Primary Sjögren's syndrome manifesting as sclerotic metabolic bone disease.

Primary Sjögren's syndrome (pSS) is a chronic slowly progressive autoimmune disease characterised by lymphocytic infiltration of salivary and lacrimal glands with varying degree of systemic involvement. Renal involvement, a recognised extraglandular manifestation of pSS, is commonly related to tubular dysfunction and generally manifests as distal renal tubular acidosis (RTA), proximal RTA, tubular proteinuria and nephrogenic diabetes insipidus. Untreated long-standing RTA is known to cause metabolic bone disease. Here, we present the report of a patient with sclerotic metabolic bone disease related to pSS with combined distal and proximal RTA and negative workup for other causes of sclerotic bone disease. A significant clinical and biochemical improvement, including recovery of proximal tubular dysfunction, was noted with alkali therapy. This case suggests the need to consider pSS in the diagnostic algorithm of a patient presenting with sclerotic bone disease.

Sensitivity of ventrolateral posterior thalamic nucleus to back pain in alcoholism and CD4 nadir in HIV.

Volumes of thalamic nuclei are differentially affected by disease-related processes including alcoholism and human immunodeficiency virus (HIV) infection. This MRI study included 41 individuals diagnosed with alcohol use disorders (AUD, 12 women), 17 individuals infected with HIV (eight women), and 49 healthy controls (24 women) aged 39 to 75 years. A specialized, high-resolution acquisition protocol enabled parcellation of five thalamic nuclei: anterior [anterior ventral (AV)], posterior [pulvinar (Pul)], medial [mediodorsal (MD)], and ventral [including ventral lateral posterior (VLp) and ventral posterior lateral (VPl)]. An omnibus mixed-model approach solving for volume considered the "fixed effects" of nuclei, diagnosis, and their interaction while covarying for hemisphere, sex, age, and supratentorial volume (svol). The volume by diagnosis interaction term was significant; the effects of hemisphere and sex were negligible. Follow-up mixed-model tests thus evaluated the combined (left + right) volume of each nucleus separately for effects of diagnosis while controlling for age and svol. Only the VLp showed diagnoses effects and was smaller in the AUD (p = .04) and HIV (p = .0003) groups relative to the control group. In the AUD group, chronic back pain (p = .008) and impaired deep tendon ankle reflex (p = .0005) were associated with smaller VLp volume. In the HIV group, lower CD4 nadir (p = .008) was associated with smaller VLp volume. These results suggest that the VLp is differentially sensitive to disease processes associated with AUD and HIV.

Anti-CD74 antibodies have no diagnostic value in early axial spondyloarthritis: data from the spondyloarthritis caught early (SPACE) cohort.

BACKGROUND: Anti-CD74 IgG antibodies are reported to be elevated in patients with axial spondyloarthritis (axSpA). This study assessed the diagnostic value of anti-CD74 antibodies in patients with early axSpA. METHODS: Anti-CD74 IgG and IgA antibodies were first measured in an exploratory cohort of patients with radiographic axSpA (138 patients with ankylosing spondyloarthritis (AS)) and 57 healthy controls and then were measured in patients with early axSpA (n = 274) and with non-SpA chronic back pain (CBP) (n = 319), participating in the spondyloarthritis caught early (SPACE) prospective cohort study of patients under 45 years old with early back pain (for ≥ 3 months, but ≤ 2 years). RESULTS: In the exploratory cohort, anti-CD74 IgG antibodies were present in 79.7% of patients with AS vs. 43.9% of healthy controls (p < 0.001). Anti-CD74 IgA antibodies were present in 28.5% of patients with AS vs. 5.3% of healthy controls (p < 0.001). In the SPACE cohort, anti-CD74 IgG antibody levels were present in 46.4% of the patients with axSpA vs. 47.9% of the patients with CBP (p = 0.71). Anti-CD74 IgA antibodies were present in 54.7% of the patients with axSpA and 37.0% of the patients with CBP (p < 0.001). This resulted in a positive predictive value of 58.8% (compared to a prior probability of 46.2%) and a negative predictive value of 59.1% (compared to a prior probability of 53.8%). In a regression model, total serum IgA was associated with axSpA odds ratio (OR) 1.19, p < 0.001) whereas anti-CD74 IgA was not (OR) 1.01, p = 0.33). Furthermore, anti-CD74 IgA was associated with sacroiliitis on magnetic resonance imaging (MRI) (OR) = 2.50, p = 0.005) and heel enthesitis (OR) = 2.56, p = 0.002). CONCLUSIONS: Albeit anti-CD74 IgA is elevated in patients with early axSpA, this elevation is not sufficiently specific to yield significant diagnostic value in patients under 45 years old presenting with early back pain.

