Chronic Inflammatory Arthritides Research Articles

Lyme arthritis: linking infection, inflammation and autoimmunity.

Infectious agents can trigger autoimmune responses in a number of chronic inflammatory diseases. Lyme arthritis, which is caused by the tick-transmitted spirochaete Borrelia burgdorferi, is effectively treated in most patients with antibiotic therapy; however, in a subset of patients, arthritis can persist and worsen after the spirochaete has been killed (known as post-infectious Lyme arthritis). This Review details the current understanding of the pathogenetic events in Lyme arthritis, from initial infection in the skin, through infection of the joints, to post-infectious chronic inflammatory arthritis. The central feature of post-infectious Lyme arthritis is an excessive, dysregulated pro-inflammatory immune response during the infection phase that persists into the post-infectious period. This response is characterized by high amounts of IFNγ and inadequate amounts of the anti-inflammatory cytokine IL-10. The consequences of this dysregulated pro-inflammatory response in the synovium include impaired tissue repair, vascular damage, autoimmune and cytotoxic processes, and fibroblast proliferation and fibrosis. These synovial characteristics are similar to those in other chronic inflammatory arthritides, including rheumatoid arthritis. Thus, post-infectious Lyme arthritis provides a model for other chronic autoimmune or autoinflammatory arthritides in which complex immune responses can be triggered and shaped by an infectious agent in concert with host genetic factors.

Environmental Air Pollution Is a Predictor of Poor Response to Biological Drugs in Chronic Inflammatory Arthritides.

BackgroundThere is increasing evidence that environmental air pollution is associated with the development of chronic inflammatory arthritides (CIA). The role of air pollutants on the biological treatment (biological disease‐modifying antirheumatic drugs [bDMARDs]) response of CIA is still unclear.MethodsWe retrieved longitudinal data on patients affected by CIA on biological therapies and on the daily concentration of air pollutants in the Verona area. We designed a case‐crossover study to compare the exposure to pollutants in the 60‐day period preceding a drug switch or swap due to disease progression referent to the 60‐day period preceding a visit with stable treatment for at least 6 months.ResultsA total of 1257 patients with CIA (863 with rheumatoid arthritis, 256 with psoriatic arthritis, and 138 with ankylosing spondylitis) with 5454 follow‐up visits were included in the study (median follow‐up 2.09 years [interquartile range: 0.82‐2.58 years]). A total of 282 patients were included in the case‐crossover study. We retrieved 13 636 daily air pollution records. We found that air pollutants’ concentrations were higher in the 60‐day period before a failure of bDMARD response and prior to a switch or swap compared with the period preceding a visit with stable bDMARD therapy for at least 6 months.ConclusionWe found that environmental air pollution was a determinant of poor response to bDMARDs in a cohort of patients with CIA followed over a 5‐year period. An intervention aimed at decreasing fossil combustion emissions might have beneficial effects on biologic persistence rates of patients with CIA and economic expenditures related to switches and swaps.

Is central sensitization an important determinant of functional disability in patients with chronic inflammatory arthritides?

Background:Central sensitization (CS) is a condition characterized by a disproportionate response to pain stimuli. We sought to investigate the prevalence of CS in patients with inflammatory arthritides and its association with measures of disease activity and functional disability.Methods:We conducted an observational retrospective study in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) patients. We administered to all the subjects in the study the CS inventory (CSI), a questionnaire that has been used for the diagnosis of CS. Demographic and clinical characteristics were collected as well as measures or disease activity [i.e. Simple Disease Activity Index, Disease Activity Score in PsA (DAPSA)] and functional disability [Health Assessment Questionnaire Disability Index (HAQ-DI)]. Patients with fibromyalgia were excluded from the analyses. The primary outcome measure was the presence of functional disability as assessed by HAQ-DI >1.Results:We enrolled 150 patients with inflammatory arthritides (78 PsA and 72 RA). Prevalence of CS was observed in 35.3% of the overall sample (29% in RA, 42.9% in PsA). Binary logistic regressions showed a strong, independent and linear association between functional disability and CS in both PsA and RA patients. The strength of this association was greater in PsA than in RA.Conclusion:CS is an important determinant of functional disability in patients with chronic inflammatory arthritides. PsA appeared to be more vulnerable to CS. In addition, in the presence of CS, DAPSA did not adequately capture the occurrence of functional disability. Therefore, special attention should be paid to PsA patients, in whom the concomitant diagnosis of CS should be routinely ruled out.

