Extra-articular Sites Research Articles

Impacts of Porphyromonas gingivalis periodontitis on rheumatoid arthritis autoimmunity.

In RA patients' synovial sites, citrullinated RA-related antigens such as type II collagens, fibrin (ogen), vimentin, and α-enolase could be targeted by ACCPAs. Since ACCPA production can be initiated a long time before RA sign appearance, primary auto-immunization against these citrullinated proteins can be originated from extra-articular sites. It has been shown that there is a significant association between P. gingivalis periodontitis, anti- P. gingivalis antibodies, and RA. P. gingivalis gingipains (Rgp, Kgp) can degrade proteins such as fibrin and α-enolase into some peptides in the form of Arg in the C-terminal which is converted to citrulline by PPAD. Also, PPAD can citrullinate type II collagen and vimentins (SA antigen). P. gingivalis induces inflammation and chemoattraction of immune cells such as neutrophils and macrophages through the increase of C5a (gingipain C5 convertase-like activity) and SCFA secretion. Besides, this microorganism stimulates anoikis, a special type of apoptosis, and NETosis, an antimicrobial form of neutrophil death, leading to the release of PAD1-4, α-enolase, and vimentin from apoptotic cells into the periodontal site. In addition, gingipains can degrade macrophages CD14 and decrease their ability in apoptotic cell removal. Gingipains also can cleave IgGs in the Fc region and transform them into rheumatoid factor (RF) antigens. In the present study, the effects of P. gingivalis on rheumatoid arthritis autoimmune response have been reviewed, which could attract practical insight both in bench and clinic.

The forgotten key players in rheumatoid arthritis: IL-8 and IL-17 - Unmet needs and therapeutic perspectives.

Despite the relevant advances in our understanding of the pathogenetic mechanisms regulating inflammation in rheumatoid arthritis (RA) and the development of effective therapeutics, to date, there is still a proportion of patients with RA who do not respond to treatment and end up progressing toward the development of joint damage, extra-articular complications, and disability. This is mainly due to the inter-individual heterogeneity of the molecular and cellular taxonomy of the synovial membrane, which represents the target tissue of RA inflammation. Tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) are crucial key players in RA pathogenesis fueling the inflammatory cascade, as supported by experimental evidence derived from in vivo animal models and the effectiveness of biologic-Disease Modifying Anti-Rheumatic Drugs (b-DMARDs) in patients with RA. However, additional inflammatory soluble mediators such as IL-8 and IL-17 exert their pathogenetic actions promoting the detrimental activation of immune and stromal cells in RA synovial membrane, tendons, and extra-articular sites, as well as blood vessels and lungs, causing extra-articular complications, which might be excluded by the action of anti-TNFα and anti-IL6R targeted therapies. In this narrative review, we will discuss the role of IL-8 and IL-17 in promoting inflammation in multiple biological compartments (i.e., synovial membrane, blood vessels, and lung, respectively) in animal models of arthritis and patients with RA and how their selective targeting could improve the management of treatment resistance in patients.

FDG PET/CT Imaging of Severe Polymyalgia Rheumatica.

A 68-year-old woman was referred for an 18F-FDG PET/CT for evaluation of arthralgia and raised inflammatory markers, which demonstrated intense FDG activity (SUVmax, 25.5) at numerous periarticular and extra-articular sites including the cervical and lumbar interspinous bursae, lumbar facet joints, bilateral ischial tuberosities, and greater trochanters and the aorta consistent with active polymyalgia rheumatica.

Splinting Rheumathoid Hand Deformities: A Case Report

Rheumatoid arthritis (RA) is a disease of unknown origin characterized by inflammatory changes in the synovial tissue of joints, cartilage and bone, and less frequently in extra-articular sites. The rheumatoid hand, the term used to describe the characteristic deformities of the hands of patients with RA, typically includes varying degrees of thumb deformity, finger deformities, and ulnar deviation. One of the many treatment approaches in RA hand deformities is the splinting approach. In this case, the results of splinting applied to hand deformities in a patient with RA are presented.

