MRI and clinical features of acute fungal discitis/osteomyelitis.

OBJECTIVES: To compare imaging and clinical features of fungal and Staphylococcus aureus discitis-osteomyelitis (DO) for patients presenting for CT-guided biopsies. METHODS: Our study was IRB-approved and HIPAA-compliant. A group of 11 fungal DO (FG) with MRI within 7 days of the biopsy and a control group (CG) of 19 Staphylococcus aureus DO were evaluated. Imaging findings (focal vs diffuse paravertebral soft tissue abnormality, partial vs complete involvement of the disc/endplate), biopsy location, pathology, duration of back pain, immune status, history of intravenous drug, history of prior infection, current antibiotic treatment, and history of invasive intervention. Differences were assessed using the Fisher exact test and Kruskal-Wallis test. Naïve Bayes predictive modeling was performed. RESULTS: The most common fungal organisms were Candida species (9/11, 82%). The FG was more likely to have focal soft tissue abnormality (p = 0.040) and partial disc/endplate involvement (p = 0.053). The clinical predictors for fungal DO, in order of importance, back pain for 10 or more weeks, current antibiotic use for 1 week or more, and current intravenous drug use. History of invasive instrumentation within 1 year was more predictive of Staphylococcus aureus DO. CONCLUSION: MRI features (focal partial soft tissue abnormality and partial involvement of the disc/endplate) in combination with clinical features may help to predict fungal species as a causative organism for DO. KEY POINTS: • MRI features of discitis-osteomyelitis (focal partial soft tissue abnormality and partial involvement of the disc/endplate) in combination with clinical features may help to predict fungal species as a causative organism for DO.

Vitamin D's Effect on the Proliferation and Inflammation of Human Intervertebral Disc Cells in Relation to the Functional Vitamin D Receptor Gene FokI Polymorphism.

Vitamin D is known to have immunomodulatory effects, is involved in osteo-cartilaginous metabolism, and may have a role in human intervertebral disc pathophysiology. Although a link between vitamin D receptor (VDR) gene variants and disc degeneration-related pathologies has been observed, its functional contribution to pathologic processes has not been assessed yet. The aim of this study was to investigate the response of disc cells to vitamin D in terms of the regulation of proliferation, metabolism, and inflammatory processes, with a particular focus on the FokI VDR genotype. However, although it was found that vitamin D had a pro-apoptotic effect regardless of genotype, an up-regulation of IL-1Ra and downregulation of IL-6 was found to be evident only in Ff cells. Regarding the metabolic effects, in Ff cells, vitamin D promoted an upregulation of the aggrecan in inflammatory conditions but did not have an effect on the expression of collagen-related markers. Moreover, cells bearing the Ff genotype were the most responsive to vitamin D in the upregulation of catabolic markers. In addition, in contrast to the FF genotype, vitamin D downregulated the vitamin D-dependent signaling pathway in inflamed Ff cells, counteracting the inflammation-mediated catabolic effects. In conclusion, Ff cells were found to be more responsive to the anti-inflammatory and catabolic effects of vitamin D, which is likely to be related to matrix remodeling.

The involvement of the spine in psoriatic arthritis.

Although different classification criteria have been developed for psoriatic arthritis (PsA) and spondyloarthritis (SpA), a clear distinction is still not always possible in daily practice. In addition, clinical examination of patients initially diagnosed as PsA due to peripheral symptoms and skin lesions may also show inflammation in the axial skeleton causing inflammatory back pain, stiffness and changes on imaging including sacroiliitis, spondylitis and syndesmophyte formation, similar to what is known from ankylosing spondylitis (AS), the prototype of SpA. However, and in contrast to patients with AS, the long-term radiographic progression of patients with axial disease in PsA seems to be rather independent from spinal mobility. If axial symptoms predominate, diagnosis and classification can be made as axSpA - with or without psoriasis. Furthermore, also the role of HLA-B27 appears to be different in patients with PsA. Overall, the most data about axial involvement in SpA come from AS and axSpA studies, while data about the axial involvement in PsA is limited. Finally, there are no approved therapies for treatment of axial PsA at present, despite significant clinical morbidity. In recent years, anti-TNF therapies have revolutionised the management of ax-SpA. The new GRAPPA treatment recommendations have given specific management advice for patients with axial involvement based on literature from AS and axial SpA. This review aims to give an overview of the existing evidence, the clinical and imaging presentation, and therapeutic consequences of axial involvement in patients with PsA.

