Seminars in Arthritis and Rheumatism - Articles in Press

An Open-Label Pilot Study Evaluating by Magnetic Resonance Imaging the Potential for a Disease-Modifying Effect of Celecoxib Compared to a Modelized Historical Control Cohort in the Treatment of Knee Osteoarthritis - Corrected Proof

2010-02-04

Objectives: The aim of the study was to evaluate by quantitative magnetic resonance imaging the effect of celecoxib 200 mg daily on cartilage volume loss over 12 months in knee osteoarthritis.Methods: The primary outcome of this study was to evaluate cartilage volume loss in the medial compartment of the knee (femoral condyle and tibial plateau) assessed by quantitative magnetic resonance imaging on subjects receiving continuous treatment with celecoxib 200 mg daily for 12 months compared with a modelized historical control cohort, as expressed by the percentage loss from baseline. Safety of the medication was also assessed. Comparison of the observed volume loss to the expected loss was evaluated by a multivariate linear regression model based on a historical cohort.Results: For the primary outcome, the 95% confidence intervals for the mean observed celecoxib cohort joint medial compartment cartilage volume loss (6.81% [6.01; 7.60]) and mean predicted loss (modelized historical cohort) (5.65% [5.10; 6.19]) overlap, indicating no significant difference and hence no effect of celecoxib on the medial compartment cartilage volume loss. Similar findings were demonstrated for the lateral compartment cartilage loss. The safety data reported several minor adverse events similar to those typically seen in a 1-year clinical trial.Conclusions: Although celecoxib was demonstrated to be safe for knee osteoarthritis at a 200 mg daily dose, it did not provide a protective effect on knee cartilage loss. Cohort modelization is an efficient and unbiased way to provide a comparator group for the assessment of novel treatments when classic head-to-head randomized controlled trials are not feasible.

Serum Procalcitonin in Systemic Autoimmune Diseases—Where Are We Now? - Corrected Proof

Irina Buhaescu, Robert A. Yood, Hassan Izzedine — 2010-02-04

Objectives: To review the current evidence regarding the value of measuring procalcitonin (PCT) levels in patients with systemic autoimmune diseases, with a focus on the evidence for diagnostic and analytical performance of this biomarker. A brief description of the pathophysiological basis of this biomarker is also included.Methods: Using PubMed from the National Library of Medicine, relevant English literature on PCT in patients with different systemic autoimmune diseases, from 1990 to 2009, was reviewed. The search used keywords referring to procalcitonin and systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated systemic vasculitis, Goodpasture syndrome, rheumatoid arthritis, and giant cell arteritis.Results: When used in the appropriate clinical setting, the measurement of serum PCT levels is valuable as a marker of severe systemic bacterial and fungal infections and sepsis. Information regarding plasma PCT levels in patients with active underlying systemic autoimmune diseases is limited, primarily from observational studies and case series, with considerable variability of patient characteristics and clinical settings. In the detection of systemic infection concomitant with autoimmune diseases, PCT had a diagnostic sensitivity of 53 to 100% and a specificity of 84 to 97% (depending on the selection criteria) and was superior to other inflammatory markers tested. Most of the studies used a semiquantitative test for PCT measurement (functional assay sensitivity <0.5 ng/mL), which can explain the low sensitivity of the test. PCT levels were not significantly affected by renal function abnormalities or immunosuppressive agents. Although high PCT levels commonly occurred with infection, elevated levels of PCT could be found in patients with vasculitis without evidence of infection, often correlated with high disease activity scores.Conclusions: Significantly elevated PCT levels offer good specificity and sensitivity for systemic infection in patients with systemic autoimmune diseases, regardless of the use of corticosteroids or immunosuppressive agents. PCT measurement may add to diagnostic accuracy in patients with systemic autoimmune diseases who present with a febrile illness, especially when highly sensitive PCT assays and specific PCT cutoff ranges are used in a predefined clinical setting (reflecting the likelihood of infection versus an autoimmune disease flare). However, there are limitations when using this biomarker in patients with systemic autoimmune diseases. PCT levels should not replace the necessary extensive diagnostic workup, which should include a thorough history and physical examination, combined with appropriate immunological, microbiological, radiological, and histological data.

Proliferative Glomerulonephritis in Lupus Patients With Human Immunodeficiency Virus Infection: A Difficult Clinical Challenge - Corrected Proof

2010-02-04

Objectives: To describe the unusual occurrence of systemic lupus erythematosus (SLE) with nephritis in human immunodeficiency virus (HIV)-infected individuals.Methods: Chart review-based report of a case of SLE with diffuse proliferative glomerulonephritis (DPGN) in an HIV-infected man, together with a literature review of previously published cases. We searched the English language medical literature from 1987 to 2009 using the following PubMed and Medline terms: “SLE,” “HIV,” “DPGN.” In addition, we researched the role of mycophenolate mofetil (MMF) in the treatment of patients with HIV by using the keywords “MMF” and “HIV”.Results: An 18-year-old male patient with vertically transmitted HIV-1 infection presented with malaise, weight loss, malar rash, arthritis, proteinuria, and hematuria. Kidney biopsy confirmed the diagnosis of lupus nephritis (Class IV). He was treated successfully with high-dose corticosteroids and MMF, which were added to his baseline treatment of highly active antiretroviral therapy. The review of the literature identified a total of 18 cases of SLE appearing in HIV+ individuals, of which 11 patients had lupus nephritis. Among the latter, there were only 5 cases of proliferative (focal or diffuse) glomerulonephritis, and their treatment consisted mainly of high-dose corticosteroids. The short-term outcome was favorable in 4 cases and 1 patient died.Conclusions: Proliferative lupus nephritis is rare in HIV-infected patients. A detailed analysis of the cases may lead to important insights into the pathogenic mechanisms of both diseases. Considering its complex interaction with antiviral medications, MMF may be considered for the treatment of lupus with severe proliferative glomerulonephritis in HIV-infected individuals.

Is There a Role for B-cell Depletion as Therapy for Scleroderma? A Case Report and Review of the Literature - Corrected Proof

2009-12-11

Objectives: Rituximab (RTX) has been successfully used in the treatment of several rheumatic diseases with an acceptable safety profile. We present herein a patient with systemic sclerosis (SSc) who exhibited significant improvement of his lung function and skin fibrosis following RTX administration, and review the literature regarding the role of B-cells in SSc and the potential efficacy of RTX in its treatment.Methods: We performed an internet search using the keywords systemic sclerosis, scleroderma, rituximab, B-cells, fibrosis, interstitial lung disease (ILD), and therapy.Results: Our patient, a 40-year old man with severe SSc-associated ILD, received 4 courses of RTX. The patient's lung function improved; forced vital capacity and diffusing capacity of carbon monoxide reached values of 35% and 33%, respectively, compared with 30% and 14% of pretreatment values. Skin thickening assessed clinically and histologically improved as well. Several lines of evidence suggest that B-cells may have a pathogenic role in SSc. B-cells from tight skin mice—an animal model of SSc—exhibit chronic hyperactivity; likewise, B-cells from patients with SSc overexpress CD19 and are chronically activated. Furthermore, studies have revealed that B-cell genes were specifically transcribed in SSc skin and that B-cell infiltration was a prominent feature of SSc-associated ILD. The potential clinical efficacy of RTX in SSc has been explored in a limited number of patients with encouraging results. Preliminary data suggest that RTX may favorably affect skin as well as lung disease in SSc.Conclusions: Several basic research data underscore the potential pathogenic role of B-cells in SSc and clinical evidence suggests that RTX might be a therapeutic option in SSc. Large-scale multicenter studies are needed to evaluate the potential clinical efficacy of RTX in SSc.