Early Spondyloarthritis Clinic: Organizational Improvements in the Patient Journey.

Spondyloarthritis are chronic inflammatory diseases affecting spine, peripheral joints and enthesis, as well as extra-articular sites (bowel, eyes, skin). Diagnosis of spondyloarthritis often is slow and requires a multidisciplinary approach. The “Early SpA Clinic” project aimed at improving the patient care and journeys, by solving some organizational issues existing in Rheumatology Clinics. The “Early SpA Clinic” involved 19 Italian Rheumatology Centers using in-depth organizational analyses to identify areas for improvement. From the results of the analyses, some organizational solutions were suggested, and their impact measured at the end of the project through specific KPI. With the implementation of the suggested organizational solutions, Centers achieved relevant results, positively impacting on all the phases of the patient journey: decrease in waiting lists (−23%) and in the time length to transit the Center (−22%), increase in the percentage of new diagnoses (+20%), in the saturation of outpatient clinic capacity (+16%), and in the patient satisfaction (+4%). Centers involved in the “Early SpA Clinic” implemented several organizational actions based on an overall assessment of their activities and on solutions that required no additional resources. Overall, the Centers achieved the “Early SpA Clinic” objectives in terms of better management of resources, personnel, spaces, equipment, in relation to the volumes of patients.

Urate Crystals; Beyond Joints.

Gout is the most common inflammatory arthropathy caused by the deposition of monosodium urate (MSU) crystals. The burden of gout is substantial with increasing prevalence of gout globally. The prevalence of Gout in the United States has increased by over 7% in the last two decades. Initially, it was believed that MSU crystal deposits occur only in the joints with the involvement of the periarticular soft tissues, but recent studies have shown the presence of MSU crystal deposition in extra-articular sites as well. Human plasma becomes supersaturated with uric acid at 6.8 mg/dl, a state called hyperuricemia. Beyond this level, uric acid crystals precipitate out of the plasma and deposit in soft tissues, joints, kidneys, etc. If left untreated, hyperuricemia leads to chronic gout characterized by the deposition of tophi in soft tissues such as the joints, tendons, and bursae. With the advent of newer imaging techniques such as DECT, MSU crystals can be visualized in various extra-articular sites. Extra-articular deposition of MSU crystals is believed to be the causative factor for the development of multiple comorbidities in gout patients. Here, we review the literature on extra-articular deposition of urate crystals and the role of dual-energy computed tomography (DECT) in elucidating multi-organ involvement. DECT has emerged as an invaluable alternative for accurate and efficient MSU crystal deposition detection. Future studies using DECT can help determine the clinical consequences of extra-articular deposition of MSU in gout patients.

Heel fat pad involvement in rheumatoid arthritis: a review and case series.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease affecting not only the synovial joints but also multiple extra-articular sites, including ankle and foot soft tissue. Hindfoot abnormalities usually follow those in the forefoot, with up to 4 out of 10 patients experiencing talalgia during their disease course. Enthesophytosis, retrocalcaneal bursitis, and plantar fasciitis are among the most common etiologies, while heel fat pad abnormalities like subcalcaneal bursitis are rare. Here, we report two cases of subcalcaneal bursitis, and the first case of heel fat pad and subcalcaneal bursa herniation in patients with established RA, along with a comprehensive literature review of subcalcaneal bursitis and other heel fat pad abnormalities in RA. Subcalcaneal bursitis, also referred to as panniculitis, inflammatory-edematous lesion, or adventitial (adventitious) bursitis has been reported in up to 10% of patients with RA. It appears as a compressible, heterogeneous, and hypoechoic subcalcaneal mass on ultrasound (US), with peripheral vascularization on Doppler US. Patients may present with heel discomfort. Ultrasonographic assessment is usually sufficient to confirm the presence of heel fat pad pathologies. Rest, analgesics, and mechanical aids with or without addition of disease-modifying antirheumatic drugs are usually employed, while intervention is rarely required.

