold autoinflammatory syndrome, and neonatal onset multicystemic inflammatory disease, these reflect activation of the inflammasome via the NFκB pathway, IL-1β and caspase-1. Mutations of CIAS1 (coldinduced autoinflammatory syndrome 1) and its encoding protein, cryopyrin are thought to be responsible for massive secretion of IL-1β. CIAS1 is mainly expressed in monocytes, chrondrocytes and activated T cells. Thus, the impressive response of these patients to anakinra and no other agent except perhaps high doses of corticosteroids is a “proof of concept”. What's even more exciting is the development of more potent and effective IL-1β antagonists, which will greatly improve our patient's quality of life. REFERENCE [1] Gattorno M, Pelagatti MA, Federici S, et al. Clinical presentation of autoinflammatory syndromes in childhood, Curr Rheumatol Rev 2008; 4(1): 46-49.

Autoantibodies are pathogenic in systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). These pathogenic autoantibodies are generally characterized by IgG isotype and high affinity binding to particular antigens. In SLE, antibodies to double-stranded DNA (dsDNA), nucleosomes and alpha-actinin are particularly important. In APS, pathogenic antibodies that cause thrombosis or fetal loss are particularly characterized by binding to anionic phospholipids (PL) and beta-2-glycoprotein I. Sequence analysis of human and murine monoclonal anti-dsDNA and aPL antibodies shows that high affinity for these antigens is associated with the presence of the residues arginine (Arg), asparagine (Asn) and lysine (Lys) in the complementarity determining regions (CDRs) of their heavy and light chains. In vitro expression systems have been used to create variants of the antibodies in which these amino acids have been altered. In general, removal of arginine residues reduces affinity for dsDNA, nucleosomes and anionic PL. Arginines at different positions in the sequence have different effects on binding affinity and effects on binding are not always mirrored by effects on pathogenicity. These studies, together with molecular models of antigen/antibody complexes, help us to understand exactly how pathogenic antibodies interact with antigens. Ultimately, this understanding may aid the design of therapeutic agents to block the pathogenic effects of these antibodies.

Ileocolonoscopic evidence for subclinical gut inflammation is found in a subpopulation of spondyloarthropathy (SpA) patients. The prevalence of microscopic intestinal lesions is even higher and can be classified as either an acute or a chronic type of inflammation. The latter condition is associated with an increased risk of developing overt inflammatory bowel disease (IBD), especially Crohn's disease (CD), over time. Evidence for genetic predisposition in both SpA and IBD is strong, and has resulted in the identification of several linked chromosomal loci and putative candidate genes. The regular co-existence of SpA and IBD within the same family suggests a common genetic component. Interestingly, comparison of genome-wide linkage and association data reveals thirteen disease-associated chromosomal regions that are shared between SpA and IBD. This should convince geneticists to examine genes within these regions as potential susceptibility genes for the development of both SpA and IBD. Significant association of such shared genetic determinants was established for NOD2 (16q), the major histocompatibility complex I allele HLA-B27 (6p) and recently also the interleukin 23 receptor (1p). Transgenic animals in which tumor necrosis factor alpha or HLA-B27 is overexpressed suffer both joint and gut abnormalities resembling human SpA/CD pathology, providing additional evidence for a common genetic predisposition for the onset of joint and gut inflammation. In view of a hypothetical pathway leading to intestinal and articular inflammation in SpA and IBD, we review and compare genome-wide linkage and genetic association data obtained for SpA and IBD.

T cells in SLE patients are dysfunctional as a result of altered signalling inputs and altered signal processing. They contribute to pathogenesis through expansion of autoreactive T cells, aberrant B-cell help and direct T cell-mediated tissue damage. Tissue inflammation and damage, in turn, produce nuclear autoantigens and perpetuate antigen presentation to T cells. Improvements in T cell-targeted therapy will require biomarkers of T-cell dysfunction that predict clinical response. Criteria for defining such biomarkers in SLE are discussed here. Phenotypes associated with T-cell activation, specific effector functions, and/or altered proliferative and homeostatic dynamics are promising candidates.

The autoinflammatory syndromes are group monogenic diseases related to mutations of genes involved in the control and in the regulation of the inflammatory response. All of them display an early onset in childhood. Familial Mediterranean Fever, Mevalonate-kinase deficiency and Tumour necrosis factor (TNF) Receptor-Associated Syndrome are characterised by recurrent episodes of systemic inflammation presenting as fever associated with a number of clinical manifestations, such as rash, serositis, lymphadenopathy, arthritis (also known as Periodic fevers). The mutation of the gene Cryopyrin is responsible of a spectrum of diseases (Familiary Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, and Chronic Infantile Neurological Cutaneous and Articular Syndrome) characterised by the dysregulation of IL-1 production and secretion. These disorders are characterised by a chronic or recurrent inflammatory condition variably associated with a number of clinical features, such as urticarial-like rash, arthritis, sensorineural deafness, central nervous system and bone involvement. Other diseases, such as Blau syndrome and Pyogenic Sterile Arthritis, Pyoderma Gangrenosum and Acne syndrome (PAPA) are characterised by a prevalent localisation of inflammation to specific organs and tissues, such as joints, skin and eyes. In the present review we will focus on the clinical presentation of these disorders in childhood and report on the available therapeutic strategies.