The Involvement of Heat-Shock Proteins in the Pathogenesis of Autoimmune Arthritis: A Critical Appraisal - Corrected Proof

Min-Nung Huang, Hua Yu, Kamal D. Moudgil — 2009-12-07

Objectives: To review the literature on the role of heat-shock proteins (HSPs) in the pathogenesis of autoimmune arthritis in animal models and patients with rheumatoid arthritis (RA).Methods: The published literature in Medline (PubMed), including our published work on the cell-mediated as well as humoral immune response to various HSPs, was reviewed. Studies in the preclinical animal models of arthritis as well as RA were examined critically and the data are presented.Results: In experimental arthritis, disease induction by different arthritogenic stimuli, including an adjuvant, led to immune response to mycobacterial HSP65 (BHSP65). However, attempts to induce arthritis by a purified HSP have not met with success. There are several reports of a significant immune response to HSP65 in RA patients. However, the issue of cause and effect is difficult to address. Nevertheless, several studies in animal models and a couple of clinical trials in RA patients have shown the beneficial effect of HSPs against autoimmune arthritis.Conclusions: There is a clear association between immune response to HSPs, particularly HSP65, and the initiation and propagation of autoimmune arthritis in experimental models. The correlation is relatively less convincing in RA patients. In both cases, the ability of HSPs to modulate arthritis offers support, albeit an indirect one, for the involvement of these antigens in the disease process.

Quadriceps Arthrogenic Muscle Inhibition: Neural Mechanisms and Treatment Perspectives - Corrected Proof

David Andrew Rice, Peter John McNair — 2009-12-03

Objectives: Arthritis, surgery, and traumatic injury of the knee joint are associated with long-lasting inability to fully activate the quadriceps muscle, a process known as arthrogenic muscle inhibition (AMI). The goal of this review is to provide a contemporary view of the neural mechanisms responsible for AMI as well as to highlight therapeutic interventions that may help clinicians overcome AMI.Methods: An extensive literature search of electronic databases was conducted including AMED, CINAHL, MEDLINE, OVID, SPORTDiscus, and Scopus.Results: While AMI is ubiquitous across knee joint pathologies, its severity may vary according to the degree of joint damage, time since injury, and knee joint angle. AMI is caused by a change in the discharge of articular sensory receptors due to factors such as swelling, inflammation, joint laxity, and damage to joint afferents. Spinal reflex pathways that likely contribute to AMI include the group I nonreciprocal (Ib) inhibitory pathway, the flexion reflex, and the gamma-loop. Preliminary evidence suggests that supraspinal pathways may also play an important role. Some of the most promising interventions to counter the effects of AMI include cryotherapy, transcutaneous electrical nerve stimulation, and neuromuscular electrical stimulation. Nonsteroidal anti-inflammatory drugs and intra-articular corticosteroids may also be effective when a strong inflammatory component is present with articular pathology.Conclusions: AMI remains a significant barrier to effective rehabilitation in patients with arthritis and following knee injury and surgery. Gaining a better understanding of AMI's underlying mechanisms will allow the development of improved therapeutic strategies, enhancing the rehabilitation of patients with knee joint pathology.

Serum Urate Levels in Different Regions of the Chinese Subcontinent and Their Possible Relationship to Gross Domestic Product per Capita, Predominance of Sedentary Occupations, and Prevalence of Obesity - Corrected Proof

Chin-Hsiu Liu, Hou-Heng Su, David T.Y. Yu — 2009-11-18

Gout is a common inflammatory arthritis in Asia, and hyperuricemia is the most important risk factor. Here, we review 12 cohorts derived from China and Taiwan involving 66,849 subjects, to attempt to rank the hierarchy of the different regions regarding their serum urate levels ().

Tumor Necrosis Factor Inhibitors and Lung Disease: A Paradox of Efficacy and Risk - Corrected Proof

Atul A. Khasnis, Leonard H. Calabrese — 2009-11-17

Objective: Tumor necrosis factor inhibitors (TNFi) are being increasingly used for a wide range of indications. There are increasing reports of pulmonary toxicity related to the use of TNFi. In this review, we have attempted to synthesize the available literature regarding noninfectious complications related to TNFi use.Methods: We reviewed case reports, case series, and clinical trials accessed from the PubMed database (www.pubmed.gov), European League Against Rheumatism web archive (http://www.abstracts2view.com/eular/index.php), and the British Society of Rheumatology Biologics Register Newsletter website (http://www.rheumatology.org.uk/publications) using 23 search terms.Results: There are increasing data available about use of TNFi in treatment of systemic inflammatory rheumatologic disorders and their attempted use for various pulmonary indications. Currently reported noninfectious pulmonary complications related to TNFi use include most commonly granulomatous disease and pulmonary fibrosis/interstitial lung disease and rarely alveolar hemorrhage and antisynthetase syndrome. De novo granulomatous disease seems to be mostly reversible, whereas pulmonary fibrosis carries the worst prognosis especially in the setting of prior lung fibrosis.Conclusions: Serious and potentially fatal pulmonary toxicity has been reported during the use of TNFi, specifically from pulmonary fibrosis. Increased awareness during trial design and increased postmarketing surveillance is needed to provide more information about the epidemiology of these complications. Early recognition of these complications may help avert therapeutic misadventures.

Systemic Sclerosis: Bilateral Improvement of Raynaud's Phenomenon with Unilateral Digital Sympathectomy - Corrected Proof

Amy Wasserman, Ernest Brahn — 2009-11-02

Objectives: To demonstrate that unilateral digital sympathectomy, in patients with Raynaud's phenomenon (RP) and systemic sclerosis (SSc), may result in bilateral resolution of RP and digital ulcerations.Methods: We report a case of SSc and RP that had bilateral benefits from unilateral digital sympathectomy. A computer-assisted Medline/PubMed search of the medical literature was performed for 1960 through June 2009 using the keywords sympathectomy, Raynaud's phenomenon, systemic sclerosis, CREST, and digital ulcers. These searches were also combined with text words unilateral, ipsilateral, bilateral, digital sympathectomy, selective sympathectomy, autonomic nervous system, hyperhidrosis, etiology, pathogenesis, hypothesis, and treatment. Only pertinent literature, primarily in the English language, was included.Results: The majority of patients with SSc have RP and many suffer from digital ulcerations. Medical and behavioral management may have limited benefit and surgical intervention can be considered in recalcitrant cases, although efficacy data are sparse. We describe a man with limited SSc who underwent unilateral digital sympathectomy but manifested bilateral benefit. To our knowledge, this is the first published report of contralateral response with this procedure. The patient ultimately demonstrated these digital benefits when stressed with extreme cold and hypoxia while mountaineering. Despite the onset of high-altitude sickness and cerebral edema, his fingers remained unaffected while other mountaineers sustained severe frostbite or died of hypothermia.Conclusions: Selective unilateral sympathectomy in SSc, for RP with digital ulcerations, can result in bilateral benefits despite intense challenge with cold and hypoxia.

Fatigue Is a Frequent and Clinically Relevant Problem in Ehlers-Danlos Syndrome - Corrected Proof

2009-11-02

Objectives: Ehlers-Danlos Syndrome (EDS) is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Fatigue and musculoskeletal pain are associated features but have never been studied systematically. We used a multidimensional assessment method to measure fatigue, its clinical relevance, and possible determinants.Methods: A questionnaire study was performed among 273 EDS patients. The following dimensions were assessed: fatigue severity, functional impairment in daily life, physical activity, psychological distress, sleep disturbances, concentration problems, social functioning, self-efficacy concerning fatigue, causal attribution of fatigue, pain, and disease-related factors.Results: More than three-quarters of EDS patients suffer from severe fatigue. Patients who are severely fatigued are more impaired than nonseverely fatigued patients and report a higher level of psychological distress. The 5 possible determinants involved in fatigue are sleep disturbances, concentration problems, social functioning, self-efficacy concerning fatigue, and pain severity.Conclusions: This is the first study of fatigue and its possible determinants in EDS and shows that fatigue is a frequent and clinically significant problem in EDS. The 5 possible determinants of fatigue could form a starting point for the development of an effective cognitive behavioral intervention for fatigue in EDS.