Ixekizumab for treating ankylosing spondylitis.

Axial spondyloarthritis (axSpA) is an umbrella term that includes ankylosing spondylitis and nonradiographic axSpA. Presence or absence of definitive sacroiliitis on radiographs differentiates ankylosing spondylitis (also called radiographic axSpA) from nonradiographic axSpA. There is growing evidence that indicates IL-17 pathway is a key contributor to the pathogenesis of axSpA. Ixekizumab (IXE) is an IL-17A inhibitor (IL-17i) with data to support its use in patients with radiographic axSpA. The pharmacologic properties of IXE were reviewed. Data regarding the use and efficacy of IXE in patients with radiographic axSpA were evaluated. Quality life outcomes and safety profiles of IXE were examined as well. By comparison with other chronic inflammatory arthritides, the number of targeted treatment options for axSpA is currently limited to tumor necrosis factor inhibitor (TNFi) and IL-17i secukinumab. IXE has good evidence of improved outcomes in terms of clinical efficacy, patient reported outcomes and imaging outcomes, with an acceptable safety profile in patients with radiographic axSpA. The current results discussed in this article support use of IXE as a treatment option for TNFi naive as well as in subjects with prior inadequate response to or intolerance to TNFi agents.

Clinical Applications of Synovial Biopsy.

The synovial tissue is a primary target of multiple diseases characterized by different pathogenic mechanisms, including infective, deposition, neoplastic, and chronic immune-inflammatory pathologies. Synovial biopsy can have a relevant role in differential diagnosis of specific conditions in clinical practice, although its exploitation remains relatively limited. In particular, no validated synovial-tissue-derived biomarkers are currently available in the clinic to aid in the diagnosis and management in most frequent forms of chronic inflammatory arthropathies, namely rheumatoid arthritis (RA) and the spondyloarthritides (SpA). In this brief review, we will discuss the current spectrum of clinical applications of synovial biopsy in routine rheumatologic care and will provide an analysis of the perspectives for its potential exploitation in patients with chronic inflammatory arthritides.

Histopathology of the synovial tissue: perspectives for biomarker development in chronic inflammatory arthritides.

The histopathological and molecular analysis of the synovial tissue has contributed to fundamental advances in our comprehension of arthritis pathogenesis and of the mechanisms of action of currently available treatments. On the other hand, its exploitation in clinical practice for diagnostic or prognostic purposes as well as for the prediction of treatment response to specific disease-modifying anti-rheumatic drugs is still limited. In this review, we present an overview of recent advances in the field of synovial tissue research with specific reference to the methods for synovial tissue collection, approaches to synovial tissue analysis and current perspectives for the exploitation of synovial tissue-derived biomarkers in chronic inflammatory arthritides.

The danger from within: alarmins in arthritis.

Alarmins (also known as danger signals) are endogenous molecules that are released to the extracellular milieu after infection or tissue damage. Extracellular alarmins interact with specific receptors expressed by cells that are engaged in host defence to stimulate signalling pathways that result in initiation of innate and adaptive immune responses, triggering inflammation or tissue repair. Alarmins are considered to be markers of destructive processes that occur in degenerative joint diseases (primarily osteoarthritis (OA)) and chronic inflammatory joint diseases (such as rheumatoid arthritis, psoriatic arthritis and spondylarthropathy). In OA, high mobility group protein B1 (HMGB1) and S100 proteins, along with many other alarmins, are abundantly secreted by joint cells, promoting cartilage matrix catabolism, osteophyte formation, angiogenesis and hypertrophic differentiation. The involvement of alarmins in chronic inflammatory arthritides is suggested by their presence in serum at high levels in these conditions, and their expression within inflamed synovia and synovial fluid. S100 proteins, HMGB1, IL-33 and other endogenous molecules have deleterious effects on joints, and can recruit immune cells such as dendritic cells to inflamed synovia, initiating the adaptive immune response and perpetuating disease. Improving our understanding of the pathological mechanisms associated with these danger signals is important to enable the targeting of new therapeutic approaches for arthritis.

