Current Rheumatology Reviews - Volume 5, Issue 2, 2009

The presence of antiphospholipid antibodies (aPL) in association with vascular thromboses (VT) and/or pregnancy morbidity (PM) is the hallmark of the Antiphospholipid Syndrome (APS). Increasingly, evidence indicates that PM in the APS involves direct targeting of endometrium and invading fetal trophoblast by aPL. Intravascular or intervillous blood clots are rarely found on histological examination of miscarriage samples from APS patients. In primary human trophoblast culture, aPL inhibit the expression of human chorionic gonadotrophin, induce apoptosis, decrease trophoblast fusion, alter expression of cell adhesion molecules, and limit trophoblast invasiveness. Maternal tissues may also be targeted by aPL since aPL have been shown to inhibit decidualization of cultured endometrial stromal cells and target the decidua when injected in pregnant mice, resulting in recruitment of neutrophils, complement activation, and a rapid increase in TNF-α levels. Thus the mechanism of pregnancy failure in APS is complex and involves local inflammation, impaired decidualisation, disruption of normal trophoblast function and cell death. In this article we review the evidence that different subsets of aPL directly target trophoblast and endometrial cells and the mechanisms that may be involved. The potential diagnostic and therapeutic implications of these findings will then be discussed.

The resorption and formation of bone are closely linked during bone remodeling. The cessation of bone resorption precedes bone formation, and is characterized by osteoclast apoptosis. The two most common apoptotic pathways consist of the activation of one of the membrane death receptors, including Fas that binds FasL, and the TRAIL receptors that bind TRAIL (TNF-Related Apoptosis-Inducing Ligand), and the mitochondrion-activated pathway involving members of the Bcl-2 family. Apoptosis occurs in osteoclasts, and is an important point of control of bone resorption. M-CSF and RANKL, the two critical factors involved in osteoclast formation and activation, are osteoclast survival factors and down-regulate osteoclast apoptosis. The regulation of this process may be important in controlling bone homeostasis, and could be altered in vivo under conditions characterized by a high level of osteoclast formation. Bone diseases, such as osteoporosis, malignant osteolysis, and Paget's disease of bone, are characteristically associated with bone hyper-resorption, as rheumatoid arthritis where peri-articular or subchondral bone resorption may occur. There is now increasing evidence suggesting that changes in the regulation of osteoclast death may contribute to these clinically important bone diseases, and that the induction of osteoclast apoptosis is a potential therapeutic tool for treating them.

Alkaptonuria is a rare autosomal recessive disorder caused by the absence of homogentisate 1,2 dioxygenase (HGD) in the liver. Ochronosis and arthropathic ochronosis are characteristic sequelae of this metabolic disorder. We report here the clinical and molecular findings in 29 alkaptonuric patients (17 males and 12 females) from mainland France and the Reunion Island. We searched for living members of theses families, 14 to 45 years after their observations were described in the literature, and performed molecular analysis and a clinical evolution of the most relevant organ systems involved by ochronosis. Molecular data from 16 families, revealed the presence of six missense mutations at homozygous (p.Y62C, p.W97G, p.V181F, p.V300G) or heterozygous state (p.D153G, p.V300G and p.M368V), four frameshift mutations at homozygous (p.G152fs and p.T196fs) or heterozygous state (p.F10fs and p.R58fs) and three splice site mutations at heterozygous state (IVS1-1G > A, IVS9-56G > A and IVS13+1G > T). Three patients, natives from La Reunion Island, a French department located in the Indian Ocean, were studied. Molecular analysis revealed in a female a homozygous missense mutation p.V300G and in one male, a compound heterozygous mutations: p.V300G inherited from the caucasian father and p.R58fs from the black mother. The p.R58fs mutation is important for two reasons: it is the first AKU mutation described in a black subject and second it has been described in four other countries (Finland, India, Slovakia and Turkey) sharing the same HGD haplotype, which suggests that it is an old mutation, that probably originated in Africa and spread throughout Eurasia during human migrations.

Sexuality is an important aspect of quality of life that is often neglected in research studies and is rarely assessed in routine clinical practice. Patients may feel embarrassed to mention their sexual concerns and many health care providers feel uncomfortable taking a sexual history. The exact prevalence of sexual dysfunction in the general population is not known, but it is clearly very common and women are affected more often than men. Since the majority of connective tissue diseases have a female predilection, sexual dysfunction likely has a large impact on many of our patients. Furthermore, the clinical manifestations of these diseases such as joint pain, deformity and decreased physical function among many others have a major effect on sexual function. We will report results on the prevalence of sexual dysfunction among women with systemic sclerosis from our own institution. A validated questionnaire, The Female Sexual Function Index (FSFI), consisting of six domains was used to assess the multidimensional nature of female sexual dysfunction among women with scleroderma. Our results show a high prevalence of sexual dysfunction among female scleroderma patients compared to a healthy control population. We will also provide a review of the literature on sexual dysfunction among women in a variety of other connective tissue diseases including rheumatoid arthritis, systemic lupus erythematosus, and Sjogren's syndrome.

Introduction: Mixed Connective Tissue Disease (MCTD) has originally been described as a syndrome that consisted of a combination of features typically found in patients with Systemic lupus erythematosus (SLE), Systemic Sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), or rheumatoid arthritis (RA). Objective: The diagnosis of MCTD still remains controversial and it is critically dependent on the demonstration of high-titer anti-U1-RNP antibodies. When first described, MCTD, was believed to have a good prognosis. After longer follow-up studies this opinion has now been revisited: the prognosis in MCTD is in fact worse than that in LES, most of the deaths being due to pulmonary hypertension. The main question is whether or not MCTD patients have a distinctive clinical course, prognosis and treatment requirements. Conclusion: The importance of MCTD is not much in terms of diagnosis, but rather what antibody tells us about patients. The clinician must anticipate by treating the potential lethal complication of pulmonary hypertension, myositis and fibrosing alveolitis, and the tendency of the disease to evolve into one of its sister disease.

Serine proteases are active in many physiological and pathological processes within bone tissue. Although essential to adequate maintenance of bone and cartilage, their inappropriate expression can lead to exacerbation of tissue destruction and inflammation. Their effects are exerted through multiple pathways, including interaction with signalling molecules such as transforming growth factor β (TGFβ), binding to protease-activated receptors (PARs), and direct proteolysis of extracellular matrix proteins, in some cases working synergistically with matrix metalloproteases in the remodelling of bone tissue. The overall effect of these interactions is not yet clear, but there are strong links between some serine proteases and arthropathies, in addition to metastatic bone invasion. Understanding the contribution of each of these enzymes to the molecular disease process is crucial to developing effective treatment based on inhibitors or agonists. Serine protease inhibitors have shown promise in reducing the severity of arthritis, but greater specificity is required to avoid undesired systemic effects.