JAK/STAT Activation: A General Mechanism for Bone Development, Homeostasis, and Regeneration.

The Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway serves as an important downstream mediator for a variety of cytokines, hormones, and growth factors. Emerging evidence suggests JAK/STAT signaling pathway plays an important role in bone development, metabolism, and healing. In this light, pro-inflammatory cytokines are now clearly implicated in these processes as they can perturb normal bone remodeling through their action on osteoclasts and osteoblasts at both intra- and extra-articular skeletal sites. Here, we summarize the role of JAK/STAT pathway on development, homeostasis, and regeneration based on skeletal phenotype of individual JAK and STAT gene knockout models and selective inhibition of components of the JAK/STAT signaling including influences of JAK inhibition in osteoclasts, osteoblasts, and osteocytes.

New developments in ultrasound in rheumatology: innovative tools and promising applications

In the setting of rheumatology, the assessment of the involvement of joints and peri-articular structures was the first application of ultrasonography in the management of rheumatic diseases. In this field, the main novelties are related to the development of new technical tools to help overcome some of the limitations of conventional ultrasonographic assessment. In the meantime, there has been a growing interest in the application of ultrasound to extra-articular sites, relying on the definition of new indications. The present review aims to provide a critical analysis of the technical developments and new fields of application of ultrasonography in rheumatology.

Disseminated cutaneous gout: a rare manifestation of a common disease

Disseminated cutaneous gout is a rare atypical cutaneous manifestation of gout in which widespread dermal and subcutaneous tophi develop at extra-articular body sites. Given the lack of joint involvement that is typically a feature in tophaceous gout, the diagnosis may not be initially suspected. We present the case of a 50-year-old Hispanic man with poorly controlled gout who was evaluated for several years of firm papulonodules over the trunk and upper and lower extremities, sparing the joints; histopathology confirmed, the diagnosis of disseminated cutaneous gout. Per our literature review, disseminated cutaneous gout presents with polymorphous papules and nodules that can mimic other, more common cutaneous diseases. There is a preponderance of cases in males, Asians, and patients with longstanding gout. The lower extremities are involved in nearly all reports. Uric acid-lowering therapy with allopurinol has been reported to decrease the size and number of lesions in a minority of treated patients.

Skin in rheumatoid arthritis and seronegative arthritis

Rheumatoid arthritis is a multisystem inflammatory disorder affecting the joints, soft tissue, as well as extraarticular sites like the skin. Cutaneous manifestations occur in up to 40% cases and vary from specific to nonspecific lesions. Specific changes consist of rheumatoid nodules, neutrophilic dermatoses such as palisaded neutrophilic granulomatous dermatoses, rheumatoid neutrophilic dermatoses, pyoderma gangrenosum, and Sweet's syndrome; nonspecific changes include skin atrophy, wrinkling, palmar erythema, and Raynaud's phenomenon. Seronegative arthritis is a group of chronic inflammatory arthritis, which is typically negative for rheumatoid factor, and is often associated with HLA-B27. There is asymmetric peripheral polyarthritis with sacroiliitis and is often associated with cutaneous, ocular, genitourinary, and gastrointestinal abnormalities. Psoriatic arthritis, reactive arthritis, inflammatory bowel disease-associated arthritis, and ankylosing spondylitis are the major conditions seen in this group.

Beyond the TNF-α Inhibitors: New and Emerging Targeted Therapies for Patients with Axial Spondyloarthritis and their Relation to Pathophysiology.