AB1317 The effect of biological agents on participation in paid work in patients with chronic inflammatory arthritides: A meta-analysis of randomized controlled trials

BackgroundThe addition of biological agents in treatment strategies in chronic inflammatory arthritides have improved the possibility of controlling disease activity and slowing the progression of joint damage. However their impact...

Parity in patients with chronic inflammatory arthritides childless at time of diagnosis

Objective: To assess parity in women with chronic inflammatory arthritides (CIA) childless at time of diagnosis.Methods: Patients were selected from the Norwegian Disease-Modifying Anti-Rheumatic Drug (NOR-DMARD) registry. Each patient was matched by year of birth with 100 reference women from the Norwegian Population Registry. Data linkage for patients and references with the Medical Birth Registry of Norway (MBRN) identified all offspring until time of linkage (October 2007). Patients and corresponding references childless at the time of diagnosis were included in the analyses. Kaplan–Meier curves visualized the proportion of childless women and were compared by a log rank test.Results: In all, 156 rheumatoid arthritis (RA), 107 other chronic arthritides (OCA), and 75 juvenile idiopathic arthritis (JIA) patients were childless at time of diagnosis. At the time of data linkage, the proportions (%) of childless RA/OCA/JIA patients versus references were 61.5/62.6/57.3 versus 46.9/42.9/41.0, respectively, all differences statistically significant. The log rank test showed lower parity in all diagnostic groups compared with references (p < 0.001 for RA and OCA and p = 0.002 for JIA). No difference in parity was observed between RA and OCA patients, but both diagnostic groups had lower parity than JIA patients (p = 0.001). Disease characteristics were similar between childless and fertile patients.Conclusions: Reduced parity was observed in all diagnostic groups compared with references. RA and OCA patients had lower parity than JIA patients, indicating that having the disease as a young adult may influence parity more than having the disease in childhood.

Pregnancy and delivery in women with chronic inflammatory arthritides with a specific focus on first birth

To examine possible associations between chronic inflammatory arthritides and pregnancy outcomes with separate analyses of first and subsequent births before and after diagnosis. Linkage of data from a registry of patients with chronic inflammatory arthritides and the Medical Birth Registry of Norway enabled a comparison of pregnancy outcomes in women with chronic inflammatory arthritides and pregnancy outcomes in reference subjects. Outcomes of first birth and subsequent births before and after diagnosis were analyzed separately. Associations between chronic inflammatory arthritides and the women's health during pregnancy and delivery as well as perinatal outcomes were assessed in logistic regression analyses with adjustments for maternal age at delivery and gestational age. We analyzed 128 first births and 151 subsequent births after diagnosis and 286 first births and 262 subsequent births before diagnosis in patients and compared them with first and subsequent births in reference subjects. Firstborn children of women diagnosed as having chronic inflammatory arthritides were more often preterm (odds ratio [OR] 1.85 [95% confidence interval (95% CI) 1.09-3.13]) and small for gestational age (OR 1.60 [95% CI 1.00-2.56]). They also had lower mean birth weight (P=0.01) and higher perinatal mortality (OR 3.26 [95% CI 1.04-10.24]). Birth by caesarean section (all classifications) was more frequent in patients than in reference subjects, and elective caesarean section was 2-fold more frequent in patients, both in first birth (OR 2.60 [95% CI 1.43-4.75]) and in subsequent births (OR 2.18 [95% CI 1.33-3.58]). No excess risks of clinical importance were observed prior to diagnosis of chronic inflammatory arthritides. Excess risks were related to first birth in women diagnosed as having chronic inflammatory arthritides, including a higher rate of perinatal mortality. A higher caesarean section rate was related to all patient deliveries. Mainly, pregnancy outcomes before diagnosis did not differ from those in reference subjects.

