The role of CXCR3 and its ligands expression in Brucellar spondylitis.

AIM: Brucellar spondylitis (BS) is one of the most serious complications of brucellosis. CXCR3 is closely related to the severity of disease infection. This research aimed to study the degree of BS inflammatory damage through analyzing the expression levels of CXCR3 and its ligands (CXCL9 and CXCL10) in patients with BS. METHODS: A total of 29 BS patients and 15 healthy controls were enrolled. Real-Time PCR was used to detect the mRNA expression levels of IFN-γ, CXCR3, CXCL9 and CXCL10 in peripheral blood mononuclear cells (PBMCs) of BS patients and healthy controls. Hematoxylin-Eosin staining was used to show the pathological changes in BS lesion tissues. Immunohistochemistry staining was used to show the protein expression levels of Brucella-Ab, IFN-γ, CXCR3, CXCL9 and CXCL10 in BS lesion tissues. At the same time, ELISA was used to detect the serum levels of IFN-γ, CXCL9 CXCL10 and autoantibodies against CXCR3 in patients with BS. RESULTS: In lesion tissue of BS patients, it showed necrosis of cartilage, acute or chronic inflammatory infiltration. Brucella-Ab protein was abundantly expressed in close lesion tissue. And the protein expression levels of IFN-γ, CXCR3 and CXCL10 were highly expressed in close lesion tissue and serum of BS patients. At the same time, the mRNA expression levels of IFN-γ, CXCR3 and CXCL10 in PBMCs of BS patients were significantly higher than those in controls. CONCLUSION: In our research, the expression levels of IFN-γ, CXCR3 and its ligands were significantly higher than those in controls. It suggested that high expression levels of IFN-γ, CXCR3 and its ligands indicated a serious inflammatory damage in patients with BS.

Case report: Candida krusei spondylitis in an immunocompromised patient.

BACKGROUND: Invasive infections with Candida krusei are uncommon and rarely complicated by spondylitis. Previous described cases were solely treated with antimycotic therapy, despite guidelines recommending surgical interventions. CASE PRESENTATION: We describe a case of C. krusei spondylitis in a patient treated with chemotherapy for acute myeloid leukemia. After induction chemotherapy, the patient developed a candidemia, which was treated with micafungin. One month after the candidemia, the patient was admitted with severe lumbar pain. Spondylitis of the L4 and L5 vertebra was diagnosed on MR-imaging, with signs suggesting an atypical infection. The patient was treated with anidulafungin combined with voriconazole. Despite maximal conservative management symptoms gradually worsened eventually requiring surgical intervention. CONCLUSIONS: In contrast to previous case reports, antimycotic treatment alone could be insufficient in treating C. krusei spondylitis.

Pyogenic spondylitis and paravertebral abscess caused by Salmonella Saintpaul in an immunocompetent 13-year-old child: a case report.

BACKGROUND: Salmonella spondylitis is an uncommon complication of Salmonella infection in immunocompetent children. To prevent treatment failure and neurological deficits, it needs prompt diagnosis and sufficient effort to identify the causative organism. There are some options to identify the causative organism such as Computed Tomography (CT) guided biopsy or surgical debridement, however when to perform these invasive interventions remains controversial. CASE PRESENTATION: A 13-year-old boy presented with occasional high fever and lower back pain. He was diagnosed with spondylitis of the L4-5 vertebral bodies and paravertebral abscess. Initial blood cultures were negative, therefore empirical antibiotic treatment was started. He responded well to conservative management, and was discharged after clinical improvement. However, he was re-hospitalized 2 weeks after discharge, and surgical debridement was performed which led to the detection of Salmonella Saintpaul as the causative pathogen. It was revealed that the possible source of infection was consumption of raw poultry eggs, or contact with poultry. Definitive antibiotic therapy was started. He was discharged with good recovery after a 6-week hospitalization. CONCLUSIONS: This is the very first case report of pyogenic spondylitis caused by Salmonella Saintpaul. Salmonella should be considered as a causative pathogen of pyogenic spondylitis in immunocompetent children. Identifying the causative organism is essential to prevent treatment failure, and a high index of suspicion is needed for prompt diagnosis especially when blood cultures are negative. Invasive interventions such as CT-guided biopsy should be considered even if the clinical course seems to be uncomplicated.

