Journal of Clinical Rheumatology and Musculoskeletal Medicine (JCRMM), Vol 1 Issue 1

The CX3CL1/CX3CR1 Axis is a Sensitive Marker of the Response to Anti-Tumor Necrosis Factor Therapy in Patients with Rheumatoid Arthritis

Review Article


Tsuyoshi Kasama^1, Michihito Sato^1, Ryo Takahashi^1, Tsuyoshi Odai^1, Takeo Isozaki¹ and Kazuo Kobayashi²

Affiliations: ¹Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan and ²Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan

ABSTRACT

The tumor necrosis factor (TNF) antagonists (anti‐TNF biologics) infliximab (IFX), adalimumab (ADA), and etanercept (ETN) are commonly used worldwide for rheumatoid arthritis (RA), have produced clinical improvement in signs and symptoms, disability, and quality of life, and have significantly inhibited the progression of joint damage in early and long‐standing disease. However, although anti‐TNF biologics often induce rapid clinical improvement in patients with RA, 20–40% of RA patients show little or no clinical response. To maximize the clinical response to these agents, the mechanism underlying the variable response in individual patients must be understood; furthermore, a strategy is needed to predict responders and non‐responders. Recently, several reports have demonstrated that cytokines and chemokines seem to be important and sensitive mediators in RA patients treated with anti‐TNF biologics. We showed that serum CX3CL1 levels were decreased in response to IFX treatment, whereas there were no significant and uniform alterations after IFX treatment in other chemokines that have crucial roles in the pathogenesis of RA development. In addition, the most interesting result in the present study was that the lack of response in the active RA group despite treatment with IFX could be related to higher basal levels of CX3CL1 and its receptor, CX3CR1. In conclusion, the CX3CL1/CX3CR1 axis and other chemokine receptors, such as CCR3 and CCR5, in patients with active RA may be sensitive to anti‐TNF therapy. These results also suggest that basal serum CX3CL1 levels correlate with the responsiveness of RA patients to IFX therapy.

Keywords: anti-TNF therapy, chemokine, CX3CL1, CX3CR1, cytokine, fractalkine, infliximab, rheumatoid arthritis

Correspondence: Tsuyoshi Kasama, Division of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, 142-8666, Japan. Tel: +81-33784-8942; Fax: +81-33784-8946; e-mail: tkasama@med.showa-u.ac.jp

The Use of Biomarkers to Predict and Monitor Treatment Outcomes in Rheumatoid Arthritis

Ultrasound Imaging of Rheumatoid Arthritis and the Importance of Image Data for the Diagnosis and Treatment of Early Disease

Review Article

Walter Grassi, Luca Di Geso and Emilio Filippucci

Affiliation: Clinica Reumatologica, Universita` Politecnica delle Marche, Ancona, Italy

ABSTRACT

Physical examinations and conventional radiography have low sensitivity for the detection of joint inflammation and damage in patients with rheumatoid arthritis, especially early in the course of the disease. New imaging modalities such as ultrasound allow for accurate and sensitive assessments of both synovitis and bone erosions. The latest generation of ultrasound systems has several advantages over other imaging methods that make them ideal tools for assessing and monitoring early disease. These advantages include reproducibility, repeatability, reduced capital expenditure, high resolution, low running costs and multi‐site examination capability. The impact of the systematic use of ultrasound in the clinical setting of early rheumatoid arthritis still needs further assessment, but there is growing evidence in favor of its value for early diagnosis and in monitoring short‐term therapy. These advantages are particularly important in light of the availability of new and effective disease‐modifying therapies that claim to rapidly induce disease remission. While very recent studies have highlighted the predictive value of sonographic signs of joint disease in terms of the progression of joint damage as documented by conventional radiography, very few reports have documented its role in the assessment of tendons and hyaline cartilage.
Advances in the ultrasound field have not yet reached the plateau phase, and new technologies such as higher frequency volumetric probes and fusion imaging will further enhance the utility of ultrasound for diagnostic applications in the near future.