Fertility in women with chronic inflammatory arthritides

To compare fertility rates in women with RA, other chronic arthritides (OCAs) and JIA with reference women from the general population. Each woman from a Norwegian patient registry was matched by year of birth with 100 reference women randomly selected from the National Population Registry. Data linkage of patients and references with the Medical Birth Registry of Norway (MBRN) identified all offspring in patients and references until October 2007, and indirectly also nulliparous (childless) women. Groups were compared with Mann-Whitney U-test for continuous variables and chi-squared tests for categorical variables. Poisson regression analysis was applied to calculate relative fertility rates in the diagnostic groups vs references. Among 631 patients 849 children were registered in MBRN. Of these, 289 children (34.0%) were born after time of diagnosis vs 44.3% in references. Altogether, 206 of 631 patients (32.6%) were nulliparous vs 26.4% in references (P < 0.001). Among RA patients, 28.4% (96 of 338) were nulliparous vs 24.5% in references (P = 0.09), 30.7% (67 of 218) in OCA patients vs 24.5% in references (P = 0.03) and 57.3% (43 of 75) in JIA patients vs 40.9% in references (P = 0.004). Adjusted relative fertility rates in RA, OCA and JIA after diagnosis were 0.88, 0.84 and 0.84, respectively, compared with references. A higher proportion of women with chronic inflammatory arthritides were nulliparous compared with references, and relative fertility rates were reduced in all patient groups.

Identification of the major fibroblast growth factors released spontaneously in inflammatory arthritis as platelet derived growth factor and tumour necrosis factor-alpha

Rheumatoid arthritis is characterized by chronic inflammation and proliferation of a number of important elements within the joint including the synovial fibroblasts. Elevated levels of a number of cytokines such as Il-1, IL-2, IL-6, interferon-gamma (IFN-gamma), transforming growth factor-beta and tumour necrosis factor-alpha (TNF-alpha) have been detected in the synovial fluid of patients with rheumatoid arthritis and other inflammatory arthritides. It seems likely that local release of such mediators may be responsible for the proliferation and overgrowth of connective tissue elements in these disorders. In order to ascertain whether there was evidence to suggest local production or release of fibroblast growth factors in the joint in inflammatory arthritis, and to determine their identity, cells were obtained from the synovial fluid of 15 patients with chronic inflammatory arthritides. All subjects' synovial fluid cells spontaneously released growth factor activity for fibroblasts. This was present in large amounts, being detectable in culture supernatants diluted to a titre of at least 1/625. By a series of depletion experiments using solid-phase bound antibodies to cytokines, it was possible to demonstrate that this activity was due to TNF-alpha and platelet-derived growth factor (PDGF). Thus, this study showed for the first time that functionally active PDGF was released from synovial fluid cells. Both PDGF and TNF-alpha appeared to contribute in approximately equal amounts to this fibroblast growth factor activity, and were synergistic in effect. Thus this study provides evidence for the local production and release of these two cytokines and suggests that together they are the dominant factors in fibroblast proliferation within the synovial cavity.

Mycobacterium kansasii tenosynovitis in a rheumatoid arthritis patient with long‐term therapeutic immunosuppression