Antiphospholipid Syndrome and Reversible Posterior Leukoencephalophaty Syndrome - Corrected Proof

2009-11-02

We commend Arnson and coworkers for their review, which opportunely highlights the relevance of antiphospholipid syndrome (APS) as a neurological disease (). We read with interest all the central nervous system manifestations associated with antiphospholipid antibodies described in the article, such as stroke, headache, migraine, epilepsy, movement and psychiatric disorders, ocular syndromes, cognitive dysfunction, dementia, and neurologic symptoms possibly associated with or possibly mimicked by APS. As described by the authors, acute encephalopathy is a rare clinical diagnosis in APS, but we want to underscore the importance of this condition because of its potential reversibility in some cases. In particular, the occurrence of reversible posterior leukoencephalopathy syndrome (RPLS) in APS has been recently reported in 1 patient with a history of systemic lupus erythematosus and secondary APS who developed bilateral blindness with brain computed tomography findings of white matter hypodensity mostly in the posterior cerebral region ().

Magnetic Resonance Imaging and Brain Histopathology in Neuropsychiatric Systemic Lupus Erythematosus - Corrected Proof

2009-11-02

Objective: Magnetic resonance imaging (MRI) often demonstrates brain lesions in neuropsychiatric systemic lupus erythematosus (NPSLE). The present study compared postmortem histopathology with premortem MRI in NPSLE.Methods: Two hundred subjects with NPSLE were studied prospectively with MRI over a 10-year period during which 22 subjects died. In 14 subjects, a brain autopsy with histopathology, that permitted direct comparison with premortem MRI, was successfully obtained. Surface anatomy was used to determine the approximate location of individual lesions.Results: Premortem MRI findings in fatal NPSLE were small focal white matter lesions (100%), cortical atrophy (64%), ventricular dilation (57%), cerebral edema (50%), diffuse white matter abnormalities (43%), focal atrophy (36%), cerebral infarction (29%), acute leukoencephalopathy (25%), intracranial hemorrhage (21%), and calcifications (7%). Microscopic findings in fatal NPSLE included global ischemic changes (57%), parenchymal edema (50%), microhemorrhages (43%), glial hyperplasia (43%), diffuse neuronal/axonal loss (36%), resolved cerebral infarction (33%), microthomboemboli (29%), blood vessel remodeling (29%), acute cerebral infarction (14%), acute macrohemorrhages (14%), and resolved intracranial hemorrhages (7%). Cortical atrophy and ventricular dilation seen by MRI accurately predicted brain mass at autopsy (r = −0.72, P = 0.01, and r = −0.77, P = 0.01, respectively). Cerebral autopsy findings, including infarction, cerebral edema, intracranial hemorrhage, calcifications, cysts, and focal atrophy, were also predicted accurately by premortem MRI.Conclusion: Brain lesions in NPSLE detected by MRI accurately represent serious underlying cerebrovascular and parenchymal brain injury on pathology.

Leishmaniasis and Biologic Therapies for Rheumatologic Diseases - Corrected Proof

Antonio Cascio, Maurizio Iaria, Chiara Iaria — 2009-09-27

In his article in Seminars in Arthritis and Rheumatism, Furst () provides an accurate analysis of the infections that are related to the use of biologic therapies for rheumatoid arthritis. We would like to add Leishmania spp to the list of the infectious agents that can cause disease during the course of biologic therapies.

The Antiphospholipid Syndrome as a Neurological Disease - Corrected Proof

Yoav Arnson, Yehuda Shoenfeld, Eisen Alon, Howard Amital — 2009-07-14

Objectives: To examine currently known and additional potential neurological manifestations of the antiphospholipid syndrome (APS) and to discuss current and experimental therapeutic options in light of the present knowledge of the disease mechanism.Methods: The PubMed database was searched for articles published between the years 1980 and 2008 for keywords referring to APS and several neurological conditions. Relevant English language articles were reviewed.Results: APS is characterized by diverse neurological manifestations. These include cerebral ischemic events, epilepsy, dementia, cognitive deficits, headaches, psychiatric disorders, chorea, multiple sclerosis-like, transverse myelitis, and ocular symptoms. Some of the symptoms can be associated with ischemia; however, other mechanisms that could lead to similar outcomes have been described, such as direct binding of antiphospholipid antibodies to neural tissue. Current treatment guidelines concern cerebrovascular events only. We propose several different therapeutic options related to the autoimmune nature of the syndrome.Conclusion: Neurological manifestations in APS are diverse and may be confused with other neurologic syndromes. This information is important for the proper diagnosis and management of patients. Experimental therapeutic alternatives expand the treatment options for patients and physicians.

Retropharyngeal Calcific Tendinitis: Case Report and Review of the Literature - Corrected Proof

Richard Park, Daniel E. Halpert, Alan Baer, Dario Kunar, Peter A. Holt — 2009-06-22

Objectives: Retropharyngeal calcific tendinitis (RCT) is an under-recognized benign condition that results in significant neck pain and may mimic a retropharyngeal abscess (RPA). We describe the clinical presentation, diagnosis, and treatment of RCT as well as features that differentiate it from RPA.Methods: We present a case report and analyze the clinical features, diagnosis, and treatment of 71 additional patients with RCT identified through a PubMed literature review between 1964 and early 2008. We then compared these findings with those of RPA.Results: The most common symptoms of RCT at presentation were neck pain (94%), limited range of motion (45%), odynophagia (45%), neck stiffness (42%), dysphagia (27%), sore throat (17%), and neck spasm (11%). Other frequent findings include low-grade fever, mild leukocytosis, and a slightly elevated erythrocyte sedimentation rate. Seventy-five percent of patients with RPA present with similar symptoms and cervical radiographic abnormalities are comparable in the majority of cases with either pathology.Conclusions: RCT frequently mimics the clinical features of RPA and recognizing the key symptoms and signs of RCT versus RPA can be challenging but important in avoiding unnecessary interventions. We recommend that computed tomography of the neck be considered as a first step in differentiating the 2 conditions. The presence of an amorphous calcification anterior to the C1 and/or C2 vertebral body(s) with a non-ring-enhancing fluid collection in the prevertebral space should be considered highly suspicious for RCT. RCT can be self-limiting and will usually resolve in 2 weeks. Effective treatment typically consists of nonsteroidal anti-inflammatory drugs, steroids, or opiate analgesics.

Hand Osteoarthritis: An Epidemiological Perspective - Corrected Proof

Leonid Kalichman, Gabriela Hernández-Molina — 2009-06-01

Objectives: Hand osteoarthritis (OA) is a highly prevalent condition with a wide spectrum of clinical presentations. We review herein the prevalence, impact on hand function, and various risk factors related to hand OA.Methods: PubMed and MEDLINE databases (1950-2009) were searched for the keywords: “hand,” “hand osteoarthritis,” “distal interphalangeal,” “proximal interphalangeal,” “metacarpophalangeal,” and “carpometacarpal.” Published material emphasizing cohort, cross-sectional, and case-control studies regarding epidemiology, clinical features, functional impairment, and associated risk factors of hand OA were included.Results: Hand OA is a heterogeneous, age- and gender-dependent disorder, occurring more frequently in women over 50 years of age. In the elderly population, the prevalence of radiographic hand OA can reach 80%. OA has a strong genetic predisposition, apparently gender- and phenotype-specific. A history of heavy manual labor or a repetitive use of the hand also has been linked to OA. Other variables such as weight, smoking, joint hyperlaxity, age of menarche, bone and cartilage mineralization factors, grip strength, and handedness may play a role. Symptomatic hand OA may cause functional impairment due to loss of strength, thus limiting the individual's ability to perform daily tasks.Conclusions: Several risk factors for hand OA have been identified; however, their interrelationship is not clearly understood. The development of preventive strategies and future research goals is needed.