Although depression is known to be an important complication in patients with rheumatoid arthritis (RA) or Sjogren's syndrome (SS), at present little is known about the mental states of RA patients who also have SS. To address that issue, we recently used a standardized questionnaire, the self-rating depression scale (SDS), to compare the mental states of patients with RA alone and those with RA complicated by SS. There were no significant differences between the two groups with respect to age, sex, arthralgia, patient global assessment or dosage of steroid. On the other hand, the SDS scores of RA patients with SS were significantly higher than those of RA patients without SS. Among the twenty items on the SDS questionnaire, RA patients with SS complained of “constipation” significantly more often than RA patients without SS. Collectively, our findings suggest SS exacerbates depression in RA patients. In discussing our findings, we describe the features of the depression seen in patients with RA, SS and RA with secondary SS, and make comparisons among these three groups.

The association between malignancy and rheumatic diseases is complex and many factors contribute to it. Malignancies may lead to rheumatic manifestations either directly by invasion or metastases, or indirectly by remote paraneoplastic effects. Chemotherapeutic agents and bone marrow stimulatory biologic agents such as G-CSF and GM-CSF used in the treatment of malignant diseases may also result in rheumatic symptoms. While many of these rheumatic symptoms occur during the course of the malignant disease, often these rheumatic manifestations are the initial presenting features of a hidden malignancy or sometimes occur as late complications of them. Most of the cancer associated rheumatic disorders have no distinguishing features. As well, it is generally held that an extensive search for occult malignancy, beyond routine age-appropriate cancer screening, is not cost efficient and is not recommended unless accompanied by symptoms and signs suggestive of cancer. In this review, we identify rheumatic manifestations associated with malignancy and call attention to possible features that may suggest the presence of an occult malignancy. Awareness of these features may permit earlier diagnosis of the malignancy or its relapse.

What is the magnitude of cancer risk in systemic lupus erythematosus (SLE) compared to the general population? Recent data confirmed a slight increased risk in SLE for all cancers combined, as well as a moderate increased risk of lung cancer, and a strikingly increased risk for hematological malignancies. The hematological cancer type most clearly elevated in SLE is non-Hodgkin's lymphoma (NHL); Hodgkin's lymphoma appears to be increased as well. In SLE, the most commonly identified NHL subtype is diffuse large B-cell lymphoma. Recent analyses suggest that lymphoma in autoimmune rheumatic diseases, including SLE, often presents extra-nodally and/or in advanced stages. Some data suggest that mortality risk in SLE patients with NHL has a bimodal pattern, with a number of patients succumbing early on, and the remainder experiencing fairly good survival rates. Key issues remaining under study relate to the links between cancer risk, clinical features, and medication exposures. New data suggest that disease-related factors may be as or more important, compared to other exposures such as immunosuppressive therapy. The challenge of establishing the independent influences of medication exposures versus disease activity on the risk of malignancy in SLE remains. Work in progress should shed light on these very important issues.

Rheumatoid arthritis is an autoimmune disease that results in joint deformity and disability. Conventional nonsteroidal anti-inflammatory drugs (NSAIDs), steroids and disease modifying antirheumatic drugs (DMARD's) are used for its treatment. Unconventional therapies, like enzyme oligodeoxy nucleotides, boron neutron capture therapy & radioisotopes are also being tried. The use of all these drugs is limited by a number of adverse effects. These side effects have been overcome to a large extent by the use of liposomes as delivery systems. This review presents rationale for the use of liposomes for the treatment of arthritis. Systemic as well as intra-articular delivery of liposome encapsulated anti-arthritic drugs is discussed. Success and limitations of this approach are also discussed by taking examples of different drug classes.

Henoch-Schonlein Pupura (HSP) is a small vessel vasculitis resulting from immunoglobulin A (IgA)-mediated inflammation and characterized by leukocytoclastic angiitis and predominant cutaneous involvement. It is more common in children and characterized by a more benign, shorter and self-limiting course, in contrast to adults where it is relatively rarer but associated with a higher frequency of renal involvement and morbidity. This review discusses the contrasting epidemiological and clinical features between adult and childhood onset HSP, pathogenesis, uncommon clinical manifestations and the evidence for the use of corticosteroids and other immunosuppressive therapies and their influence on longterm outcomes.

In rheumatoid arthritis (RA) chronic inflammation results in pain, swelling and ultimately destruction of joints. This inflammation is also related to systemic bone loss and an increased fracture risk. Glucocorticoids (GC) are widely used to suppress the symptoms of inflammation in RA. There is increasing evidence from clinical studies that GC are disease modifying, in early disease and in combination with slow acting anti-rheumatic drugs. The effects of GC on joint destruction remain a matter of debate. However, some safety issues remain to be considered for long-term treatment, related to high cumulative doses such as the dose-related risk for glucocorticoid induced osteoporosis (GIOP). Moreover, data from in vitro studies on chondrocyte cultures question the cartilage-preserving function that has been attributed to GC. Combination with bisphosphonates can be advocated as these compounds protect against GIOP and chondrocyte apoptosis. In conclusion, GC may have a disease modifying role in RA, but they have to be used in combination with other disease modifying anti-rheumatic drugs and a bisphosphonate.