Pain in ankylosing spondylitis: a neuro-immune collaboration.

Clinicians have commonly differentiated chronic back pain into two broad subsets: namely, non-inflammatory (or mechanical) back pain and inflammatory back pain. As the terminology suggests, the latter category, in which ankylosing spondylitis (AS) is prominent, presupposes a close link between pain and inflammation. Advances in research into the genetics and immunology of AS have improved our understanding of the inflammatory processes involved in this disease, and have led to the development of potent anti-inflammatory biologic therapeutic agents. However, evidence from clinical trials and from biomarker and imaging studies in patients with AS indicate that pain and inflammation are not always correlated. Thus, the assumption that pain in AS is a reliable surrogate marker for inflammation might be an over-simplification. This Review provides an overview of current concepts relating to neuro-immune interactions in AS and summarizes research that reveals an increasingly complex interplay between the activation of the immune system and pain pathways in the nervous system. The different types of pain experienced by patients with AS, insights from brain imaging studies, neurological mechanisms of pain, sex bias in pain and how the immune system can modify pain in patients with AS are also discussed.

[A comparative study of immune and clinical indicators in radicular and myofascial back pain]. / Sravnitel'nyi analiz immunokhimicheskikh i klinicheskikh pokazatelei pri dorsalgiiakh koreshkovogo i reflektornogo geneza.

AIM: To compare immunochemical and clinical parameters in patients with chronic radicular and myofascial back pain. MATERIAL AND METHODS: A study included 92 patients (55 men and 37 women) with radicular pain syndrome and 97 patients (33 men and 64 women) with myofascial pain syndrome. Pain status was assessed with the differential visual analogous scale (at rest, on movement, at night and during spontaneous pain). Tensor algometry was used to measure pain intolerance thresholds at day and night. Levels of natural antibodies (nAB) to endogenous pain regulators (ß-endorphin, orphanin, serotonin, dopamine, histamine and angiotensin) were determined in the blood serum by ELISA. Patients were examined at admission to the hospital, on 10th and 21st days of treatment. RESULTS AND CONCLUSION: There was a significant decrease in pain syndrome in all patients to the 21st day. Pain intensity was higher in patients with radicular pain syndrome (р<0.05) in all functional states. Pain intolerance thresholds were initially reduced in both groups. No significant between-group differences in the dynamics were not found either in men or women. Women had lower pain intolerance thresholds compared to men. An analysis of nAB profiles to pain regulators showed that they were correlated with higher and high indices, with the predominance of nAB to ß-endorphin, orphanin and histamine in both groups. The increased levels of antibodies circulate in the blood serum of patients with dorsalgia for a long time can further be a factor of pain chronification.

Inhibition of Complement Retards Ankylosing Spondylitis Progression.

Ankylosing spondylitis (AS) is a chronic axial spondyloarthritis (SpA) resulting in back pain and progressive spinal ankyloses. Currently, there are no effective therapeutics targeting AS largely due to elusive pathogenesis mechanisms, even as potential candidates such as HLA-B27 autoantigen have been identified. Herein, we employed a proteoglycan (PG)-induced AS mouse model together with clinical specimens, and found that the complement system was substantially activated in the spinal bone marrow, accompanied by a remarkable proportion alteration of neutrophils and macrophage in bone marrow and spleen, and by the significant increase of TGF-ß1 in serum. The combined treatment with a bacteria-derived complement inhibitor Efb-C (C-terminal of extracellular fibrinogen-binding protein of Staphylococcus aureus) remarkably retarded the progression of mouse AS by reducing osteoblast differentiation. Furthermore, we demonstrated that two important modulators involved in AS disease, TGF-ß1 and RANKL, were elevated upon in vitro complement attack in osteoblast and/or osteoclast cells. These findings further unravel that complement activation is closely related with the pathogenesis of AS, and suggest that complement inhibition may hold great potential for AS therapy.

Occurrence of Donor Cell-derived Lymphoid Blast Crisis 24 Years Following Related Bone Marrow Transplantation for Chronic Myeloid Leukemia.