Kikuchi Fujimoto Disease in Israel—More Than a Pain in the Neck - Corrected Proof

2009-05-29

Objective: Kikuchi Fujimoto disease (KFD) is a rare, benign disorder, usually characterized by cervical lymphadenopathy. Most available data on KFD has come from the Far East. We examined the characteristics of KFD in Israel.Methods: A retrospective analysis of the records of all patients diagnosed as KFD in seven medical centers in Israel and all the cases previously reported as having occurred in Israel in the literature.Results: Nineteen patients were included, 13 new cases and six from the literature. Mean age of patients was 23 (range 9-50) years. Female/male ratio was 1.1:1. Cervical lymphadenopathy, the hallmark of KFD in the Far East (97%), was less frequent in Israel (44%). However, Israeli patients presented more often with generalized (26%) or retroperitoneal (21%) lymphadenopathy (P < 0.01). Systemic signs such as fever (73%), night sweats (21%), weight loss (21%), hepatomegaly or splenomegaly (25%), and elevated sedimentation rate (52%) were more common in Israeli patients compared to most reports from other parts of the world, excluding Germany (P < 0.05). Leukopenia was evident in most Israeli patients (72%) in contrast to other countries (P < 0.01). Clinical presentation of KFD in Germany was comparable to Israel in most aspects.Conclusion: The clinical presentation of KFD in Israel often resembles a systemic disease with fever, leukopenia and generalized or retroperitoneal lymphadenopathy in more than half of the cases, contrary to the presentation in the Far East, which typically includes cervical lymphadenitis, and less frequently, systemic manifestations.

Nerve Growth Factor in Rheumatic Diseases - Corrected Proof

Matthias F. Seidel, Marjeta Herguijuela, Randolf Forkert, Uwe Otten — 2009-05-29

Objectives: The nervous system modulates the immune response in many autoimmune syndromes by neurogenic inflammation. One of the pivotal mediators is nerve growth factor (NGF), which is known for its effects on neuronal survival and growth. There is considerable evidence that NGF acts as an important mediator of many immune responses. This article reviews the role of NGF in rheumatic diseases and strategies for potential therapeutic interventions.Methods: We conducted a database search using Medline and Medpilot. Eight hundred abstracts containing the keyword NGF and 1 of the following terms were reviewed: arthritis, neurogenic inflammation, rheumatoid arthritis, osteoarthritis, collagen arthritis, arteritis, psoriasis, psoriatic arthritis, Sjogren syndrome, systemic lupus erythematosus, gout, osteoporosis, lower back pain, lumbar disc herniation, nerve root compression, spondyloarthritis, spondylarthropathy, algoneurodystrophy, fibromyalgia, Kawasaki syndrome, polyarteritis nodosa, cytokine, vasculitis, pain, therapy, and antagonist. Articles were analyzed based on relevance and content. Most clinical trials and studies with human specimens were included. Studies with experimental animal models were selected if they contained relevant data.Results: NGF is overexpressed in many inflammatory and degenerative rheumatic diseases. Concentrations differ to some extent and sometimes even show contradictory results. NGF is found in serum, synovial fluid, and cerebrospinal fluid, and tissue specimens. NGF concentrations can be correlated with the extent of inflammation and/or clinical activity in many conditions. In rheumatoid arthritis, NGF levels are significantly higher as compared with osteoarthritis.Conclusions: NGF is a significant mediator and modulator of inflammation. NGF sometimes shows detrimental and sometimes regenerative activity. These findings indicate potential therapeutic interventions using either NGF antagonists or recombinant NGF.

Steroid-resistant Protracted Febrile Myalgia - Corrected Proof

Zelal Bircan — 2009-05-29

Protracted febrile myalgia (PFM) is a rare and severe manifestation of familial Mediterranean fever (FMF). Several cases and small case series were reported (). Corticosteroids are the drug of choice and provides prompt relief for severe crippling myalgia (). In undiagnosed patients, PFM lasts nearly 6 weeks (). To date, no steroid resistance has been reported in PFM. Here we report of a patient with PFM who showed resistance to steroid therapy.

Prevalence of Fibromyalgia: A Survey in Five European Countries - Corrected Proof

2009-03-02

Objective: A survey was performed in 5 European countries (France, Germany, Italy, Portugal, and Spain) to estimate the prevalence of fibromyalgia (FM) in the general population.Methods: In each country, the London Fibromyalgia Epidemiological Study Screening Questionnaire (LFESSQ) was administered by telephone to a representative sample of the community over 15 years of age. A positive screen was defined as the following: (1) meeting the 4-pain criteria alone (LFESSQ-4), or (2) meeting both the 4-pain and the 2-fatigue criteria (LFESSQ-6). The questionnaire was also submitted to all outpatients referred to the 8 participating rheumatology clinics for 1 month. These patients were examined by a rheumatologist to confirm or exclude the FM diagnosis according to the 1990 American College of Rheumatology classification criteria. The prevalence of FM in the general population was estimated by applying the positive-predictive values to eligible community subjects (ie, positive screens).Results: Among rheumatology outpatients, 46% screened positive for chronic widespread pain (LFESSQ-4), 32% for pain and fatigue (LFESSQ-6), and 14% were confirmed FM cases. In the whole general population, 13 and 6.7% screened positive for LFESSQ-4 and LFESSQ-6, respectively. 3The estimated overall prevalence of FM was 4.7% (95% CI: 4.0 to 5.3) and 2.9% (95% CI: 2.4 to 3.4), respectively, in the general population. The prevalence of FM was age- and sex-related and varied among countries.Conclusion: FM appears to be a common condition in these 5 European countries, even if data derived from the most specific criteria set (LFESSQ-6) are considered.

Laboratory Tests in the Diagnosis and Follow-Up of Pediatric Rheumatic Diseases: An Update - Corrected Proof