Keywords: early rheumatoid arthritis, ultrasound, power Doppler, synovitis, bone erosion.
Correspondence: Walter Grassi , MD, Clinica Reumatologica, Università Politecnica delle Marche, Ospedale “A. Murri”, Via dei Colli, 52, 60035 Jesi (Ancona), Italy. Tel: +(39)‐0731‐534125; Fax: +(39)‐0731‐534124; e‐mail: walter.grassi@univpm.it

What Are the Potential Roles Magnetic Resonance Imaging Can Play in Differentiated and Undifferentiated Arthritis?

Review Article


Y Emad ¹, Y Ragab², I Bassyouni¹, H Darweesh¹, A Almansari⁴ and JJ Rasker  ³

Affiliations: ¹Rheumatology and Rehabilitation Department; ²Radiology Department, Faculty of Medicine, Cairo University, Cairo, Egypt; ³University Twente, Enschede, the Netherlands and ⁴Internal medicine department, Dr. Erfan and Bagedo general hospital, Jeddah, KSA


ABSTRACT

Magnetic resonance imaging (MRI) has advanced our understanding of many types of arthritis, with respect to both inflammatory processes and articular damage. The role of MRI in differentiating between different forms of arthritis is still debatable and under discussion. The current available data suggest that MRI can separate subsets of early synovitis patients on the basis of two principal imaging patterns: one in which the inflammatory changes are located primarily in the synovium; and another in which the periarticular entheses are inflamed in association with intense edema of the adjacent bone. These two patterns are proposed to broadly classify patients with early synovitis into an “RA” phenotype where synovitis is the primary process, and a “spondyloarthropathy” (SpA) phenotype where enthesitis is the primary process and synovitis occurs on a secondary basis. Enthesitis is a common feature on MRI in SpA, which can help to determine the evolving pattern of patients with undifferentiated arthritis of the knee joint, and may have important clinical implications for classification purposes.

Keywords: enhanced magnetic resonance imaging (MRI), undifferentiated arthritis,
knee enthesitis, rheumatoid arthritis, seronegative spondylarthropathy (SpA)
Correspondence: Yasser Emad, Rheumatology and Rehabilitation Department, Faculty of Medicine, Cairo University, Cairo, Egypt. Rheumatology and Rehabilitation Department Dr Erfan and Bagedo General Hospital, Jeddah, KSA. e‐mail: Yasseremad68@yahoo.com

Sexuality of Male Adolescents and Adults with Juvenile Idiopathic Arthritis

Review Article


Cláudia Goldenstein‐Schainberg and Lilian de Avila Lima Souza

Affiliation: Rheumatology Division, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil


ABSTRACT

Sexuality is an important component in a person’s life, including patients with juvenile idiopathic arthritis (JIA). This chronic inflammatory joint disease affects over 0.1% of children worldwide, and persistent chronic synovitis plays a major role in the development of joint damage, growth, and limb disturbances contributing to functional disability, which may all impair sexual life. During adulthood, signs and symptoms of active disease may remain, causing physical and psychological effects, which may influence sexual behavior. In fact, sexuality as a quality of life issue is important for a person’s complete and satisfying life as a whole. Although this subject is an often neglected area of quality of life among patients with rheumatic disorders, sexual function is influenced by many relevant disease‐associated aspects such as fatigue, pain, stiffness, functional impairment, depression, anxiety, negative body image, hormonal imbalance, drug treatment, and reduced libido. Therefore, because JIA affects not only the musculoskeletal but also other organ systems and psychological aspects, this disease may have a relevant impact and influence patients’ sexuality, especially when adolescence and adulthood are reached, which will be discussed in this review.