Introduction Atypical or nontuberculous mycobacteria are normal commensals of water, soil, dust, and cattle milk. Human infections are relatively uncommon, but an increasing number of cases have been reported in the context of human immunodeficiency virus (HIV) or therapeutic immunosuppression (1). Mycobacterium avium complex and Mycobacterium kansasii account for most episodes of nontuberculous systemic diseases. Besides many reports of patients with HIV, there are only rare published examples of patients with chronic inflammatory arthritides under immunosuppression therapy. Most of these reports describe Mycobacterium marinum infections (2–4). In the last 7 years, there have been only a few reports of M kansasii infections in patients with chronic inflammatory rheumatic diseases (5–11). Nakamura et al (8) collected references on 11 patients from the literature since 1963. Bernard et al (9) described a French retrospective study of 26 patients from their own clinic and the literature who had M kansasii septic arthritis and no underlying disease. This indicates that, overall, this infectious complication is very rare. However, the incidence might increase as we tend to use more aggressive immunosuppressants (especially tumor necrosis factor inhibitors) with a more relevant impact on the immune system. Moreover, with better diagnostic possibilities and better awareness of the necessity of an aggressive treatment, immunosuppression therapy will start much earlier. We report a patient with long-lasting seronegative rheumatoid arthritis and a more recent local tenosynovitis. We identified a local M kansasii infection as the cause for the tenosynovitis on the basis of a positive bacterial culture result. AlthoughM kansasii is second only toM avium complex as the causative agent of nontuberculous lung disease, which often involves the upper lobe, it is rarely identified as a cause of extrapulmonary infection, especially arthritis or tenosynovitis. The infection primarily infects the lungs with rare precipitation in joints, tendons, or bone (9,12). When affecting the joints, monarthritis is usually erosive (11,13). Infections with M kansasii are environmentally acquired. It has been isolated from tap water in the warm southern US states (Texas), where it can survive for up to 12 months (14,15).

PRODUCTION OF INTERLEUKIN (IL)-1β, IL-1 RECEPTOR ANTAGONIST AND IL-10 BY BLOOD MONONUCLEAR CELLS IN CHRONIC ARTHRITIS

Joint erosion is a prevalent feature of rheumatoid arthritis (RA) but not of many other chronic inflammatory arthritides (non-RA). Joint destruction is mediated by cytokines, primarily interleukin (IL)-1 and tumour necrosis factor. Less erosive activity in patients with non-RA compared to RA might be related to factors that inhibit production and/or function of IL-1. Release of IL-1β, and the two antagonists, IL-1 receptor antagonist (IL-1ra) and IL-10 from blood mononuclear cells were therefore quantitated by ELISA in 22 patients with RA, 11 with non-RA and 15 healthy age-matched controls. Release of IL-1β was comparable between the three groups but only detectable in cultures stimulated with lipopolysaccharide; it decreased in patients treated with prednisolone: 3.8ng/106monocytes (median) vs 11.7 (P=0.045). Release of IL-1ra was in all but IgG-stimulated cultures comparable between groups. The ratio of IL-1ra/IL-1β was elevated in LPS-stimulated cells from RA patients only: 2.0 versus 1.3 (P=0.02). In contrast, IgG-induced IL-1ra release was significantly elevated only in non-RA patients: 95ng/106monocytes vs 40 (P=0.014), and the levels correlated positively to those of blood CRP (P=0.02). Though stimulated release of IL-10 was similar between the three groups, the levels were lower in non-erosive than erosive arthritis patients, and controls (P=0.05). In conclusion, increased IgG-stimulated IL-1ra release and elevated IL-1ra/IL-1β ratio may protect against actions of IL-1 in vivo, and decreased release of IL-10 might be related to features of non-erosive arthritis.

Chronic arthritis in children.

Chronic inflammatory arthritides in children include a wide range of various diseases. One of the main concerns of physicians who treat these disorders is the risk of permanent physical disability resulting from joint damage. Actual classification relies mainly on clinical features, particularly the number of joints affected at onset, although the general feeling is that chronic childhood arthritis exists in many different entities gathered together under the common names juvenile chronic arthritis or juvenile rheumatoid arthritis. The past 2 years were rather fertile in debates for proposing a progression for more objectivity in nomenclature, which was the theme of the Pediatric Rheumatology Study Group session at the American College of Rheumatology annual meeting held in Atlanta in 1992. The viewpoints from North America and Europe addressed at this meeting were published in a supplement of the Journal of Rheumatology in 1993. A debate on this topic was also organized at the International League Against Rheumatism Congress held in Barcelona in 1993. At present, the main criteria rely on clinical experience and natural history of the diseases and on biology and immunogenetics. Another important concern among pediatric rheumatologists is efficacy of treatment. Questions include, "Are we doing enough?" and "How safe are the therapeutic strategies?" In this review some of the recent studies that may be important for classification and nomenclature and therapy and management are discussed.