Luciana Breda, Manuela Nozzi, Sara De Sanctis, Francesco Chiarelli — 2009-02-27

Objectives: We reviewed the literature to evaluate the role of common laboratory tests and to examine the recent progress in the laboratory diagnosis of pediatric rheumatic diseases.Methods: We used the PubMed database (1950-2008) to search for the keywords “laboratory,” “erythrocyte sedimentation rate” (ESR), “C-reactive protein” (CRP), “blood cytology,” “procalcitonin” (PCT), “complement system,” “ferritin,” “antistreptolysin O titer” (ASO), “autoantibodies,” “genetic studies,” in conjunction with “rheumatic disease in children” and “pediatric autoimmune diseases.” All relevant original and review articles in English were reviewed as well as textbooks of pediatric rheumatology.Results: Laboratory tests (ESR, CRP, blood cytology, complement system, ferritin, ASO titer) play an important role in confirming a diagnosis and in the follow-up of rheumatic diseases in the pediatric age group. The ESR is probably the most widely measured index of the acute phase response. Measurement of CRP is very useful in the rapid diagnosis of infection as a progressive increase can be shown in the first 48 hours. Also, the subsequent fall in serum CRP concentration on resolution of inflammation is useful for monitoring the efficacy of treatment. In chronic diseases, a combination of CRP and ESR may provide the most useful information. Cytopenia and different forms of anemia can be encountered in many rheumatic diseases: they can be related to disease activity or to therapeutic side effects. Determination of complement levels (C3 and/or C4) is useful in the follow-up of systemic lupus erythematosus (SLE) and membranoproliferative glomerulonephritis. Ferritin is a laboratory hallmark of primary and secondary hemophagocytic lymphohistiocytosis. ASO titer should be obtained to confirm a diagnosis of acute rheumatic fever; other important antibody markers of streptococcal infection include antihyaluronidase, antideoxyribonuclease B, and antistreptokinase antibodies. We also found that, in the pediatric age, the main indication for synovial fluid analysis is suspected joint infection. Antinuclear antibodies, anti-Smith antigen, and anti-double-stranded DNA antibodies are important in the diagnosis of SLE, are useful prognostic markers, and facilitate clinical and treatment follow-up. Anti-SSA/Ro and anti-SSB/La antibodies are associated with Sjögren's syndrome and congenital heart block, while the anti-U1 small nuclear ribonucleoprotein antibodies show high specificity for mixed connective tissue disease. Repetitive spontaneous abortions, thrombocytopenia, and many types of venous or arterial thrombosis are associated with antiphospholipid antibodies. The presence of cytoplasmic antineutrophil antibodies is essential in the diagnosis of Wegener granulomatosis. The discovery of underlying single causative gene defects led to the identification of several autoinflammatory diseases, a group of genetic disorders characterized by recurrent attacks of inflammation (hereditary periodic fever syndromes). These include familial Mediterranean fever due to mutations in the MEFV gene, hyperimmunoglobulinemia D syndrome due to mutations in the MK gene for mevalonate kinase, cryopyrinopathies such as Muckle-Wells syndrome or neonatal-onset multisystemic inflammatory disease (neonatal-onset multisystemic inflammatory disease or CINCA) associated with cold-induced autoinflammatory syndrome 1 gene mutations, and tumor necrosis factor receptor-associated periodic syndrome due to mutation of TNF receptor I gene.Conclusions: Laboratory investigations play an important role in the diagnosis and follow-up of inflammatory rheumatic diseases in children. A good history and a complete physical examination are the best screening tests. Routine laboratory tests are useful to confirm a suspected diagnosis, to assess disease activity, and to measure the response and toxicity to treatment. Only a few tests represent diagnostic criteria such as antinuclear antibodies and anti-double-stranded DNA in SLE or cytoplasmic antineutrophil cytoplasmic autoantibodies in Wegener's granulomatosis. Recent advances in molecular genetics have impacted diagnosis, pathogenesis, and treatment in genetic fever syndromes.

The Effect of Infliximab and Timing of Vaccination on the Humoral Response to Influenza Vaccination in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis - Corrected Proof

2009-02-27

Objectives: To assess the effect of the timing of vaccination in relation to administration of infliximab on the efficacy and safety of influenza vaccine in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS).Methods: The study population comprised 38 patients treated with infliximab at a mean dosage of 3 mg/kg (20 RA patients; 18 AS patients; 23 RA controls (treated with disease modifying antirheumatic drugs other than anti-tumor necrosis factor-α; and 17 healthy controls). Split-virion inactivated vaccine containing 15 μg hemagglutinin/dose of each of A/New Caledionan/20/1999 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (M) was used. Patients treated with infliximab were divided into 2 groups: 22 were vaccinated on the day of administration of infliximab, while 16 received the vaccine 3 weeks after infliximab. Baseline and 4- to 6-week clinical assessment of disease activity included erythrocyte sedimentation rate and C-reactive protein for all patients, the 28-joint disease-activity score for RA patients, and Bath Ankylosing Spondylitis Disease Activity Index for AS patients. Hemagglutination inhibition (HI) antibodies were tested by a standard World Health Organization procedure. Response was defined as ≥4-fold rise in HI antibodies 4 to 6 weeks after vaccination, or seroconversion in patients with a nonprotective baseline level of antibodies (<1/40). Geometric mean titers (GMT) were calculated to assess the immunity of the whole group.Results: At baseline, RA patients and controls had similar occurrence of protective levels of HI antibodies and GMT, while AS patients had lower levels reflecting lower rates of previous vaccination. Four weeks after vaccination, a significant and similar increase in GMT for each antigen was observed in all groups (P < 0.004) except in the RA-infliximab group, vaccinated 3 weeks after administration of infliximab, in whom the increase in GMT was not significant for H1N1 (P = 0.12) and H3 (P = 0.06). AS patients demonstrated an increase in GMT, independently of the time of vaccination. The percentage of responders was similar in all groups. The response was not affected by variables such as age, gender, methotrexate, or prednisone use. Parameters of disease activity remained unchanged. No adverse effects other than injection site pain were recorded.Conclusions: Influenza virus vaccine generated a good humoral response in RA and AS patients treated with infliximab.

Aortitis and Spondyloarthritis—An Unusual Presentation: Case Report and Review of the Literature - Corrected Proof

Lihi Eder, Mouhannad Sadek, Heather McDonald-Blumer, Dafna D. Gladman — 2009-02-17

Objectives: To report a patient with aortic regurgitation (AR) and aortitis, who failed to respond to multiple attempts at surgical replacement of the affected valve and adjacent aorta, and in whom a late diagnosis of spondyloarthritis (SpA) was made. The relevant literature on the association of SpA and aortitis is reviewed.Methods: Descriptive case report of a patient with AR secondary to aortic dilation and aortitis with a late diagnosis of SpA, and a review of the relevant literature (PubMed search 1956 through April 2008).Results: A 36-year-old man was admitted to the hospital for replacement of his aortic valve and aortic valve root as a result of AR after a dehiscence of a mechanical prosthetic valve and subsequent aortic pseudoaneurysm. His past medical history included 2 prior aortic valve replacements that failed due to late postoperative dehiscence. Histological findings from the aortic wall after the third operation showed signs of aortitis. A rheumatologic workup revealed a 6-year history of mild low back pain, radiological evidence of bilateral sacroiliitis, and presence of HLA-B27. A diagnosis of SpA, most likely ankylosing spondylitis (AS), was made. On reviewing the literature, AR has been diagnosed in 2 to 12% of the patients with AS, most of whom had long-lasting disease. There have been several reports of uncommon presentations of acute AR in young patients with juvenile AS; however, no similar adult case was found.Conclusion: This unusual case emphasizes the importance of early and adequate workup for SpA in young patients with lone AR or aortic dilation.

The Interface of Pain and Mood Disturbances in the Rheumatic Diseases - Corrected Proof

Don L. Goldenberg — 2009-02-17

Objectives: To review the overlap of pain and depression in the rheumatic diseases, focusing on fibromyalgia (FM) and rheumatoid arthritis, and to provide treatment recommendations based on an understanding of this interface.Methods: A literature search was performed through PubMed and Medline, for the years 1978 to 2008 and using the keywords: depression, mood disorders, pain, arthritis, fibromyalgia, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, scleroderma, antidepressants, exercise, and cognitive behavioral therapy.Results: This review focuses on the pain/depression interface in common rheumatic disorders. FM is an excellent model to study the proposed mechanisms of such interactions. The potential genetic, inflammatory/immune, morphologic, and neurohormonal mechanisms that have been reported in FM are reviewed and compared with similar studies in depression. The importance of the interface of pain and depression has been noted in rheumatoid arthritis and other rheumatic illnesses, although there are very few studies to investigate their pathophysiologic underpinnings. General therapeutic recommendations can be made based on these overlapping models of the interface of pain and depression.Conclusions: Clinical and pathophysiologic studies in FM demonstrate the striking overlap of pain and depression. These studies pertain to a better understanding of the pain/depression interface in all chronic rheumatic illnesses.