Keywords: Sexuality, JIA, sexual function, quality of life, functional impairment
Correspondence: Claudia Goldenstein‐Schainberg, Disciplina de Reumatologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo 455, sala 3133, São Paulo, SP, Brasil, 01246‐903. Tel/Fax: (55)‐11‐3061‐7490; e‐mail: cgs@usp.br; cgschain@uol.com.br

Fetal Safety of TNF Inhibitors in Humans

Review Article


Nada Djokanovic and Gideon Koren

Affiliation: The Motherisk Program, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, University of Toronto, Toronto, Canada


ABSTRACT

Tumor necrosis factor (TNF)‐α inhibitors (infliximab, etanercept, and adalimumab) are marked as pregnancy category B by the US Food and Drug Administration (FDA), indicating that animal studies have not demonstrated fetal risk. Previously published limited human experience has been reassuring, showing no increased risk of congenital malformations in children born to women taking TNF inhibitors. However, recently, some concerns have been raised regarding their safety in pregnancy. This review provides the most current information on the safety of anti‐TNF therapy in pregnancy. A growing body of evidence suggests that infliximab and adalimumab are low risk in pregnancy. Regarding etanercept, the data available today do not suggest that etanercept is a major human teratogen, and it is quite possible that its teratogenic risk does not exceed the baseline rate of congenital malformations in general population.

Keywords: tumor necrosis factor (TNF) inhibitors, infliximab, etanercept, adalimumab, pregnancy, women, fetal risk
Correspondence: Gideon Koren, The Motherisk Program, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. e‐mail: gkoren@sickkids.ca

Peripheral Blood Lymphocyte Subset Abnormalities in Antiphospholipid Syndrome

Review Article


Javier Carbone, Carmen Chean, Nallibe Lanio, Antonio Gallego, Nadia del Pozo and Elizabeth Sarmiento

Affiliations: Clinical Immunology Department, University Hospital Gregorio Marañon

ABSTRACT

Miscarriage and thrombosis are important causes of morbidity and mortality in patients with the antiphospholipid (Hughes) syndrome. However, the precise mechanism responsible for these complications remains unclear. Among the different immunity‐related components that could be implicated in the pathogenesis of this systemic autoimmune disease, immunophenotypic abnormalities in peripheral blood lymphocytes have rarely been sought. We review studies that have been designed to assess functionally distinct T, B, and natural killer lymphocyte subsets in patients with antiphospholipid syndrome.

Keywords: lymphocyte subsets, antiphospholipid syndrome, CD19, CD4, CD8, NK cell, flow cytometry
Correspondence: Javier Carbone, Clinical Immunology Department, University Hospital Gregorio Marañon, Dr. Esquerdo 46, 28007 Madrid, Spain. Tel: (34)‐91 ‐4265180; Fax: (34)‐91‐5866698; e‐mail: carbone@teleline.es

Functional Roles of ANKH/Ank: Insights from CPPDD‐associated ANKH Mutations and the ank/ank Mouse

Review Article

Functional Roles of ANKH/Ank: Insights from CPPDD‐associated ANKH Mutations and the ank/ank Mouse

Florence WL Tsui^1,2, Facundo Las Heras^3,4, Robert D Inman^1–3 and Kenneth PH Pritzker^4,5
Affiliations: ¹Genetics and Development Division, Toronto Western Research Institute, Canada; ²Department of Immunology and ³Institute of Medical Science, University of Toronto, Canada; ⁴Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada and ⁵Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada


ABSTRACT

Calcium pyrophosphate dihydrate crystal deposition disease (CPPD arthropathy) is a common form of degenerative arthritis afflicting the elderly. Although the relationships between CPPD crystal arthropathy and osteoarthritis are controversial, it is clear that the mechanisms of CPPD crystal deposition and the mechanisms that promote cartilage matrix changes in osteoarthritis (OA) are different. Although considerable research attention has been paid to the basic mechanisms of OA, fewer studies have been conducted in CPPD; our understanding of the underlying disease processes remains woefully deficient. Rare genetic diseases with known gene mutations are extremely informative in unraveling the underlying disease mechanisms. Rare families with multiple CPPDD patients provide a good example in this respect. Earlier genetic studies on these families mapped the disease loci to chromosome 8q and 5p. Since the molecular cloning of ANKH (human homolog of progressive ankylosis; located on chromosome 5p), several dominant ANKH mutations that co‐segregate with disease were identified in a number of CPPDD families from different countries. This short review focuses on subsequent work addressing the functional consequences of these mutant ANKH proteins in an attempt to understand how these ANKH mutations might lead to CPPDD pathogenesis. Aside from gene mutations, spontaneous mouse mutants targeting the same gene provide complementary tools for unraveling the gene functions. Our recent finding in ank/ank mice showed that the ank defect results in articular chondrocyte hypertrophy (a novel observation) and increased calcified articular cartilage matrix, all preceding overt osteophyte formation and apatite crystal deposition, consequent to a single gene defect.

