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.

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.

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.

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.

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.

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.

Cervical spine involvement in rheumatoid arthritis--a systematic review.

Rheumatoid arthritis (RA) is a systemic chronic inflammatory disorder that can compromise the cervical spine in up to 80% of the cases. The most common radiological presentations of cervical involvement are atlantoaxial subluxation (AAS), cranial settling and subaxial subluxation (SAS). We performed a systematic review in the PubMed Database of articles published later 2005 to evaluate the prevalence, progression and risk factors for cervical spine involvement in RA patients. Articles were classified according to their level of evidence. Our literature review reported a wide range in the prevalence of cervical spine disease, probably explained by the different studied populations and disease characteristics. Uncontrolled RA is probably the main risk factor for developing a spinal instability. Adequate treatment with DMARD and BA can prevent development of cervical instabilities but did not avoid progression of a pre-existing injury. MRI is the best radiological method for diagnosis cervical spine involvement. AAS is the most common form of RA. Long term radiological follow-up is necessary to diagnosis patients with late instabilities and monitoring progression of diagnosed injuries.

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.

Chronic recurrent multifocal osteomyelitis primarily affecting the spine treated with anti-TNF therapy.

STUDY DESIGN: A case report describing chronic recurrent multifocal osteomyelitis (CRMO) with initial presentation limited to spine, successfully treated by anti-TNF-alpha therapy after failure of conventional treatment methods. OBJECTIVE: To describe an unusual manifestation and treatment of a rare disease. SUMMARY OF BACKGROUND DATA: CRMO is a rare inflammatory bone disease that should be differentiated from bacterial osteomyelitis. Rarely, it can affect the spine and in this case the most important differential diagnosis is infectious spondylodiscitis. The disease has an unpredictable course with exacerbations and spontaneous remissions. Although the majority of cases remit spontaneously (or after the use of nonsteroidal anti-inflammatory drugs [NSAIDs]), some progressive and resistant cases have been reported. METHODS: We describe a case of CRMO with an unusual clinical presentation emphasizing the importance of this finding as a differential diagnosis of spondylodiscitis and comment on the available treatment alternatives. RESULTS: A 17-year-old man presented with debilitating dorsal spine pain. Magnetic resonance imaging of the spine revealed bone lesions at multiple vertebral levels. After failure of antibiotic treatment, the diagnosis of CRMO was suggested. An initial good response to NSAIDs was followed by a recurrent course and involvement of peripheral joints besides the use of corticosteroids and other drugs. The introduction of infliximab was followed by complete remission of the disease. CONCLUSION: Our observation highlights the need of awareness for the differential diagnosis in suspected cases of osteomyelitis not responding to antibiotics. Anti-TNF-alpha agents should be considered in CRMO refractory cases.

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.

Does Acute placement of instrumentation in the treatment of vertebral osteomyelitis predispose to recurrent infection: long-term follow-up in immune-suppressed patients.

STUDY DESIGN: Single institution, prospective observation study. OBJECTIVE: To determine the long-term clinical outcomes of immune-suppressed patients with pyogenic vertebral osteomyelitis (PVO) treated with spinal instrumentation in the setting of active infection. SUMMARY OF BACKGROUND DATA: The mainstay of treatment for PVO remains nonoperative. Surgical indications include neurologic compromise, deformity, abscess and failure of medical management. Some authors have been concerned regarding risk of local infection reoccurrence when spinal instrumentation has been placed in the setting of active infection. To our knowledge no long-term follow-up has been reported for this condition. METHODS: Thirty-two consecutive immune compromised patients with PVO were treated with debridement and spinal instrumentation in the setting of acute infection at a single institution. Patients were observed by a set protocol and evaluated for reoccurrence of infection at regular intervals for up to 10 years. RESULTS: The 32 patients in our study group had significant medical comorbidities and were immune compromised. All patients were treated with single stage debridement and instrumented fusion during active infection. Twenty-two patients had a full 10 years follow-up without clinical recurrence of the local infection. Four patients died during the observation period, and none had clinic or autopsy evidence of recurrence. One patient developed recurrent infection after 14 months and was successfully treated with repeat debridement and retention of the instrumentation. Although this patient had a chronically infected vascular shunt, he was disease free at final follow-up of 10 years. Four patients had their implants removed for pain, suspected nonunion or suspected recurrent infection. None of these patients had histologic or microbacteriological evidence of injection. CONCLUSION: The use of spinal instrumentation in immune-compromised patients with PVO is associated with a low risk of long-term recurrent infection.

Transplantation of mesenchymal stem cells in a canine disc degeneration model.