Exercise, injury and chronic inflammatory lesions.

The increasing frequency of injury over the last two decades reflects the activities of a more exercise conscious public. However, all too often injury may be due to ill-advised or inappropriate exercise and can be prevented by relatively simple modification of technique, equipment or gait abnormalities. Nevertheless, many injuries may simply reflect overtraining and the effects of repetitive strain on soft tissue and bony structures. This has led to an urgent need to understand better the mechanisms of injury, the importance of chronic inflammation and the factors involved in recovery of soft tissue strength. In the case of injuries to tendons or ligaments it is often difficult to define the contribution to symptomatology of collagen breakdown or chronic inflammation as a response to this. Furthermore, radiological changes at tendon and ligament attachments (entheses) through overuse can be indistinguishable from chronic inflammatory conditions such as spondarthritis, adding weight to the view that the body has a limited number of ways in which it can react to a variety of chronic stimuli. Marathon runners or footballers, for example, may develop symphysitis through chronic loading and radiologically there may be apparent erosive changes. Rheumatologists, dealing primarily with the chronic inflammatory arthritides, are beginning to understand better the factors involved in chronic inflammation and the effects of exercise. The Sports Physician must equally be aware of some of the pitfalls of misdiagnosis because of the masquerading of some primary inflammatory conditions as soft tissue injury or 'traumatic' joint effusion. This article will therefore review advances in current understanding of the influence of exercise on chronic inflammation and on recovery of tissue strength in sporting injuries. Improving understanding should lead to more defined rehabilitation programmes and a reduction in the all too common reinjury cycle.

Serum lipoprotein in active rheumatoid arthritis and other chronic inflammatory arthritides. II. Effects of anti-inflammatory and disease-modifying drug treatment

Serum lipoprotein in active rheumatoid arthritis and other chronic inflammatory arthritides. II. Effects of anti-inflammatory and disease-modifying drug treatment

Proinflammatory Microbial Products as Etiologic Agents of Inflammatory Arthritis

Muramyl peptides, peptidoglycans, peptidoglycan-polysaccharide complexes, and endotoxins are examples of proinflammatory microbial components that may play an etiologic role in various chronic inflammatory arthritides in humans. This article reviews the data supporting this hypothesis. The biologic activities of these substances are discussed, with particular emphasis on the mechanisms by which they induce various forms of arthritis in experimental animals. In addition, the current status of studies attempting to demonstrate definitively a role for these agents in human disease also is discussed.

Human interleukin 1 mediates cartilage matrix degradation

Human monocyte factors mediate cartilage matrix degradation by activation of the resident chondrocytes. In the present work, the cartilage matrix-degrading activity of partially purified human monocyte-derived interleukin 1 has been investigated. Human monocyte or blood mononuclear cell culture supernatants were sequentially purified by phenyl-Sepharose and gel filtration chromatography, or by gel filtration chromatography, isoelectric focusing, or chromatofocusing. Column fractions were simultaneously tested by the standard method that defines interleukin 1 activity—costimulation of mouse thymocyte proliferation—and for matrix macromolecule release from living bovine cartilage expiants in organ culture. The two activities showed identical profiles in purification steps that would discriminate according to molecular size, hydrophobicity, and net charge. Moreover, the thermal denaturation profiles of the material purified by chromatofocusing could not distinguish between thymocyte proliferating and matrix degrading activities. These results suggest that interleukin 1 which is present in inflammatory synovial fluids may play an important role in the mediation of cartilage damage in chronic inflammatory arthritides.