Keywords: progressive ankylosis, familial calcium pyrophosphate dihydrate crystal deposition disease, ANKH mutations, ank/ank mouse, tissue non‐specific alkaline phosphatase, sodium/phosphate co‐transporter PiT‐1, inorganic phosphate and pyrophosphate metabolism
Correspondence: F W L Tsui, Toronto Western Hospital, Mc14‐419, 399 Bathurst Street, Toronto, Ontario, M3T 2S8, Canada. Tel: (1)‐416‐603‐5904; Fax: (1)‐416‐603‐5745; e‐mail: ftsui@uhnres.utoronto.ca

Acro‐Osteolysis in Rheumatic Diseases

Review Article


Elena Bartoloni, Devid Biscontini, Alessia Alunno, Filippo Luccioli, Sheila Moscatelli, Gianluca Santoboni and Roberto Gerli
Affiliation: Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy


ABSTRACT

Acro‐osteolysis (AO) has been reported in association with different systemic diseases. Pathogenesis is not completely understood, and several mechanisms leading to this destructive process have been hypothesized. In recent years, AO has been described in patients with chronic inflammatory rheumatic and connective tissue diseases, and different mechanisms contributing to bone damage have been postulated. This review will discuss possible pathogenetic mechanisms involved in bone resorption, focusing on the description of AO in patients with rheumatic diseases.

Keywords: acro‐osteolysis, rheumatic diseases, psoriatic arthritis
Correspondence: Roberto Gerli, Rheumatology Unit, Department of Clinical and Experimental Medicine, Via E Dal Pozzo, I-06122 Perugia, Italy. Tel: (39)-075-578-3975; Fax: (39)-075-578-3105; e-mail: gerlir@unipg.it

Monocytic Cell Gene Regulation by the Hypoxic Synovial Environment in Juvenile Idiopathic Arthritis: Implications for Disease Pathogenesis

Review Article


Maria Carla Bosco and Luigi Varesio
Affiliation: Laboratory of Molecular Biology, G Gaslini Institute, Genova, Italy


ABSTRACT

Persistent synovial inflammation, extensive blood vessel neoformation, and uncontrolled fibroblast proliferation are hallmarks of juvenile idiopathic arthritis (JIA). Dysregulated angiogenesis leads to a dysfunctional vascular network, decreasing blood flow and impairing tissue oxygenation. Oxygen supply is further reduced by the formation of a hyperplastic inflammatory mass, which increases diffusion distances from blood vessels to cells, resulting in areas of hypoperfusion and hypoxia. Monocytic cells are an important component of the leukocyte infiltrate in the joints of patients affected by JIA, where they accumulate within the hypoxic synovial microenvironment, and recent advances have shed light on their role in JIA pathogenesis. The present article provides an overview of the phenotypic and functional changes triggered by hypoxia in monocytic cells both in vitro and in vivo within the JIA synovium. The discussion revolves around studies of gene expression profiles, which give a good representation of the exquisite sensitivity and the complexity of monocytic cell response to oxygen levels similar to those present in the JIA inflamed synovium. Experimental evidence demonstrating the strict regulatory control exerted by hypoxia on monocytic cell recruitment/retention and functional properties at pathological sites is summarized. Furthermore, we outline the existing literature on the transcription pathways underlying hypoxia‐regulated gene expression. Finally, we address the possible link between hypoxia signaling and activation of the proangiogenic and inflammatory phenotype of monocytic cells infiltrating the synovial microenvironment, and discuss the implications of these findings for the persistence of chronic inflammation associated with JIA and for the development of new therapeutic strategies.