Quantifying subtle but persistent peri-spine inflammation in vivo to submicron cobalt-chromium alloy particles.

PURPOSE: We evaluated the consequences of cobalt-chromium alloy (CoCr) wear debris challenge in the peri-spine region to determine the inflammation and toxicity associated with submicron particulates of CoCr-alloy and nickel on the peri-spine. METHODS: The lumbar epidural spaces of (n = 50) New Zealand white rabbits were challenged with: 2.5 mg CoCr, 5.0 mg CoCr, 10.0 mg CoCr, a positive control (20.0 mg of nickel) and a negative control (ISOVUE-M-300). The CoCr-alloy and Ni particles had a mean diameter of 0.2 and 0.6 µm, respectively. Five rabbits per dose group were studied at 12 and 24 weeks. Local and distant tissues were analyzed histologically and quantitatively analyzed immunohistochemically (TNF-α and IL-6). RESULTS: Histologically, wear particles were observed in all animals. There was no evidence of toxicity or local irritation noted during macroscopic observations in any CoCr-dosed animals. However, Ni-treated control animals experienced bilateral hind leg paralysis and were euthanized at Day 2. Histopathology of the Ni particle-treated group revealed severe neuropathy. Quantitative immunohistochemistry demonstrated a CoCr-alloy dose-dependent increase in cytokines (IL-6, TNF-α, p < 0.05) at 12 and 24 weeks. CONCLUSIONS: Subtle peri-spine inflammation associated with CoCr-alloy implant particles was dose dependent and persistent. Neuropathy can be induced by highly reactive Ni particles. This suggests peri-spine challenge with CoCr-alloy implant debris (e.g., TDA) is consistent with past reports using titanium alloy particles, i.e., mild persistent inflammation.

Clinical characteristics and genetic analysis of A20 haploinsufficiency.

PURPOSE: To evaluate the clinical and genetic characteristics of 3 children with Haploinsufficiency of A20 (HA20). METHODS: The clinical and genetic testing data of 3 children with HA20 treated at Capital Institute of Pediatrics (CIP) between August 2016 and October 2019 were retrospectively analysed. RESULT: Patient 1 presented with arthritis and inflammatory bowel disease, patient 2 presented with axial spinal arthritis and lupus-like syndrome, and patient 3 presented with recurrent oral ulcers, gastrointestinal ulcers, and perianal abscesses. Regarding laboratory tests, patients were found to have elevated white blood cell (WBC) count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The CRP and ESR was reported to be high in all the patients. The WBC was reported to be high in patient 1 and 3. Patient 2 was positive for antinuclear antibodies, anti-Sjögren's syndrome antigen A, dsDNA, rheumatoid factor and Coombs test. Genetic testing showed that all three patients had heterozygous mutation in TNFAIP3 gene. As for the treatment, patient 1 was treated with TNFα antagonist, patient 2 was treated with TNF α antagonist and sulfasalazine, and patient 3 was treated with corticosteroids and thalidomide. Patients 1 and 2 were followed for four and 3 months, respectively. There was an improvement in joint and gastrointestinal symptoms; inflammatory indices and rheumatoid factor (RF) were normal, and dsDNA and Coombs test became negative. Patient 3 was treated at another hospital and showed gradual improvement in oral ulcers and perianal abscesses. CONCLUSION: HA20 is a single-gene auto-inflammatory disease caused by mutation in tumour necrosis factor (TNF)-α-induced protein 3 (TNFAIP3) gene. It may present as Behçet-like syndrome and resemble various other autoimmune diseases as well. Corticosteroids and immunosuppressive agents are effective treatments, and cytokine antagonists can be used in refractory cases. Whole-exome genetic testing should be proactively performed for children with early-age onset or Behçet-like syndrome to achieve early diagnosis and accurate treatment.

Functional Analysis of Brain-Engrafted Monocytes After Microglia Ablation in Mouse Models.