Early pathological alterations of lower lumbar cords detected by ultrahigh-field MRI in a mouse multiple sclerosis model.

Magnetic resonance imaging (MRI) is widely employed for the diagnosis of multiple sclerosis (MS). However, sometimes, the lesions found by MRI do not correlate with the neurological impairments observed in MS patients. We recently showed autoreactive T cells accumulate in the fifth lumbar cord (L5) to pass the blood-brain barrier and cause inflammation in the central nervous system of experimental autoimmune encephalomyelitis (EAE) mice, an MS model. We here investigated this early event using ultrahigh-field MRI. T2-weighted image signals, which conform to the water content, increased in L4 and L5 during the development of EAE. At the same time, the sizes of L4 and L5 changed. Moreover, angiographic images of MRI showed branch positions of the blood vessels in the lower lumbar cords were significantly altered. Interestingly, EAE mice showed occluded and thickened vessels, particularly during the peak phase, followed by reperfusion in the remission phase. Additionally, demyelination regions of some MS patients had increased lactic acid content, suggesting the presence of ischemic events. These results suggest that inflammation-mediated alterations in the lower lumbar cord change the homeostasis of the spinal cord and demonstrate that ultrahigh-field MRI enables the detection of previously invisible pathological alterations in EAE.

Whole-body Vibration at Thoracic Resonance Induces Sustained Pain and Widespread Cervical Neuroinflammation in the Rat.

BACKGROUND: Whole-body vibration (WBV) is associated with back and neck pain in military personnel and civilians. However, the role of vibration frequency and the physiological mechanisms involved in pain symptoms are unknown. QUESTIONS/PURPOSES: This study asked the following questions: (1) What is the resonance frequency of the rat spine for WBV along the spinal axis, and how does frequency of WBV alter the extent of spinal compression/extension? (2) Does a single WBV exposure at resonance induce pain that is sustained? (3) Does WBV at resonance alter the protein kinase C epsilon (PKCε) response in the dorsal root ganglia (DRG)? (4) Does WBV at resonance alter expression of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn? (5) Does WBV at resonance alter the spinal neuroimmune responses that regulate pain? METHODS: Resonance of the rat (410 ± 34 g, n = 9) was measured by imposing WBV at frequencies from 3 to 15 Hz. Separate groups (317 ± 20 g, n = 10/treatment) underwent WBV at resonance (8 Hz) or at a nonresonant frequency (15 Hz). Behavioral sensitivity was assessed throughout to measure pain, and PKCε in the DRG was quantified as well as spinal CGRP, glial activation, and cytokine levels at Day 14. RESULTS: Accelerometer-based thoracic transmissibility peaks at 8 Hz (1.86 ± 0.19) and 9 Hz (1.95 ± 0.19, mean difference [MD] 0.290 ± 0.266, p < 0.03), whereas the video-based thoracic transmissibility peaks at 8 Hz (1.90 ± 0.27), 9 Hz (2.07 ± 0.20), and 10 Hz (1.80 ± 0.25, MD 0.359 ± 0.284, p < 0.01). WBV at 8 Hz produces more cervical extension (0.745 ± 0.582 mm, MD 0.242 ± 0.214, p < 0.03) and compression (0.870 ± 0.676 mm, MD 0.326 ± 0.261, p < 0.02) than 15 Hz (extension, 0.503 ± 0.279 mm; compression, 0.544 ± 0.400 mm). Pain is longer lasting (through Day 14) and more robust (p < 0.01) after WBV at the resonant frequency (8 Hz) compared with 15 Hz WBV. PKCε in the nociceptors of the DRG increases according to the severity of WBV with greatest increases after 8 Hz WBV (p < 0.03). However, spinal CGRP, cytokines, and glial activation are only evident after painful WBV at resonance. CONCLUSIONS: WBV at resonance produces long-lasting pain and widespread activation of a host of nociceptive and neuroimmune responses as compared with WBV at a nonresonance condition. Based on this work, future investigations into the temporal and regional neuroimmune response to resonant WBV in both genders would be useful. CLINICAL RELEVANCE: Although WBV is a major issue affecting the military population, there is little insight about its mechanisms of injury and pain. The neuroimmune responses produced by WBV are similar to other pain states, suggesting that pain from WBV may be mediated by similar mechanisms as other neuropathic pain conditions. This mechanistic insight suggests WBV-induced injury and pain may be tempered by antiinflammatory intervention.