Transplantation of mesenchymal stem cells (MSCs) is effective in decelerating disc degeneration in small animals; much remains unknown about this new therapy in larger animals or humans. Fas-ligand (FasL), which is only found in tissues with isolated immune privilege, is expressed in IVDs, particularly in the nucleus pulposus (NP). Maintaining the FasL level is important for IVD function. This study evaluated whether MSC transplantation has an effect on the suppression of disc degeneration and preservation of immune privilege in a canine model of disc degeneration. Mature beagles were separated into a normal control group (NC), a MSC group, and the disc degeneration (nucleotomy-only) group. In the MSC group, 4 weeks after nucleotomy, MSCs were transplanted into the degeneration-induced discs. The animals were followed for 12 weeks after the initial operation. Subsequently, radiological, histological, biochemical, immunohistochemical, and RT-PCR analyses were performed. MSC transplantation effectively led to the regeneration of degenerated discs. FACS and RT-PCR analyses of MSCs before transplantation demonstrated that the MSCs expressed FasL at the genetic level, not at the protein level. GFP-positive MSCs detected in the NP region 8 weeks after transplantation expressed FasL protein. The results of this study suggest that MSC transplantation may contribute to the maintenance of IVD immune privilege by the differentiation of transplanted MSCs into cells expressing FasL.

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 epidural Rosai-Dorfman disease preceding by relapsing uveitis: a case report with literature review.

STUDY DESIGN: Case report. SETTING: Tertiary referral center hospital in Taiwan. OBJECTIVES: To report a case of spinal Rosai-Dorfman disease (RDD) presenting with paraparesis and also preceding by relapsing uveitis for 6 months. A thoracic laminectomy was performed to remove the solid mass. The pathological diagnosis reveals infiltrating histiocytes, emperipolesis and positivity for S-100. There is no recurrence 1 year later with MR imaging. CONCLUSIONS: The relapsing idiopathic uveitis may be a prodrome for this unusual disease, because RDD is associated closely to defective immunogical response. Early and accurate diagnosis of CNS RDD may reverse the neurologic deficits by early decompression.

[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.

The importance of bacterial superantigens produced by Staphylococcus aureus in the treatment of atopic dermatitis using povidone-iodine.

Atopic dermatitis (AD) is frequently associated with intestinal and cervical lesions. Staphylococcus aureus produces many kinds of toxins, the bacterial superantigens. The detection rate of toxins was 80.1% from 196 S. aureus strains. Neurological examinations revealed abnormalities in 59 out of 81 AD patients. Cervical magnetic resonance imaging (MRI) was performed in 46 patients randomly and showed abnormal findings in 38 of these patients. In 23 patients who underwent MRI and duodenal biopsy, 3 were found to be normal neurologically and 2 patients showed normal duodenal tissue. However, 18 patients had abnormal findings both on neurological examination and in duodenal tissue. Serial duodenal biopsy tests were performed in 10 AD patients. In 5 patients, the findings of chronic duodenitis disappeared after the therapy with povidone-iodine. These data indicate that the therapy was effective not only for the skin lesions, but improved gastrointestinal tract lesions and cervical myelopathy, by eradicating bacterial superantigens.

[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.

[On isolated neck sarcoidosis]. / W sprawie odosobnionej sarkoidozy szyi.

The authors present actual opinions concerning etiology, pathogenesis and diagnostics of sarcoidosis with specific evaluation of the role of T lymphocytes and cytokines in formation of sarcoid granulation. Rareness of sarcoidosis in that region and difficulties in neck tumours diagnosis is emphasizing. In solitary sarcoidosis cases it is necessary to take a sarcoid reaction into consideration. It always can go into generalized form. The authors present a case of solitary sarcoidosis of the neck.

[Assessment of the immuological status in patients with nonspecific spinal osteomyelitis]. / K voprosu ob otsenke immunologicheskogo statusa u bol'nykh s nespetsificheskim osteomielitom pozvonochnika.

The authors describe results of the investigation of the immunological status of 54 patients with nonspecific osteomyelitis of the spine (NOS). The immunological status of NOS patients was shown to be substantially different in the acute and chronic phases of the disease. Cases with lower T-lymphocyte activity, with a dysfunction of the phagocytic activity of lymphocytes prevail in the acute phase. Patients with septic forms of NOS have a hyperergic systemic inflammatory response which is accompanied by functional defectiveness of T-lymphocytes and excessive stimulation of the humoral link. Patients with the chronic form of NOS as a rule have hypoergic systemic inflammatory response with the normal quantity of T-cells, non-completed phagocytosis and high activity of B-lymphocytes (CD20, CD25). So, the early immunological diagnosis of NOS allows prognosis of the disease course and a timely decision for the pathogenetical therapy.