Axial spondyloarthritis (axSpA) is a complex disease that affects the joints and entheses of axial and peripheral joints, and is associated with inflammation in extra-articular sites such as the gut. Improved knowledge on genetics and immunology has improved treatment options with the availability of treatments targeting tumor necrosis factor-α (TNF-α) and interleukin (IL)-17. However, these agents do not provide clinical benefit for about 40% of patients, and additional therapeutic options are necessary. Theories on pathogenesis includes misfolding of HLA-B*27 during its assembly leading to endoplasmic reticulum stress and autophagy/unfolded protein response (UPR). HLA-B*27 may express free heavy chain on the cell surface, which activates innate immune receptors on T, natural killer, and myeloid cells with pro-inflammatory effects. Activation of UPR genes is associated with increased TNF-α, interleukin-23 (IL-23), IL-17, interferon-γ expression, and expansion of T helper (Th)-17 cells. Certain genotypes of endoplasmic reticulum aminopeptidase (ERAP) 1 and 2 are associated with ankylosing spondylitis (AS) and functionally interact with the HLA-B27 peptidome. Innate immune cells type 3, which express RORγt, regulate expression of IL-17 and IL-22 in T cells. Stimulation of gamma-delta T cells with IL-23 also induces IL-17. Mucosa-associated invariant T cells residing in the gut mucosa express IL-17 in AS patients after stimulation with IL-7. Prostaglandin E2 induces IL-17A independent of IL-23 via IL-1β and IL-6. The pathogenic role of gut inflammation, zonulin and microbiota, which has a different composition in AS patients, remains to be elucidated. This article also includes a comprehensive review on the mechanism of action and efficacy of the biological treatments currently approved for axSpA (TNF-α inhibitors and IL-17 inhibitors) and future targets for treatment (other IL-17 family member (s), Janus kinase, IL-23, and phosphodiesterase 4).

Rheumatoid arthritis and citrullination.

Dysregulated citrullination is a key element that drives the production and maintenance of antibodies to citrullinated proteins, a hallmark in rheumatoid arthritis (RA). This article reviews recent literature on the origin of citrullinated antigens in RA. The study of synovial fluid from patients with RA has provided important insights into the identity of citrullinated proteins that accumulate in the RA joint (the RA citrullinome) and mechanisms that control their generation. Citrullinating enzymes (peptidylarginine deiminases, PADs) are tightly controlled to limit their hyperactivation. Calcium and redox conditions are important regulators of PAD activity. Studies suggest that citrullination is dysregulated both intra- and extracellularly in RA. In neutrophils, host (i.e., perforin and the membrane attack complex) and bacterial (i.e., toxins) pore-forming proteins induce prominent calcium influx, cytolysis, and hyperactivation of PADs. These factors likely drive hypercitrullination in the RA joint and at extraarticular sites of disease initiation, respectively. As oxidizing conditions present in the extracellular environment are known to inactivate PADs, extracellular citrullination in RA probably requires the constant release of active enzymes from dying cells and may be accelerated by autoantibodies that activate PADs.

Inflammatory Joint Disorders and Neutrophilic Dermatoses: a Comprehensive Review.

Rheumatoid arthritis and spondyloarthritis are inflammatory joint disorders with an autoimmune pathogenesis and systemic involvement. The skin is one of the most frequently affected extraarticular sites with a number of manifestations or distinct diseases, including common conditions, such as rheumatoid nodules and psoriasis, and rare diseases like neutrophilic dermatoses. The latter are clinically characterised by polymorphic lesions, including pustules, bullae, abscesses, papules, nodules, plaques and ulcers, and histologically by neutrophil-rich inflammatory infiltrates. Inflammatory joint disorders and neutrophilic dermatoses share a number of pathophysiological features related to their cytokine overexpression profile. Moreover, any organ system can be potentially involved in neutrophilic dermatoses, giving rise to the concept of neutrophilic disease. Among the extracutaneous manifestations of neutrophilic disease, joint involvement is regarded as the most common. It is not associated with erosions and disability and usually responds to treatment for skin involvement, consisting of systemic corticosteroids and, in refractory cases, immunosuppressants or biologics. Arthritis may also be the initial manifestation of rheumatoid arthritis or spondyloarthritis, which has a chronic or recurrent course and requires a continuous treatment with synthetic or biologic disease-modifying anti-rheumatic drugs. If not properly treated, they may be associated with disability and reduced quality of life. Skin lesions occurring during the course of rheumatoid arthritis and spondyloarthritis require a multidisciplinary approach envisaging the collaboration of dermatologists and rheumatologists in order to achieve early diagnosis and treatment. Several biomarkers may help the clinician in the differential diagnosis of arthritis while histology is pivotal for the correct classification of the skin disease. However, in some cases, only regular follow-up allows a definite diagnosis. In this review article, we focus on the prototypic neutrophilic dermatoses like pyoderma gangrenosum, Sweet's syndrome, hidradenitis suppurativa and their syndromic forms as well as on their articular involvement, providing a simple approach for their diagnosis and therapy.