Inflammatory cytokines induce fibrosis and ossification of human ligamentum flavum cells.

STUDY DESIGN: In vitro experiment using degenerated human ligamentum flavum (LF) and various inflammatory cytokines. OBJECTIVES: To examine the effect of inflammatory cytokines on LF cells and to identify their roles in the pathogenesis of LF hypertrophy and ossification. SUMMARY OF BACKGROUND DATA: Spinal stenosis is caused, in part, by hypertrophy and ossification of the LF, which are induced by the degenerative processes (ie, increased collagen synthesis and chondroid metaplasia) of ligament fibroblasts. Degenerated intervertebral disk spontaneously produces inflammatory cytokines, which might affect the adjacent LF through local milieu of the spinal canal. METHODS: The interlaminar portion of the LF was collected during surgical spinal procedures in 15 patients (age range, 49-78 y) with lumbar spinal stenosis. LF fibroblasts were isolated by enzymatic digestion of LF tissue. LF cell cultures were treated with various inflammatory cytokines: interleukin (IL)-1α, IL-6, tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), and nitric oxide (NO). Cytotoxicity was analyzed by MTT assays. DNA synthesis was measured with H-thymidine incorporation, and mRNA expression of types I, III, V, and XI collagen and osteocalcin were performed by reverse transcription-polymerase chain reaction. Histochemical stains such as Von Kossa were also performed to detect bone nodule formation. RESULTS: There was no cytotoxicity in the LF cells treated with each cytokine. There were significant increases in DNA synthesis and upregulated mRNA expression of types I, V, XI collagen and osteocalcin in LF cultures treated with various cytokines. LF cultures treated with IL-6, TNF-α, PGE2, and NO showed positive Von Kossa staining, indicating bone nodule formation from LF cells. CONCLUSIONS: Inflammatory cytokines (IL-6, TNF-α, PGE2, and NO) seem to play a crucial role in hypertrophy and ossification of LF. Degenerated, herniated intervertebral disks, and facet arthrosis may influence LF through inflammatory cytokines and cause hypertrophy and ossification of LF.

Serial kinetics of the antibody response against the complete Brucella melitensis ORFeome in focal vertebral brucellosis.

Human brucellosis is a common zoonosis worldwide. Here we present a case of focal vertebral brucellosis in a 71-year-old Mexican-American woman who contracted infection from unpasteurized goat milk. Standard agglutination serology was negative; the diagnosis was established by the isolation of Brucella melitensis from abscess fluid. A B. melitensis protein microarray comprised of nearly all proteins encoded by the bacterial genome was used to determine the kinetics of this patient's antibody responses to the complete collection of open reading frames existing in the genome (ORFeome). Three patterns of antibody responses against B. melitensis antigens were seen for serum samples obtained on days 0 (pretreatment), 14, 49, 100, and 180: (i) stable titers over time, (ii) a steady fall in titers, and (iii) an initial rise in titers followed by declining titers. Sera from this patient with chronic brucellosis recognized some of the same B. melitensis proteins as those recognized by sera from acute/subacute, blood culture-positive brucellosis patients but also recognized a distinct set of proteins. This study is the first to determine the kinetics of the human antibody responses to the complete repertoire of proteins encoded by a bacterial genome and demonstrates fundamentally different immunopathogenetic mechanisms between acute human brucellosis and chronic human brucellosis. While an extension of these findings to a larger patient population is necessary, these findings have important clinical and diagnostic implications and lead toward new insights into the fundamental immunopathogenesis of brucellosis.

Interactions between gut inflammation and arthritis/spondylitis.