We herein report a unique case of donor cell leukemia (DCL), as donor cell-derived lymphoid blast crisis of chronic myeloid leukemia (CML) was observed 24 years after related bone marrow transplantation for CML in the chronic phase. Short tandem repeat testing of the leukemic blast sample revealed full donor chimerism, strongly indicative of DCL. The original donor is healthy with a normal complete blood cell count for the past 24 years. This rare case may provide a precious opportunity to consider not only the underlying mechanism of DCL, but also the pathogenesis of CML.

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.

Delayed hypersensitivity reaction caused by metal-on-metal total disc replacement.

The authors report the case of a 53-year-old woman who underwent placement of a metal-on-metal total disc replacement (TDR) device for the treatment of discogenic back pain. The initial postoperative course was normal, but 2 months after surgery she started to complain of a recurrence of pain and she progressively developed cauda equina syndrome. Radiological and biological findings showed an inflammatory polyneuropathy associated with an epidural mass. A diagnosis of cell-mediated hypersensitivity reaction (Type IV) was made after patch testing showed positive reactions for 1% cobalt chloride and chromium. A decision was made to remove the TDR device and to perform a circumferential fusion. This report is intended to inform the reader that systemic metal release and hypersensitivity reaction are possible complications of metal-on-metal TDR.

A community-based study on the prevalence of spondyloarthritis and inflammatory back pain in Mexicans.

BACKGROUND: The prevalence of spondyloarthritis (SpA) varies across populations. In Mexicans, the prevalence of SpA is still unknown. OBJECTIVE: The objective of this study was to determine the prevalence of SpA in the community as well as that of inflammatory back pain (IBP) and ankylosing spondylitis (AS). METHODS: We identified individuals older than 18 years with nontraumatic back pain (BP) in a door-to-door nurse survey using the Community Oriented Program for the Control of Rheumatic Diseases. Then, general physicians and rheumatology fellows selected those likely to have IBP (Berlin criteria). Finally, 2 expert rheumatologists assessed IBP individuals according to clinical data and classification criteria and requested HLA-B27 and radiographic studies to determine the clinical condition of the individual and SpA (European SpA Study Group) classification. RESULTS: The prevalence of BP among 4059 individuals was 14.6% (95% confidence interval [CI], 13.6-15.8). The prevalence of IBP and SpA was 1.3% (95% CI, 1.0-1.7) and 0.6% (95% CI, 0.4-0.9), respectively. Ankylosing spondylitis prevalence was 0.1% (95% CI, 0.02-0.2). Inflammatory back pain and SpA percentage of males and females was similar. The percentage of individuals with IBP according to the 2 experts was lower than that determined by general physicians and rheumatology fellows, but all cases with HLA-B27, radiographic sacroiliitis, SpA, and AS had previous IBP confirmation by the expert. CONCLUSIONS: The prevalence and sex distribution of patients classified with SpA in this community study--as well as that of patients diagnosed with AS--are consistent with those found in recent studies. Expert assessment of individuals with positive responses to questionnaires is relevant for the classification of IBP and SpA.

Psoriasis and phenotype of patients with early inflammatory back pain.

BACKGROUND: Psoriasis is an important clinical feature in spondyloarthritis. However, the influence of psoriasis on the clinical, functional and imaging features of patients with inflammatory back pain (IBP) related to spondyloarthritis is not known. OBJECTIVES: To determine the prevalence of psoriasis and its impact in patients with recent IBP suggestive of spondyloarthritis. METHODS: The prevalence of psoriasis was determined in 692 patients (mean age 33.3±8.5 years, 53.8% female, 58.3% human leucocyte antigen B27 positive) included in the DESIR cohort. Demographic characteristics, imaging features and blood tests of patients with and without psoriasis were compared. RESULTS: The prevalence of psoriasis was 16.6%. Patients with rather than without psoriasis more often presented with enthesitis (59.1% vs 47.5%; p=0.02) and had more active disease (BASDAI 4.8±1.8 vs 4.4±2.0; p=0.05) and poorer functional status (BASFI 3.6±2.2 vs 3.0±2.3; p=0.006; SF-36 (physical function) 61.9±24.4 vs 66.9±24.9; p=0.04). Patients with psoriasis showed higher levels of C-reactive protein (p=0.02), total cholesterol (p=0.01) and triglycerides (p=0.02). The two groups did not differ in structural changes as assessed by standard x-rays or MRI at the spinal and sacroiliac levels. However, ultrasonography of the Achilles tendon revealed psoriasis associated with bone erosions (p=0.0003) and abnormal vascularisation (p=0.04). Multivariate regression analysis revealed BASFI score (p=0.03), cholesterol level (p=0.02), dactylitis (p=0.0006) and family history of psoriasis (p<0.0001) as independent predictors of psoriasis. CONCLUSIONS: In patients with recent IBP suggestive of spondyloarthritis, psoriasis is associated with active axial disease and frequent concomitant enthesopathy and dactylitis.