During insults and disease blood-borne monocytes can invade brain and spinal cord, contributing to the neuroimmune response together with brain-resident microglia. The specific function of brain-infiltrating monocytes has been difficult to ascertain because of shared marker expression and morphology of these two immune cell types. Here we describe our method of repopulating the brain with circulating monocytes after microglia ablation to investigate the physiology of brain-invading monocytes, which engraft under these conditions.

The pathogenetic role of HLA-B27 in chronic arthritis.

Population and peptide specificity analyses and studies in transgenic rodents support a role of HLA-B27 as an antigen-presenting molecule in spondyloarthropathy. The interplay between HLA-B27 and arthritogenic bacteria on infected cells suggests that HLA-B27 might also influence disease by other mechanisms. Recent genetic advances promise the identification of additional susceptibility genes.

Seronegative spondyloarthropathy--studies from the Asia Pacific region.

Recent therapeutic advances, in particular the use of anti-tumour necrosis factor (anti-TNF) agents, have revived interest in the seronegative spondyloarthropathies (SpA), a group of arthritides characterised by axial skeletal involvement and the absence of rheumatoid factor. The purpose of this article is to review the studies that have been done in the Asia Pacific region, as a broad understanding of the scope and severity of this group of diseases would enable rheumatologists and physicians in this part of the world to better manage their patients. The majority of genetic studies have focused on the associations of HLA-B27 with ankylosing spondylitis (AS) and SpA, while a few studies examined the associations of the CARD, IL-1, LMP2, TAP and TGF with AS. There are a handful of studies on the immunological responses to bacteria and cytokine levels in AS. The onset and clinical features of SpA have been reported from most countries in the region, but no data on patient outcomes, using current measurement tools such as the Bath Ankylosing Spondylitis Disease Activity index (BASDAI), is available. Validation of these instruments of measurement as well as classification criteria in different ethnic populations is necessary where no prior data exist. Future studies will likely be focused on better clinical characterisation of patient cohorts, particularly with regard to the use of currently used measurement tools for disease activity and spinal function and mobility, and the identification of the need for biologic therapy in each country.

[Spinal osteochondrosis, mesenchymal dysplasia and herpes infection].

36 intervertebrate disks (IVD) were studied in spinal osteochondrosis concurrent with herniation. Expression of herpes simplex types 1 and 2 (HSV-1 and HSV-2) antigens, which was absent in IVD of the control group (autopsy cases without disk hernia). The similarity of herniation in osteochondrosis and cardiac mesenchymal dysplasia, a frequent concomitance of these processes and the presence of HSV-1 and HSV-2 antigens in the IVD cells and cardiac valves may indicate the same nature of these diseases.

[Decision on the immunomodulating therapy in unspecific osteomyelitis of the spine].

Immunomodulating therapy was used in treatment of 54 patients with unspecific osteomyelitis of the spine (UOS). The age of the patients was from 15 through 76 years. The authors consider that immunocorrection should be included in the complex of obligatory measures of treatment of patients with purulent infections of the spine and is dependent on the type of immunological impairments. For its success it is necessary to determine the type and degree of immunity impairment. Since in most cases of UOS there is a disorder in the T-cell link of immunity, it is preferable to use cytomedins (T-activin, thymalin, thymogen etc) or cytokines (e.g. roncoleukin). In cases of an insufficient B-cell link the medicines of choice are licopid and myelopid.

Juxta-vertebral lesions in granulomatosis with polyangiitis.

OBJECTIVES: To describe the clinical, pathological, serological, and radiological characteristics of juxta-vertebral masses occurring in patients with granulomatosis with polyangiitis (GPA). METHODS: We analyzed the clinical records of patients with juxta-vertebral lesions from our GPA study cohort and reviewed the English literature for other cases of GPA with juxta-vertebral localization. RESULTS: Out of 74 patients in our GPA study cohort, six (8%) had juxta-vertebral lesions. We found 10 cases of juxta-vertebral GPA described in the English literature. Overall, juxta-vertebral lesions were detected at GPA onset in 11/16 (69%) patients, and preferentially occurred on the right side of the spine (12/15 patients, 80%). Fifteen patients (94%) with juxta-vertebral lesions had systemic GPA. Juxta-vertebral lesions were associated with back pain at GPA onset in 8/16 (50%) patients. In all of them juxta-vertebral lesions resolved or improved after treatment. CONCLUSIONS: Preference for the right-anterior side of the spine, increased 18FDG uptake on PET scan, low or absent invasiveness of the surrounding tissues, and occurrence in the context of systemic disease were the main features of juxta-vertebral GPA. Symptomatic lesions showed a better response to immunosuppressive therapies.