PURPOSE OF REVIEW: The spectrum of spondyloarthritis is characterized by the intriguing co-occurrence of gut and joint inflammation, although no obvious anatomical link exists. RECENT FINDINGS: Data from animal models identify stromal cells as important players in pathogenesis, although signalling through TNFRI appeared to be sufficient for development of combined gut and joint inflammation. Interleukin-23 receptor was identified as a susceptibility locus for ankylosing spondylitis. SUMMARY: Human genome studies combined with animal model research provide us with new evidence in the fascinating field of the gut-joint axis. However, how these newly identified genetic associations can influence the immunological environment remains to be elucidated.

Modic changes and interleukin 1 gene locus polymorphisms in occupational cohort of middle-aged men.

According to recent systematic reviews, Modic changes are associated with low-back pain. However, their pathophysiology remains largely unknown. A previous study of Northern Finnish males implicated that IL1A and MMP3 polymorphisms play a role in type II Modic changes. The purpose of the current study was to examine the association of IL1 cluster polymorphisms with Modic changes amongst middle-aged men in Southern Finland. The final study sample consisted of 108 men from three different occupations, who underwent magnetic resonance imaging (MRI) with a 0.1 T-scanner. Six single nucleotide polymorphisms (SNP) in the IL1 gene cluster (IL1A c.1-889C>T; IL1B c.3954C>T; IL1RN c.1812G>A; IL1RN c.1887G>C; IL1RN c.11100T>C; IL1RN c.1506G>A) were genotyped with the SNP-TRAP method or by allele-specific primer extension on modified microarray. In all, 45 subjects had Modic changes at one or more disc levels. The presence of the minor allele of IL1A (c.1-889C>T) was associated with these changes (any Modic change p = 0.031, type II changes p = 0.036). The carriers of the T-allele had a 2.5-fold risk of Modic change and the association was independent of the other IL1 gene cluster loci studied. In addition, a minor haplotype, with a frequency of 7.5% in the study population, including the minor alleles of IL1A c.1-889C>T, IL1RN c.1812G>A, and IL1RN c.1506G>A, was significantly associated with Modic changes. This observation is in accordance with the previous finding from a different geographical area, and thus confirms the importance of the IL1A gene in the pathophysiology of Modic changes.

The treatment of psoriatic arthritis and inflammatory spondylitis.

NSAIDs still remain the initial therapeutic modality for psoriatic arthritis and inflammatory spondylitis. Disease-modifying antirheumatic drugs have only been proven to be useful in peripheral arthritis, without efficacy in axial inflammatory spondylitis. In recent years, the introduction of tumor necrosis alpha inhibitors into clinical practice has produced a substantial impact in both peripheral and axial disease, with improvement in pain, function, and quality of life. Factors such as cost-effectiveness and safety will need to be better characterized over time.

Surgical treatment for delayed pyogenic spondylitis after percutaneous vertebroplasty and kyphoplasty. Report of 4 cases.

Only 6 cases of pyogenic spondylitis following vertebroplasty or kyphoplasty have been reported, and their causes remained unclear. The authors report on 4 cases of delayed pyogenic spondylitis (DPS) following vertebroplasty or kyphoplasty for osteoporotic compression fractures and metastatic disease. Four patients presented with DPS after vertebroplasty or kyphoplasty and underwent surgical treatment. Clinical history, laboratory examination, and MR imaging confirmed the diagnosis of DPS. Anterior debridement, reconstruction, and posterior instrumented fusion were performed. The mean interval for the delayed occurrence of pyogenic spondylitis after surgery was 12.3 months. The infections were primarily bacterial in origin, but most patients also suffered diverse medical comorbidities. Despite successful treatment of the infections, comorbidity was and is a factor that compromises good results. Medical comorbidities associated with compromised immunity may increase susceptibility to DPS after vertebroplasty or kyphoplasty. In cases of incapacitating back pain after a pain-free period following either of these surgeries, evaluation of the erythrocyte sedimentation rate and C-reactive protein level and examination of contrast-enhanced MR imaging studies are essential to rule out delayed vertebral infection. Surgical treatment requires cement removal and anterior reconstruction with or without additional posterior instrumented fusion.