Low frequency of axial involvement in southern Italian Caucasian children with HLA-B27 positive juvenile onset undifferentiated spondyloarthritis.

OBJECTIVES: To establish how many children with HLA B27-positive juvenile undifferentiated spondyloarthritis (JuSpA) living in southern Italy develop axial disease after 5 years of disease. METHODS: All children with B27-positive enthesitis-related arthritis (ERA) consecutively seen in a 7-year period were entered in a special register and were followed prospectively. Each patient was examined at 6-month intervals, even if asymptomatic. In patients with inflammatory spinal pain and/or buttock pain, MRI of the sacroiliac joints and spine was performed. Five years after inclusion, sacroiliac joint plain radiographs were obtained and read blindly after being mixed with those of control subjects. RESULTS: Thirteen children, 9 boys and 4 girls, with B27-positive ERA and one girl with B27-positive isolated SpA dactylitis were seen in the study period. Their median age at disease onset and at our first examination were 10 (range 2-16) and 12 years (range 3-16), respectively. During follow-up, only one patient had axial symptoms, i.e. alternate buttock pain. MRI revealed moderate bone oedema at both sacroiliac joints. After five years of disease, no patient showed reduced spinal movement. No sign of sacroiliitis was seen in any patient and control on plain films. A new MRI of the sacroiliac joints of the patient who showed bone oedema in the first years of disease was normal. CONCLUSIONS: This study confirms that the onset of axial involvement in Italian Caucasian HLA-B27 positive children with ERA is rare in the first five years of disease.

Smokers in early axial spondyloarthritis have earlier disease onset, more disease activity, inflammation and damage, and poorer function and health-related quality of life: results from the DESIR cohort.

OBJECTIVES: To investigate the association of smoking with various clinical, functional and imaging outcomes in patients with early axial spondyloarthritis (SpA). METHODS: 647 patients with early inflammatory back pain (IBP) fulfilling at least one of the internationally accepted SpA criteria and with available smoking data were included in the analyses. Clinical, demographic and imaging parameters were compared between smokers and non-smokers at a cross-sectional level. Variables with significant differences in univariate analyses were used as dependent variables in multivariate linear and logistic regression models adjusted for potential confounding/contributing factors. RESULTS: Multivariate analysis showed that smoking was associated with an earlier onset of IBP (regression coefficient (B)=(-1.46), p=0.04), higher disease activity (ankylosing spondylitis disease activity score B=0.20, p=0.03; Bath ankylosing spondylitis disease activity index B=0.50, p=0.003), worse functional status (Bath ankylosing spondylitis functional index B=0.38, p=0.02), more frequent MRI inflammation of the sacroiliac joints (OR 1.57, p=0.02) and the spine (OR 2.33, p<0.001), more frequent MRI structural lesions of the sacroiliac joints (OR 1.54, p=0.03) and the spine (OR 2.02, p=0.01), and higher modified Stoke ankylosing spondylitis spine score (B=0.54, p=0.03) reflecting radiographic structural damage of the spine. Smoking was also associated with poorer quality of life (Euro-quality of life questionnaire B=1.38, p<0.001, short form 36 physical B=(-4.89), p<0.001, and mental component score B=(-5.90), p<0.001). CONCLUSION: In early axial SpA patients, smoking was independently associated with earlier onset of IBP, higher disease activity, increased axial inflammation on MRI, increased axial structural damage on MRI and radiographs, poorer functional status and poorer quality of life.

Distribution of HLA-B27 and CYP2D6*4 mutations in the middle Black Sea area (Tokat) of Turkey.