Keywords: juvenile idiopathic arthritis, monocytes/macrophages, hypoxia, angiogenic factors, chemokines, gene regulation, inflammation
Correspondence: Maria Carla Bosco, Laboratorio di Biologia Molecolare, Istituto Giannina Gaslini, Padiglione 2, Lgo Gerolamo Gaslini 5, 16147 Genova Quarto, Italy. Tel: (39)‐010‐5636633; Fax: (39)‐010‐3733346; e‐mail: mariacarlabosco@ospedale‐gaslini.ge.it

Osteoarthritis as the Presenting Pathology in Patients with Skeletal Dysplasias

Review Article


Peter Kannu ^{1 2 3}, Ravi Savarirayan ^{2 3} and F John Bateman ³
Affiliations: ¹Division of Medical Genetics, Department of Paediatrics, Queen’s University, Kingston, Canada; ²Department of Paediatrics, University of Melbourne, Parkville, Melbourne, Australia and ³Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Melbourne, Australia


ABSTRACT

The understanding of common diseases and disease mechanisms is facilitated by the study of rare disorders, in which mutations associated with a significant functional effect cause an observable phenotype. The challenge clinicians currently face is with regard to patients who are increasingly aware of the importance of genes in common disease development, and expect their physician to clarify their individual disease risks using a genetic model. This review focuses on a subset of genes that have been shown to be responsible for a range of inherited bone and cartilage disorders (chondrodysplasias), which present clinically with disproportionate short stature and/or orthopedic deformity, with the aim of illustrating the growing evidence that mutations/polymorphisms of lesser effect in these genes might predispose to osteoarthritic phenotypes in the general population. The discussion is structured to review chondrodysplasias arising from mutations in different parts of the cellular and extracellular pathways. If we are able to identify robust genetic “profiles” of individuals who are at greater risk of osteoarthritis, this might then enable preventative strategies to be tailored to these groups, as well as enhancing our understanding of this complex disease phenotype.

Keywords: complex disease, osteoarthritis, transcription factors, cell signaling, matrix enzymes, cilia, matrix proteins
Correspondence: Peter Kannu, Queen’s University, Division of Medical Genetics, Kingston K7L3J6, Canada. e‐mail: kannu@queensu.ca

Prevention of Tuberculosis among Patients with Inflammatory Rheumatic Diseases receiving Tumor Necrosis Factor‐α Inhibitors

Review Article


Anand N Malaviya
Affiliation: Rheumatology Services, ISIC Superspeciality Hospital, Vasant Kunj, New Delhi, India


ABSTRACT

High therapeutic efficacy of inhibitors of tumor necrosis factor‐α (iTNF‐α) in the treatment of rheumatoid arthritis (RA), ankylosing spondylitis (AS)–spondyloarthritides (SpA), and several other inflammatory rheumatic diseases (IRDs) has been well established over the past decade. Large registries on the use of these biologicals and extensive experience with their use worldwide have shown that overall these agents have a good safety profile with a highly favorable risk–benefit ratio with the exception of the problem of reactivation of tuberculosis infection (TBI) among patients with latent tuberculosis infection (LTBI) with their use. Observational studies have established that the risk of developing TB is several fold higher with monoclonal antibodies against TNF‐α than with soluble TNF‐α receptor fusion protein. It has also been observed that almost all the TB flare seen with iTNF‐α is reactivation of LTBI. Therefore, key to the prevention of TB flare associated with the use of iTNF‐α is detection of LTBI among prospective users of these agents. There is, however, no “gold standard” for the diagnosis of LTBI. Therefore, different strategies for the screening of LTBI and its treatment have been recommended in different regions of the world. This review discusses the problems related to TB screening especially among patients with IRDs who may have an inherent immunocompromised state, outlining the pros and cons of different strategies and the issues related to the treatment of LTBI prior to the use of iTNF‐α agents. The review focuses especially on TB preventive strategies in high‐burden TB regions of the world.

Keywords: Tuberculosis, latent tuberculosis infection (LTBI), latent tuberculosis infection screening (LTBI screening), inflammatory rheumatic diseases, tumor necrosis factor‐α inhibitors
Correspondence: , Flat 2015/B‐2, Vasant Kunj, New Delhi – 110070, India. Tel: (91)‐11‐26130664; Fax: (91)‐11‐26130725; e‐mail: anand_malaviya@yahoo.com