One-stage computer-assisted total knee arthroplasty and tibial osteotomy

Same-stage tibial osteotomy may deserve consideration in candidates to total knee arthroplasty (TKA) who have severe bone deformities, particularly at extra-articular sites. This strategy obviates the need for either a major and technically difficult ligament release procedure, which may compromise ligament balancing, or the use of a semi-constrained prosthesis. This technical note describes a one-stage, computer-assisted technique consisting in TKA, followed by corrective tibial osteotomy to obtain an overall mechanical axis close to 180° without extensive ligament balancing. This technique provided satisfactory outcomes in 8 patients followed-up for at least 3years, with no specific complications or ligament instability and with a hip-knee-ankle angle close to 180°. After planning, intra-operative computer assistance ensures accurate determination of both implant position and the degree of correction achieved by the osteotomy.

Anticitrullinated protein antibodies: origin and role in the pathogenesis of rheumatoid arthritis.

This article reviews recent literature on the origin and pathogenic role of anticitrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA). ACPAs and ACPA-immune complexes interact with immune cells to facilitate articular inflammation. Findings from recent in vitro and in vivo studies are congruent with epidemiologic observations in RA supporting a pathogenic role of ACPAs. ACPAs target proteins/peptides with citrullinated epitopes and serve as informative RA biomarkers. ACPAs are generated within synovium and possibly at extra-articular sites prior to disease onset. Proximate to RA onset, critical qualitative and quantitative changes to ACPAs occur that drive proinflammatory responses. Unable to induce arthritis alone, the administration of ACPAs enhances the development and severity of inflammation in mice when a mild synovitis is already present. In vitro studies have elucidated several possible mechanisms linking ACPA to disease progression including: first, activation of inflammatory cells by ACPA-immune complexes; second, ACPA-mediated neutrophil cell death producing neutrophil extracellular traps, which drives inflammation and autoimmunity by releasing citrullinated autoantigen; and finally, direct binding of ACPAs to osteoclasts and resulting osteoclastogenesis. Together, these recent investigations have begun to elucidate the different mechanisms by which ACPAs may be directly pathogenic in RA.

Ankylosing Spondylitis with Peripheral Neuropathy - A Rare Case Report

Ankylosing Spondylosis (AS) is a chronic inflammatory disorder of joints predominantly affecting the sacroiliac joints and spine. Besides the joints, it affects many extra articular sites like heart, eye, lungs etc. Neurological complication is very rare in AS. Here we report a case of a 30 years old man of AS with peripheral neuropathy.J MEDICINE January 2016; 17 (1) : 36-38

Intra-articular onabotulinumtoxinA in osteoarthritis knee pain: effect on human mechanistic pain biomarkers and clinical pain