Seronegative rheumatoid arthritis. Fact or fiction?

Patients with clinical features of rheumatoid arthritis (RA) but negative rheumatoid factor (RF) present a diagnostic challenge. The seronegative spondyloarthropathy (SNSA) syndromes, previously believed to be "rheumatoid arthritis variants," eg, Reiter's syndrome and psoriatic arthritis, are now considered to be genetically separate from RA and have been shown to be closely associated with HLA-B27. This syndromic discrimination has raised question as to the validity of RF negative RA (ie, seronegative RA). Demographic, clinical, and roentgenologic features of seronegative RA and SNSA are compared. Also, more common diagnoses that may stimulate seronegative RA are outlined according to onset age of arthritis. Recent concepts of RF positivity and HLA-DR4 correlations are reviewed. Multiple unknown factors contribute to the currently recognized syndrome of RA. Its diagnosis continues to rest on an aggregate of host, clinical, immunologic, and radiologic features.

Seronegative spondyloarthropathy in familial Mediterranean fever.

To define a possible association between familial Mediterranean fever (FMF) and seronegative spondyloarthropathy (SNSA) and to study features of SNSA in FMF patients, we screened for the presence and manifestations of SNSA in 3,000 FMF patients attending the National Center for FMF in our institution. This population included 160 patients with chronic arthritis, most who suffered from SNSA. Patients were considered to suffer from SNSA if they had chronic arthritis, inflammatory back/neck pain, and sacroiliitis. Patients who had other diseases associated with SNSA were excluded. Eleven patients, nine men and two women, with chronic monoarthritis or oligoarthritis, grade 2 (four patients) or grades 3 to 4 (seven patients), sacroiliitis, and inflammatory back pain met the criteria for diagnosis of SNSA of FMF. These patients were rheumatoid factor (RF) and HLA-B27 negative. In seven patients, spondyloarthropathy developed while they received colchicine, and in four before colchicine. Most patients responded to treatment with nonsteroidal antiinflammatory drugs, but three required second-line agents. These findings suggest that SNSA is one of the musculoskeletal manifestations of FMF that may occur despite colchicine therapy and requires specific treatment.

The interplay of nature versus nurture in predisposition to the rheumatic diseases.

The revolution in microbiology and genetics that has transpired in the past few years has brought fresh debate in the question of the relative contributions of nature and nurture in susceptibility to the rheumatic diseases. For nature, a variety of immunologically relevant genes have been identified whose presence has been shown to be associated either with an increased risk for certain diseases or for complications or subsets thereof. For nurture, the role of infectious agents in disease triggering and modification has been found.

Immunogenetics of spondyloarthropathies.

The association of HLA-B27 with ankylosing spondylitis and related spondyloarthropathies has been known for two decades and has provided a great impetus to the epidemiologic studies and also helped broaden the clinical spectrum of these diseases. The etiology of these diseases is likely to be multifactorial and include genetic, immunologic, and environmental mechanisms. The detailed three-dimensional x-ray crystallographic structure of B27 has now been reported. It has revealed electron density compatible with oligopeptides that are nine amino acid-long (nonamers) bound in the antigen-binding cleft of the molecule. Microsequence analysis of 11 peptides eluted from the antigen-binding cleft has confirmed that all are nonamers. The most restricted position in the bound peptide is the second position, where all the 11 peptides contain arginine. The side chain of arginine extends into the B pocket ("45 pocket"), which seems to act as a specificity side pocket in the antigen-binding cleft of the B27 molecule. It is very likely that an understanding of the detailed structure of B27, including the peptide-binding motif and the structural domains recognized by cytotoxic T cells, along with the recent development of the B27 transgenic rat model for spondyloarthropathies, will further enhance our understanding of the immunogenetics of these diseases. It is hoped that this will lead to the source of the arthritogenic triggers and possibly disease prevention by antigen-specific immunomodulation. Because T-cell activation is initiated by the formation of antigen-MHC complexes that are the ligands that are recognized by the antigen-specific T-cell receptor (TCR), it might be possible to inhibit this activation by blocking the antigen-binding cleft of MHC molecules by using high-affinity MHC-binding peptides (MHC blockade) or by a novel, new, and more efficient method of TCR antagonism.