Immunity to the G1 globular domain of the cartilage proteoglycan aggrecan can induce inflammatory erosive polyarthritis and spondylitis in BALB/c mice but immunity to G1 is inhibited by covalently bound keratan sulfate in vitro and in vivo.

Earlier work from this laboratory showed that the human proteoglycan aggrecan from fetal cartilages can induce a CD4+ T cell-dependent inflammatory polyarthritis in BALB/c mice when injected after removal of chondroitin sulfate chains. Adult keratan sulfate (KS)-rich aggrecan does not possess this property. We found that two CD4+ T cell hybridomas (TH5 and TH14) isolated from arthritic mice recognize bovine calf aggrecan and the purified G1 domain of this molecule, which also contains a portion of the interglobular domain to which KS is bound. These hybridoma responses to G1 are enhanced by partial removal of KS by the endoglycosidase keratanase or by cyanogen bromide cleavage of core protein. KS removal results in increased cellular uptake by antigen-present cells in vitro. After removal of KS by keratanase, G1 alone can induce a severe erosive polyarthritis and spondylitis in BALB/c mice identifying it as an arthritogenic domain of aggrecan. The presence of KS prevents induction of arthritis presumably as a result of an impaired immune response as observed in vitro. These observations not only identify the arthritogenic properties of G1 but they also point to the importance of glycosylation and proteolysis in determining the arthritogenicity of aggrecan and fragments thereof.

An increase of blood squamous cell carcinoma antigen in Pseudomonas aeruginosa spondylitis.

Squamous cell carcinoma antigen (SCCA) is traditionally engaged for detecting and following up malignancy from a squamous cell origin. We encountered an unusual increase of blood SCCA but no other cancer markers in a patient associated with an infective lumbar spondylitis due to Pseudomonas aeruginosa. An overshooting of Th1 expression, such as tumor necrosis factor alpha, bumped up by his uremia as a result of P. aeruginosa infection may hasten SCCA. Therefore, SCCA might additionally serve as a serological marker for infection besides squamous cell cancer, and its false-positive increase also highlights the appropriateness of tumor marker screening.

[Genetics in patients with psoriatic arthritis]. / Arthritis psoriaticaában szenvedo betegek genetikai vizsgálata.

OBJECTIVES: HLA antigens were studied in 100 Hungarian patients suffered from psoriatic arthritis. Genetic markers for the development of different clinical pattern of the disease and skin disorder were identified. METHODS: Determination of class I and class II antigens was performed by using microlymphocytotoxicity assay. RESULTS: The frequency of HLA-Cw6, HLA-B16 (and its split B-39) and HLA-B27 antigens were significantly higher in psoriatic arthritis patients than in the Hungarian general population. No connection was found between HLA-DR4, DR7, B17 antigens and psoriatic arthritis. The patients were classified according to the subgroups proposed by Gladman. The comparisons between the clinical subgroups revealed a significant association of HLA-B27 with spondylitis (Gladman 4, 5, 6, 7). There was no association between HLA DR4 and polyarticular pattern of the disease (Gladman 3, 7). Psoriasis seemed to be significantly associated only with HLA-Cw6. There was a higher frequency of HLA-B38 in psoriatic arthritis patients with erythroderma.

Clinical and immunogenetic characterization in psoriatic arthritis patients.