Is Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE) a Subset of Rheumatoid Arthritis? - Corrected Proof

Qingping Yao, Xiangqian Su, Roy D. Altman — 2009-02-17

Objectives: To contrast and compare the spectrum of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) with rheumatoid arthritis (RA) using an illustrative case.Methods: The relevant English literature of RS3PE was searched using the keywords “RS3PE” alone and in combination with terms such as neoplasia and rheumatic disease. Original and review articles were reviewed and the clinical setting was exemplified with a case report.Results: RS3PE initially was reported to represent a form of RA. However, RS3PE has clinical features that are different from both early- and late-onset RA, such as lack of bony erosions and rheumatoid factor. RS3PE is thought to involve vascular endothelial growth factor, suggesting an infectious etiology, generally has an excellent prognosis, and is associated with neoplasia not commonly seen in RA, and the RA associated human leukocyte antigen (HLA) DRB1 genotype is absent.Conclusions: Based on the clinical, laboratory, suspected infectious etiology, genetic differences, and types of associated malignancies, RS3PE appears to be a distinct entity rather than a subset of RA.

Bronchoalveolar Lavage Fluid in Scleroderma Interstitial Lung Disease: Technical Aspects and Clinical Correlations: Review of the Literature - Corrected Proof

Otylia Kowal-Bielecka, Krzysztof Kowal, Kristin B. Highland, Richard M. Silver — 2009-01-19

Objectives: Bronchoalveolar lavage (BAL) has been used for clinical and research purposes in scleroderma interstitial lung disease (SSc-ILD). However, inconsistencies regarding technical aspects of BAL are obstacles in the reproducibility and interpretation of BAL results. This review summarizes clinical correlations and methodological issues of using BAL in the assessment of patients with SSc-ILD. In addition, we review the investigational use of BAL in SSc-ILD.Methods: The PubMed database from inception through May 2008 was searched using the following keywords: “systemic sclerosis, scleroderma, interstitial lung disease, and bronchoalveolar lavage.” The search was limited to English-language studies that included at least 15 SSc patients that had BAL.Results: An increased percentage of neutrophils, eosinophils, and/or lymphocytes, often referred to as “alveolitis,” was reported in a significant percentage of SSc patients (range, 38 to 100%) irrespective of patient selection criteria, cytological cutoff values, or technical aspects of BAL processing. Alveolitis is associated with more severe lung impairment as defined by lung function tests and overall lung high-resolution computed tomography scores, but there is insufficient evidence at this time to recommend BAL cytology as an independent predictor of outcome in SSc-ILD patients. Myofibroblasts have been cultured from BAL fluid, and inflammatory and fibrogenic mediators can be measured in the supernatant of BAL fluid from patients with SSc-ILD.Conclusions: Further studies using standardized BAL protocols are required to establish the role of BAL fluid in the clinical evaluation of SSc-ILD. When performed for research purposes, BAL has provided valuable insight into the pathogenesis of SSc-ILD.

Long-Term Safety, Tolerability, and Efficacy of Duloxetine in the Treatment of Fibromyalgia - Corrected Proof

2009-01-19

Objectives: To assess the long-term safety, tolerability, and efficacy of duloxetine in patients with fibromyalgia.Methods: We report results from the 6-month extension phases of 2 randomized, double-blind, placebo-controlled clinical trials having 6-month placebo-controlled phases. In Study 1, all patients received duloxetine 120 mg/d after 28 weeks on placebo or duloxetine 60 or 120 mg/d. In Study 2, patients taking placebo were titrated to duloxetine 60 mg/d after 27 weeks on treatment, while duloxetine-treated patients remained on their dosages of 60 or 120 mg/d. Safety and tolerability were assessed via discontinuation rates, treatment-emergent adverse events (TEAEs), and changes in vital signs and laboratory measures. The primary efficacy measure was the Brief Pain Inventory average pain severity score.Results: The percentage of patients entering and completing the extension phase was 56% (156/278) for Study 1 and 69% (140/204) for Study 2. Groups titrating from placebo to duloxetine showed the highest discontinuation rates due to an adverse event (Study 1, 25%; Study 2, 19%) and TEAE rates (Study 1, 82%; Study 2, 77%). The most common TEAEs were nausea and dry mouth. No significant within-group changes in blood pressure occurred in any group. Significant within-group mean increases in pulse (bpm) were observed in the placebo/duloxetine 120 mg group in Study 1 (3.7 [SD = 11.2], P ≤ 0.01) and the placebo/duloxetine 60 mg group in Study 2 (4.8 [SD = 10.2], P ≤ 0.001). Most treatment groups showed small mean change improvements in the Brief Pain Inventory average pain severity score.Conclusions: These findings support a positive risk/benefit profile for duloxetine in the long-term treatment of fibromyalgia.

The Pathophysiologic Role of Monocytes and Macrophages in Systemic Lupus Erythematosus: A Reappraisal - Corrected Proof

Christina G. Katsiari, Stamatis-Nick C. Liossis, Petros P. Sfikakis — 2009-01-16

Objectives: To review current developments, regarding the pathophysiologic role of monocytes and macrophages in systemic lupus erythematosus (SLE).Methods: We searched Medline for articles written in the English language using the following terms: monocyte(s) or macrophage(s) and lupus. Although our search spanned the years 1971 to 2008, the majority of the short-listed articles belonged to the period 2000 to 2008. Published literature on phenotypic and functional properties of monocytes/macrophages (Mo/Mφ) in SLE was reviewed. References from identified articles were also selected. Currently available experimental data and their relevance to the pathogenesis of SLE are critically discussed.Results: It has traditionally been held that impaired phagocytosis by monocytes and macrophages in SLE allows for the accumulation of apoptotic debris leading to a sequel of autoimmune phenomena. Recent paradigms derived from animal models of systemic autoimmunity, however, has broadened our understanding regarding the possible pathophysiologic roles of Mo/Mφ in SLE. Data derived from studies in patients with SLE show multiple aberrations in activation status and secretory functions of circulating and tissue-infiltrating Mo/Mφ. Such aberrations may be associated with dysregulation of T-cell function and autoantibody production in SLE. Moreover, emerging evidence suggests that phagocytic capacity and antigen-presenting properties of Mo/Mφ are enhanced in some patients with SLE.Conclusions: While defective phagocytosis represents a distinctive feature of monocyte function in some patients with SLE, aberrant activation of the Mo/Mφ system may be a more appropriate concept to encompass the broad spectrum of Mo/Mφ disorders in SLE. Aberrant function of lupus Mo/Mφ appears to play a dynamic role in the initiation and perpetuation of the systemic autoimmune response and organ damage. Delineation of the altered biology of lupus Mo/Mφ could provide possible future therapeutic targets for patients with SLE.

Sleep as a Marker in the Effective Management of Chronic Osteoarthritis Pain with Opioid Analgesics - Corrected Proof

Dennis C. Turk, Mitchell J.M. Cohen — 2009-01-12

Objectives: Sleep disturbances frequently accompany chronic pain from osteoarthritis (OA), and their effective management may reflect successful treatment of chronic pain. The objective of this article is to provide a rationale for using improvement in sleep as a marker for effective management of chronic OA pain with opioid analgesics. For this purpose, available evidence evaluating the relationship between successful management of chronic pain with opioids and improvements in sleep in patients with OA is reviewed.Methods: We conducted a comprehensive PubMed search to identify studies that systematically measured the impact of opioid treatment on pain and sleep parameters in the context of chronic pain from OA. Our search criteria included publication in a recognized peer-reviewed journal, randomized placebo-controlled design, and assessment of both pain intensity and sleep as outcomes.Results: In each of the 10 placebo-controlled studies identified, concurrent improvements in pain intensity and measured sleep disturbances were observed in patients receiving the long-acting opioid analgesics under study. Improved overall sleep quality, reduced awakenings from pain, and increased duration of sleep were among the favorable changes observed in patients with OA treated with long-acting opioids.Conclusions: Current evidence suggests that various long-acting opioid analgesics simultaneously achieve pain control and improve sleep. However, the complex interaction between reduced pain and improved sleep requires further study.