We analyzed distribution of HLA-B27 and CYP2D6*4 mutations in 249 patients from Tokat province in Turkey with symptoms of arthritis, sacroiliac, joint and back pain, using a LightCycler 480 II Real-Time PCR thermal cycler. The Genes-4U was applied for studying HLA-B27 mutation, and the Tib-Molbiol commercial kit was used to examine the CYP2D6*4 mutation. Among the 249 patients, 18.5% had the HLA-B27 mutation. The CYP2D6*4 mutation was found in 22.0% (six homozygotes). Ten patients had both mutations. These frequencies are similar to what has been reported from other populations.

Inflammatory and degenerative sacroiliac joint disease in a primary back pain cohort.

OBJECTIVE: The prevalence of sacroiliac (SI) joint abnormalities in a primary low back pain population remains unresolved. The aims of our study were to define the prevalence of SI joint disease in this cohort, and to identify clinical features that might accurately predict radiographic changes in the SI joint and spine. METHODS: Lumbar spine and anteroposterior pelvis radiographs taken over a 3-year period for the evaluation of back pain at a major chiropractic college were scored for the presence of inflammatory or degenerative features. Data were subsequently extracted by means of a predetermined template from the clinical notes. The outcomes were correlated using Spearman's correlation coefficients. RESULTS: We identified 315 patients (173 men, 142 women), ages 18-60 years. Of these, 100 patients (31.7%) demonstrated SI joint abnormalities: 75 (23.8%) degenerative, 25 (7.9%) inflammatory. Sex was strongly associated with type of SI joint pathology; degenerative disease was predominantly found in women (68%), whereas inflammatory disease was predominantly found in men (63%). In women there was no correlation between degenerative SI joint abnormalities and degenerative changes in the lumbar spine. Of the clinical descriptors evaluated, none were associated with the radiographic findings with the exception of buttock pain, which was associated with inflammatory sacroiliitis. Neither being overweight nor pregnancy history was associated with degenerative changes in the SI joint. CONCLUSION: In a primary back pain cohort, degenerative SI joint disease may be an under-recognized clinical entity. It is strongly influenced by sex but is unrelated to degenerative changes in the lumbar spine. Currently proposed clinical discriminators performed poorly in correlating with radiographic changes in the SI joint.

Possible key role of immune system in Schmorl's nodes.

Schmorl's nodes (SNs) are common abnormalities in the human spine, which represent herniation of the nucleus pulposus of the intervertebral disc into the adjacent cartilaginous endplate of the vertebra. However, the principle mechanism of SNs is still not fully understood. And the relationship of SNs in the spine and their clinical significance as a source of low back pain in the general population remains unknown. It is therefore important to get better understanding of this. Here, we review the clinical and experiment evidence on inducing of the SNs and correlative back pain, and propose a possible mechanism. Studies showed that once the nucleus pulposus enters into vascular tissue, the immune system could recognize it as a foreign body, and induces the immunological reaction. Then, there would be osteoimmunology action, a crosstalk between the immune system and bone, leading to bone loss by dysregulating T-lymphocyte function, and resulting to the bone absorption. Furthermore, the cytokines are involved in the development of immunological reactions and could be responsible for the significant pathology of symptomatic SNs. Given the above background, we hypothesize that immune system could be a key role in SNs and result in the pain.

Early spondyloarthritis: usefulness of clinical screening.

OBJECTIVES: To evaluate the usefulness of clinical parameters in screening for early SpA in patients meeting Calin's criteria for inflammatory back pain (IBP). METHODS: General practitioners used Calin's criteria for IBP to refer patients younger than 45 years to our early SpA clinic. We obtained the patients' medical history and performed a clinical examination including plain X-rays and magnetic resonance images of all affected areas. Laboratory tests for acute-phase reactants and HLA-B27 were also obtained. Two rheumatologists made a diagnosis of SpA according to the existing criteria. RESULTS: Of the 92 patients referred, 30 (33%) were diagnosed with SpA and 62 (67%) with a non-inflammatory disorder. Spontaneous awakening night pain, the presence of Calin's criteria for IBP and tenderness of the SI joints (SIJs) were independently associated with SpA. Neck pain and reduced cervical spine sagittal movement occurred mostly with non-inflammatory disease. A history of night pain and improvement of pain with exercise but not with rest, as well as expression of HLA-B27 and abnormal CRP levels were significantly more common in patients with SpA. CONCLUSIONS: Specific clinical symptoms such as spontaneous awakening night pain, cervical pain and tenderness of the SIJs on clinical examination appear useful in screening younger patients with back pain for early SpA.