In psoriatic arthritis (PsA), genetic factors play a substantial role in disease susceptibility as well as in its expression. This study aims to determine the distribution of class I and class II HLA antigens in PsA patients and secondly to analyze the influence of genetic factors in the clinical expression of the disease. Consecutive PsA patients (CASPAR criteria) with less than 1 year of disease duration were included. Sociodemographic and clinical data were recorded. Blood samples were obtained, DNA was extracted by polymerase chain reaction (PCR), and class I (A, B, and C) and class II (DR) HLA antigens were determined by oligotyping. A control group of 100 nonrelated healthy controls from the general population served as control. p values were corrected (pc) according to the number of alleles tested. A total of 73 patients were included, 37 were females (50.7 %) with a median disease duration of 72 months (interquartile range (IQR) 24-149). Thirty-three patients (45.2 %) had a family history of psoriasis. When analyzing all the class I and class II HLA antigens, a significantly higher frequency of B38 (odds ratio (OR) 2.95, p = 0.03) and Cw6 (OR 2.78, p = 0.009) was found in PsA patients compared to the control group. On the contrary, the HLA-A11 (OR 0.14, p = 0.04) and B7 (OR 0.31, p = 0.03) were significantly more frequent among healthy controls. Furthermore, B18 was significantly more frequent in patients with early arthritis onset (less than 40 years): seven patients (22.6 %) with early onset compared to two patients (4.8 %) with late onset (p = 0.03). No association between HLA-B27 and spondylitis or HLA-DR4 with polyarticular involvement was observed. The HLA-B38 and Cw6 alleles are associated with a greater PsA susceptibility in Argentine population.

Prevalence of HLA-B27 in patients with back pain attending a pain clinic.

101 patients presenting to a pain clinic with low back pain were tested for HLA-B27 status. Eight (7.9%) of the patients were positive for HLA-B27. This prevalence is similar to that recorded in the general population and suggests that few patients referred to our clinic with back pain have undiagnosed spondyloarthropathies.

Novel approaches in the treatment of ankylosing spondylitis and other spondyloarthritides.

The therapeutic options for patients suffering from severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is now accumulating evidence that anti-TNF therapy is highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Based on the data recently published on what is now several hundred AS and PsA patients, this treatment seems to be even more effective than the same therapy in rheumatoid arthritis (RA). The anti-TNF-alpha agents currently available, infliximab (Remicade); Centocor), etanercept (Enbrel); Amgen) and adalimumab (Humira; Abbott), are approved for the treatment of RA in the US; infliximab and etanercept are approved in Europe. The situation in SpA is different to RA because there is an unmet medical need, especially in AS, since no therapies with disease-controlling antirheumatic drugs are available for severely affected patients, especially with spinal disease. Thus, TNF blockers might even be considered as first-line immunosuppressive agents in patients with active AS and PsA who are not sufficiently treated by non-steroidal anti-inflammatory drugs and sulfasalazine, if peripheral arthritis is present. For infliximab, a dosage of 5 mg/kg at intervals between 6 and 12 weeks was necessary to constantly suppress disease activity; this is also a major aim of long-term treatment. No dose-finding studies have yet been performed. The standard dose of etanercept is 25 mg s.c. twice-weekly. No studies on adalimumab (standard RA dose 20 - 40 mg s.c. every 2 weeks) have yet been conducted in SpA. The efficacy of etanercept was first demonstrated in PsA and etanercept is now approved for this indication. A double-blind study has also been performed in AS, with similarly clearcut efficacy. There is preliminary evidence that both agents do also work in other SpA such as undifferentiated SpA. Infliximab has recently been approved for short-term treatment of severe uncontrolled AS; the approval for etanercept is pending. Studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis might be preventable but it remains to be shown whether patients benefit from long-term anti-TNF therapy and whether radiological progression and ankylosis can be stopped. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. Tuberculosis can be mostly prevented if patients are checked for previous contact with tuberculosis. Currently, the benefits of anti-TNF therapy in AS seem to outweigh these shortcomings.

Second-line treatment in seronegative spondylarthropathies.

The literature concerning second-line treatment of seronegative spondylarethropathies from 1940 to August 1993 was reviewed. Sulfasalazine appeared to be effective in the treatment of ankylosing spondylitis (AS) and promising in reactive arthritis (ReA) and Reiters' syndrome (RS). Methotrexate and azathioprine were associated with a remarkable improvement in some cases of AS and RS. Methylprednisolone and levamisole were both efficacious in AS, but levamisole was associated with occasional severe side effects. Radiation therapy led to short-term improvement in AS, but was abandoned because of severe long-term side effects. Only sulfasalazine has been studied in sufficient detail to allow definitive conclusions, but methotrexate and azathioprine may be promising drugs.