The Risk of Infections with Biologic Therapies for Rheumatoid Arthritis - Corrected Proof

Daniel E. Furst — 2009-01-05

Objectives: To assess the risk of serious and nonserious bacterial and viral infections associated with the use of biologic therapy (abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab) in patients with rheumatoid arthritis (RA).Methods: Information was derived from PubMed, EMBASE, and the Cochrane clinical trials register and database of systematic reviews and relevant congress abstracts up to and including February 2008.Results: Compared with the general population, patients with RA have a heightened risk of infection, including tuberculosis. Long-term clinical trials and postmarketing studies indicate that anakinra and the tumor necrosis factor (TNF) inhibitors are associated with an increased risk of infections versus conventional disease-modifying antirheumatic drugs (DMARDs), especially early in the course of treatment. The most common sites of infection are the respiratory tract (including pneumonia), skin and soft tissue, and the urinary tract. The risk of tuberculosis also appears higher with TNF inhibitors (in particular, infliximab) versus DMARDs, although this can be reduced by screening and prophylaxis. TNF inhibitors do not appear to significantly increase the risk of reactivating chronic viral infections. Influenza and pneumococcal vaccinations are generally effective in the face of TNF inhibitors or abatacept. Available data suggest that the risk of infections and serious infections with abatacept and rituximab may be similar to that of the TNF inhibitors. To date, there have been no reports from clinical trials of increased tuberculosis or opportunistic infections with abatacept or rituximab.Conclusions: All marketed TNF inhibitors for compared to control RA appear to increase the risk of serious and nonserious infections compared with DMARDs. Although suggestive, data for abatacept and rituximab are less definitive and longer periods of patient exposure to these agents are needed before an assessment of their risks can be made.

Maternal Mixed Connective Tissue Disease and Offspring with Chondrodysplasia Punctata - Corrected Proof

2008-12-25

Objectives: To describe the case of a mother with mixed connective tissue disease (MCTD) whose male and female offspring from 2 successive pregnancies had chondrodysplasia punctata (CDP) in the absence of identifiable biochemical or genetic abnormalities or teratogen exposure.Methods: Description of a male and female offspring from a mother with MCTD harboring high-titer anti-ribonucleoprotein (RNP) antibodies. Maternal autoantibody assays were performed employing quantitative multiplex suspension arrays and flow cytometry, and autoantibody titer and pattern were determined by indirect immunofluorescence. Assays of phytanic acid, plasmalogen, and very long-chain fatty acids were performed employing commercially available reagents. Chromosomal analysis was performed on both offspring employing standard cytogenetic analysis. Review of the relevant literature was performed (PubMed search 1966 through July 2008).Results: Two children with CDP born to a mother with MCTD who harbored anti-RNP autoantibodies at high titer are described. Genetic and chromosomal studies and biochemical analysis of peroxisome function and very long-chain fatty acids excluded known biochemical or genetic defects or mutations as the cause of CDP in these children. Furthermore, detailed review of the clinical history failed to disclose any evidence of maternal teratogen exposure during the 2 pregnancies.Conclusions: Maternal MCTD is the most likely explanation for the occurrence of CDP in the 2 children reported here. Review of previously published cases of CDP associated with autoimmune disease suggests that placental crossing of maternal autoantibodies during pregnancy specifically affecting the normal development of fetal growth plates is responsible for CDP in the offspring in these cases.

Systemic Immune Presentations of Coxiella burnetii Infection (Q Fever) - Corrected Proof

2008-12-25

Objectives: Q fever is a worldwide zoonosis caused by Coxiella burnetii. Its presentation can be atypical, delaying and complicating the diagnosis. We report 7 cases of Q fever mimicking vasculitis, systemic inflammatory disease, or auto-immune disorder.Methods: Seven cases of Q fever diagnosed between 1995 and 2007 in Nantes University Hospital (France) are described. They occurred in a nonendemic region and were selected on the basis of initial clinical presentation suggesting systemic immune disease. C. burnetii was detected using indirect immunofluorescence serology.Results: Q fever was acute in 4 of the 7 patients and chronic in 3. None had endocarditis. The initial presentations suggested Crohn's disease, Goodpasture's syndrome, polymyalgia rheumatica, adult-onset Still's disease, polyarteritis nodosa, giant-cell arteritis, and essential type II cryoglobulinemia. Two patients had antiphospholipid antibodies, 1 had transient IgG kappa monoclonal gammopathy, and 1 had polyclonal T CD8+ large granular lymphocyte expansion.Conclusion: Clinicians must be aware of the potential diagnosis of Q fever, and C. burnetii serology is a helpful diagnostic tool in the investigation of fever of unknown origin with atypical systemic symptoms suggesting vasculitis or inflammatory disease.

Willingness-to-Pay Stated Preferences for 8 Health-Related Quality-of-Life Domains in Psoriatic Arthritis: A Pilot Study - Corrected Proof

Stephanie W. Hu, Elizabeth W. Holt, M. Elaine Husni, Abrar A. Qureshi — 2008-12-19

Objectives: Psoriatic arthritis (PsA) is a seronegative inflammatory arthritis found in up to 5 to 42% of patients with psoriasis. As current instruments do not fully capture health-related quality of life (HR-QOL) in PsA from the patient's perspective, we piloted a novel application of “willingness-to-pay” (WTP) as a Patient Reported Outcome to measure the relative impact of PsA in 8 domains of HR-QOL.Methods: Fifty-nine PsA patients were interviewed on 8 WTP HR-QOL domains (physical, emotional, sleep, work, social, self-care, intimacy, and concentration). Participants were asked to rank the 8 domains of health in order of HR-QOL impact. In each domain, participants were asked whether PsA affected that domain, whether they were willing to pay for a cure in that domain, and the amount they were willing to pay. Median WTP amounts were compared with the proportion of participants affected by and willing to pay in each domain. Responses in US dollars were interpreted as strength of preference rather than absolute monetary values.Results: The majority of participants were white (98%), ≥45 years of age (70%), insured (98%), and earned >$65,000/yr (66%). The physical domain was most affected by PsA; intimacy and concentration were ranked lowest. Participants reported a wide range of WTP amounts ($0 to $1,000,000), and median WTP amounts were highest in the physical, work, sleep, and self-care domains. Related domains elicited median WTP amounts that were highly correlated. No significant differences in median WTP amounts were found across ages, genders, and income levels for the different domains.Conclusions: WTP is a novel quantitative patient-perspective measure that is comprehensible and feasible to administer in PsA patients. It represents a unique tool for capturing the complex manifestations of PsA and its impact on the individual, allowing the quantification of specific HR-QOL parameters and providing the potential for comparison across various disease processes in a given individual.

Wnt Pathway and IL-17: Novel Regulators of Joint Remodeling in Rheumatic Diseases. Looking Beyond the RANK-RANKL-OPG Axis - Corrected Proof

Dimitrios Daoussis, Andrew P. Andonopoulos, Stamatis-Nick C. Liossis — 2008-12-19

Objectives: During the last decade research has focused on the RANK-RANKL-OPG (Receptor Activator of Nuclear factor KappaB-Receptor Activator of Nuclear factor KappaB Ligand-Osteoprotegerin) pathway that is currently considered the final common route to bone and joint remodeling. The potential role of novel additional mediators has been highlighted by several reports. This review focuses on the recent information about the pathophysiology of the Wingless (Wnt) pathway and interleukin-17 (IL-17) in relation of their role in bone and joint remodeling.Methods: An extensive internet search was performed (PubMed) from 1998 and onward using the following keywords: Wnt, bone remodeling, bone, rheumatic diseases, rheumatoid arthritis, IL-17, Th17, osteoblastogenesis, and osteoclastogenesis.Results: Several members of the Wnt pathway play an important role in bone remodeling. Recent experimental data indicate a key role for Dickkopf-1, a soluble inhibitor of the Wnt pathway, in bone remodeling. Increased Dickkopf-1 levels are linked to bone resorption and decreased levels to new bone formation. Low-density lipoprotein receptor-related protein-5, the main receptor that mediates Wnt signaling, plays a critical role in bone mass regulation. Gain-of-function mutations of lipoprotein receptor-related protein-5 cause high bone mass phenotypes, whereas loss-of-function mutations are linked to severe osteoporosis. IL-17 is a proinflammatory cytokine that is produced by a recently described T-cell subset, known as Th17 cells. Evidence suggests that IL-17 is a critical mediator of joint destruction in animal models of arthritis. IL-17 blockade has beneficial effects on murine arthritis, a fact that points to the direction of this cytokine as a potential therapeutic target in human inflammatory arthritides as well.Conclusions: The available data suggest that mediators in these 2 biologic systems are critical in joint remodeling and may be appropriate targets in the treatment of bone and joint abnormalities that characterize a variety of inflammatory arthritides and bone diseases.