Psoriatic arthritis.

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. It is classified with the human leukocyte antigen B27 seronegative spondyloarthropathies because it shares certain features with other conditions included in that group. Specific features of PsA, however, distinguish it from both rheumatoid arthritis and other spondyloarthropathies. Although the cause and pathogenesis of PsA are not known, genetic, immunologic, and environmental factors are thought to play a role, and provide a rationale from therapeutic modalities.

Genetic regulation of nerve avulsion-induced spinal cord inflammation.

In the animal model for multiple sclerosis (MS), experimental autoimmune encephalitis (EAE), genetic loci correlating with incidence or severity of disease are located both within and outside of the major histocompatibility complex (MHC). Whereas polymorphisms within MHC class I and II molecules are likely to be a major determinant of MHC gene influence in rat EAE, it is still unclear how non-MHC gene regions influence disease. Genetic control of inflammation can hypothetically be either general or specific for a particular target tissue. For the latter, gene regulation of pathomechanisms in the CNS could affect reactivity of microglia or astrocytes, local cytokine/chemokine production, or even neuronal vulnerability. We have obtained strong support for this notion by observations of rat strain-dependent variation in the inflammatory response after ventral root avulsion, a model in which mainly non-antigen-specific elements of the immune system promote inflammation. A comparison of strains with similar MHC haplotypes on different backgrounds and strains with different MHC haplotypes on the same background, respectively, demonstrates that the inflammatory phenotype is regulated mainly by non-MHC genes. Interestingly, different features of the inflammatory response, such as induction of MHC class II expression, glial activation, cytokine expression, and neuronal vulnerability, varied between rat strains and were largely independent of each other. The genetic control of several basic features of inflammation in the CNS is of great relevance not only for MS/EAE, but also for several other neurological conditions with inflammatory components such as cerebrovascular and neurogenerative dieases and trauma.

Seronegative spondyloarthritides.

Recently, there has been enormous growth in the clinical importance of the spondyloarthropathies, in part because of their close association with HLA, and in part because of the recognition that a substantial number of patients suffer from different forms of these disorders. Over the years, immunogeneticists, geneticists, epidemiologists, bacteriologists, membrane biologists, and clinicians have joined in the attempt to clarify our understanding of ankylosing spondylitis, Reiter's disease, psoriatic arthropathy, and other interrelated conditions. This article provides a summary of clinical and research developments in what is now recognized as a major area in rheumatology.

Paraparesis induced by inflammatory contents of a pneumonectomy cavity. Case report.

The authors report on a patient who developed acute-onset paraparesis after underoing a thoracotomy 40 years earlier for a carcinoid adenoma. No infectious or neoplastic origin could be found to explain the patient's current clinical course and radiographic findings. The postoperative events in this case are discussed, as well as the literature regarding postthoracotomy complications.

Pre- and postoperative changes in serum myelin basic protein immunoreactivity in neurosurgical patients.

In 44 patients undergoing neurosurgical procedures for intracranial tumors, subarachnoid hemorrhage, or spinal and peripheral nerve lesions, serum myelin basic protein (MBP) immunoreactivity was measured preoperatively and serially in the first 10 postoperative days. The double-antibody radioimmunoassay method was used, with a detection limit of 2.5 ng/ml in serum. Clinical evaluation was carried out at admission and on successive days during the period of neurosurgical management; outcome was assessed later. In the early postoperative phase, there was a fall in MBP immunoreactivity in all groups of patients. In the groups with intracranial tumor and subarachnoid hemorrhage, there was a subsequent rise in MBP immunoreactivity before the end of the 10-day period, which was not found in the group with spinal and peripheral nerve lesions.