Objectives: OnabotulinumtoxinA (onabotA) attenuates peripheral nociceptive transduction and consequently neuronal firing. The aim of this mechanistic study was to evaluate the effect of intra-articular (IA) onabotA in patients with painful knee osteoarthritis (OA).Method: We conducted a double-blind, randomized, placebo-controlled, 12-week trial using a single ultrasound-guided IA injection of onabotA (200 U). Patients (N = 121) were randomized to receive onabotA (n = 61) or placebo (n = 60). Mechanistic pain biomarkers and clinical outcomes were used for profiling the effect. The biomarkers were pressure pain thresholds (PPTs) from the knee joint (localized sensitization) and extra-articular sites (widespread sensitization), and wind-up pain (central sensitization). Clinical assessments included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), average daily pain (ADP), patient global impression of change (GIC), and rescue medication. The painDETECT questionnaire (PD-Q) was used for subgrouping patients (nociceptive, neuropathic, and mixed/uncertain).Results: The nociceptive and non-nociceptive groups were identical with respect to all baseline data. No significant differences in clinical efficacy parameters were found between onabotA and placebo in the entire population. The nociceptive group showed significant improvement after IA onabotA at week 8 for all WOMAC outcomes, ADP at weeks 9 and 10, and patient GIC at week 12, and significant reduction in rescue medication counts within each 14-day period at weeks 9 and 10. After 4, 8, and 12 weeks, significant correlations were obtained in the onabotA group between ADP (both the entire group and the nociceptive group) and various sensitization parameters. The nociceptive group showed pronounced effects on widespread sensitization.Conclusions: Intra-articular onabotA given to patients with nociceptive knee OA reduced pain sensitization together with improvement in pain and function.

Observed Incidence of Uveitis Following Certolizumab Pegol Treatment in Patients With Axial Spondyloarthritis

ObjectiveAxial spondyloarthritis (axial SpA) is characterized by inflammation of the spine and sacroiliac joints and can also affect extraarticular sites, with the most common manifestation being uveitis. Here we report the incidence of uveitis flares in axial SpA patients from the RAPID‐axSpA trial, including ankylosing spondylitis (AS) and nonradiographic (nr) axial SpA.MethodsThe RAPID‐axSpA (NCT01087762) trial is double‐blind and placebo‐controlled to week 24, dose‐blind to week 48, and open‐label to week 204. Patients were randomized to certolizumab pegol (CZP) or placebo. Placebo patients entering the dose‐blind phase were re‐randomized to CZP. Uveitis events were recorded on extraarticular manifestation or adverse event forms. Events were analyzed in patients with/without history of uveitis, and rates reported per 100 patient‐years.ResultsAt baseline, 38 of 218 CZP‐randomized patients (17.4%) and 31 of 107 placebo‐randomized patients (29.0%) had past uveitis history. During the 24‐week double‐blind phase, the rate of uveitis flares was lower in CZP (3.0 [95% confidence interval (95% CI) 0.6–8.8] per 100 patient‐years) than in placebo (10.3 [95% CI 2.8–26.3] per 100 patient‐years). All cases observed during the 24‐week double‐blind phase were in patients with a history of uveitis; in these patients, rates were similarly lower for CZP (17.1 [95% CI 3.5–50.1] per 100 patient‐years) than placebo (38.5 [95% CI 10.5–98.5] per 100 patient‐years). Rates of uveitis flares remained low up to week 96 (4.9 [95% CI 3.2–7.4] per 100 patient‐years) and were similar between AS (4.4 [95% CI 2.3–7.7] per 100 patient‐years) and nr‐axial SpA (5.6 [95% CI 2.9–9.8] per 100 patient‐years).ConclusionThe rate of uveitis flares was lower for axial SpA patients treated with CZP than placebo during the randomized controlled phase. Incidence of uveitis flares remained low to week 96 and was comparable to rates reported for AS patients receiving other anti–tumor necrosis factor antibodies.

Autoimmunity of the lung and oral mucosa in a multisystem inflammatory disease: The spark that lights the fire in rheumatoid arthritis?

There is a growing body of evidence to suggest that autoimmunity in patients with rheumatoid arthritis (RA) is initiated outside the joint. This is supported by the observation that circulating autoantibodies, including both rheumatoid factor and anti-citrullinated protein antibody, can be detected in many subjects years before the development of initial joint symptoms leading to an RA diagnosis. Of the potential extra-articular sites implicated in disease initiation, mucosal tissues have garnered increasing attention. Several lines of investigation have separately implicated mucosal tissues from varying anatomic locations as possible initiating sites for RA, including those from the lung and oral cavity. In this review we summarize recent reports incriminating these mucosal tissues as the initial site of autoantibody generation and inflammation in patients with RA.