Pancreatitis, Panniculitis, and Polyarthritis - Corrected Proof

2008-12-15

Background and Objective: Lobular panniculitis, together with polyarthritis and intraosseous fat necrosis, may occasionally complicate pancreatic disease. This triad is known in the literature as the pancreatitis, panniculitis, and polyarthritis (PPP syndrome). We describe a case of the PPP syndrome and review the available literature to summarize the clinical characteristics of patients with this condition.Methods: A patient with the PPP syndrome, with evidence of extensive intraosseous fat necrosis in the joints involved revealed by magnetic resonance imaging, is described and the relevant literature based on a PubMed search from 1970 to February 2008 is reviewed. The keywords used were pancreatitis or pancreatic disease, panniculitis, arthritis, and intraosseous fat necrosis.Results: Including our case, 25 well-documented patients with the PPP syndrome have been reported. Our patient had few abdominal symptoms despite high serum levels of pancreatic enzymes. In our review of the literature, almost 2/3 of patients had absent or mild abdominal symptoms, leading to misdiagnosis. The delay in diagnosis and specific treatment of the underlying pancreatitis worsens the prognosis of this condition, which has a mortality rate as high as 24%.In nearly 45% of the patients, the arthritis follows a chronic course with a poor response to nonsteroidal anti-inflammatory drugs and corticosteroids, and the rapid development of radiographic joint damage.Conclusion: Certain forms of pancreatic disease can very occasionally cause arthritis and panniculitis. Although uncommon, physicians should be alert to the possible presence of this syndrome for 2 reasons: first, unrecognized pancreatic disease can be fatal if not treated promptly; second, to avoid inappropriate and risky therapy to improve joint symptoms.

Amyloidosis—Recent Developments - Corrected Proof

Tom Pettersson, Yrjö T. Konttinen — 2008-11-20

Objectives: To describe the clinical presentation, diagnosis, classification, grading, evaluation of prognosis, and treatment of amyloidosis against the background of its pathomechanisms.Methods: PubMed and MEDLINE databases (1990 to October 2007) and internet were searched for the key word amyloidosis and evaluated on the basis of the authors' own clinical experience and work on the topic.Results: A clinical suspicion of amyloidosis arises when a patient with a chronic inflammatory disease, plasma cell dyscrasia, or a family history of hereditary amyloidosis develops “an amyloid syndrome” or more rare but specific signs. Microscopy of Congo red stained tissue specimens under polarized light shows birefringent amyloid, which is typed by identification of the amyloid precursor by immunohistochemistry, amino acid sequencing, or proteomics. The diagnosis can be supported by genetic tests. Amyloidosis now covers biochemically and clinically 27 distinct types in man and 9 in animals. Grading to mild, moderate, and severe disease based on laboratory tests and radiology is introduced. Prognosis is affected by the rate of synthesis and the concentration of the circulating precursor. Accurate diagnosis of the underlying disease is mandatory as the treatment is based on disease control and inhibition of amyloid precursor production. Organ-specific treatment, such as transplantation, hemodialysis, treatment of heart failure, pacemakers, and substitution to prevent nutritional deficiencies, is often needed.Conclusions: As our knowledge of the pathogenesis of amyloidosis and the structure–function relationship of amyloid proteins increases, new therapies will be developed to prevent protein misfolding and aggregation, inhibit fibrillogenesis, and enhance clearance of amyloid.

Nailfold Capillary Microscopy in Adults with Inflammatory Myopathy - Corrected Proof

2008-11-20

Objectives: To study the presence and characteristics of nailfold capillary changes in a cohort of adult patients with inflammatory myopathies, determine correlations with disease activity and severity, and investigate any relationship between capillary findings and the immunological or clinical characteristics of the groups.Methods: Fifty-three consecutive adult patients followed in our outpatient clinic were evaluated using a Wild M3 stereomicroscope with an Intralux 5000 Volpi cold light lamp. A semiquantitative rating scale was used to score capillaroscopy changes. Disease activity and severity were assessed with the Myositis Disease Activity Assessment Tool and Myositis Damage Index, respectively. Associations between capillaroscopy findings and other factors were calculated with the χ2 and Mann–Whitney U tests. Serum autoantibody profile was determined in all patients.Results: Twenty-three patients (43%) showed relevant capillaroscopy changes. No significant association was observed between the number of capillaroscopy alterations and the clinical or immunological groups, or disease duration. Disease activity and severity were both significantly associated with a larger number of capillaroscopy findings (P < 0.05). The combination of microhemorrhages and capillary enlargement was significantly more frequent in patients with dermatomyositis (OR, 8.9; 95% CI, 1.8-45.2), and a characteristic capillaroscopy pattern was associated with paraneoplastic myositis (OR, 14.7; 95% CI, 2.0-106.4). Interstitial lung disease significantly correlated with higher capillary score (OR, 3.7; 95% CI, 1.1-13.0).Conclusions: Nailfold microcirculation as determined by semiquantitative simple capillaroscopy appears to provide useful information in patients with idiopathic inflammatory myopathy, contributing to an early diagnosis and identifying patients with a poor prognosis.

Thymic Hassall's Corpuscles, Regulatory T-Cells, and Rheumatoid Arthritis - Corrected Proof

Jean-Marie Berthelot, Benoît le Goff, Yves Maugars — 2008-10-30

Objective: To review evidence for the involvement of thymic Hassall's corpuscles (HC) in the pathogenesis of rheumatoid arthritis (RA).Methods: We used PubMed to search for articles dedicated to the involvement of HC and regulatory T-cells (Tregs) in the pathogenesis of RA, and articles on thymic B-cells.Results: Tregs are central players mediating tolerance to self. The functional defects in Tregs observed in patients with active RA may contribute to RA pathogenesis, promoting the premature immunosenescence of T-cells. This may partly explain the persisting expansion of CD4+ effector T-cell clones in peripheral blood, as well as the parallel improvement of RA activity and numbers of Tregs observed in the third trimester of pregnancy. HC play a major role in the selection of natural Tregs in the thymus, potentially altering the peripheral Tregs repertoire. The promiscuous expression of tissue-specific antigens by thymic medullary epithelial cells shapes the repertoire of natural Tregs. Thus, the presence of 2 major RA autoantigens (immunoglobulins and filaggrin) in the cytoplasm of normal human HC is puzzling, particularly given that thymic B-cells are also concentrated around HC, where CD55 (DAF) and CD59 are strongly expressed. Defects in HC could alter the repertoire of thymic B-cells and Tregs in RA patients, promoting the onset of this disorder.Conclusion: The identification of other joint-specific antigens, like gp-39, in HC and medullary epithelial cells, would provide new insights into the mechanisms of RA pathogenesis and may lead to more specific and physiologic methods of immunomodulation.