Extractable Nuclear Antibodies Research Articles

Red blood cell distribution width as a surrogate biomarker of damage and disease activity in patients with systemic lupus erythematosus.

Red blood cell distribution width (RDW) is a measure of variability in mean corpuscular volume. Alterations in RDW can be observed in a variety of human disorders, including inflammatory, cardiovascular, and hepatic or renal diseases. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect virtually any organ in the body. In this work, our objective was to analyse how a complete characterisation of disease characteristics in a large series of patients with SLE is related to RDW values. 284 patients with SLE and 181 age- and sex-matched healthy controls were recruited. Complete blood count including RDW was assessed. Multivariable analysis was performed to analyse the relationship between RDW and SLE disease characteristics, including composite scores of disease activity and damage. After multivariable adjustment, RDW was higher in patients with SLE compared to controls (beta coefficient 0.8 [95% confidence interval: 0.3-1] %, p=0.003). Several disease characteristics, such as the presence of extractable nuclear antibodies and antiphospholipid syndrome, and the use of prednisone and azathioprine, were significantly associated with higher levels of RDW after adjustment for confounders. Of note, cumulative disease damage and disease activity scores were associated with higher RDW values after controlling for covariates. RDW may serve as a surrogate biomarker of accrual disease damage and activity in patients with SLE.

The risk of development of primary biliary cholangitis among incidental antimitochondrial M2 antibody-positive patients.

This study investigated the risk of the development of primary biliary cholangitis (PBC) in individuals who were incidentally identified as having positive antimitochondrial antibodies (AMA)-M2. We retrospectively reviewed extractable nuclear antibody (ENA) panel test results to identify the incidental AMA-M2-positive patients. Patients who filled the diagnostic criteria for PBC were excluded. AMA-M2-positive patients were further evaluated by physical examination, liver biochemistry, liver ultrasonography, and transient elastography (TE) and were also closely followed. We included 48 (n=45, 93% female) individuals with a median age of 49 (range: 20-69) years. The median follow-up duration was 27 months (range: 9-42) after the detection of AMA-M2. Thirty-three (69%) patients had concomitant autoimmune/inflammatory disorders. Twenty-eight (58%) individuals showed seropositivity for ANA, and 21 had (43%) positive AMA. Fifteen (31%) patients developed typical PBC according to the international PBC diagnostic criteria during the follow-up, and five of them (18%) had significant fibrosis (≥8.2 kPA) by TE at the time of PBC diagnosis. Two-thirds of the incidental AMA-M2-positive patients developed typical features of PBC after a median 27-month follow-up. Our results suggest that AMA-M2 patients should be closely followed up to detect the late development of PBC.

Resolvins Modulate Netosis and Autoimmunity in Sickle Cell Disease

Sickle cell disease (SCD) is a genetically determined hematological disease which is characterized by anemia, chronic hemolysis, and multi-organ chronic inflammatory vasculopathy with acute vaso-occlusive painful crises and chronic organ damage. The pathophysiology of SCD is complex and involves several other cell types and metabolic pathways than erythrocytes, including neutrophils and soluble factors such as cytokines or alternative complement pathway which affect the function of vascular endothelium. An inflammatory vasculopathy with chronically activated neutrophils releasing Neutrophil Extracellular Traps (NETs) is a key component of the pathophysiology of sickle cell disease (SCD). Chiang et al. have recently shown that resolvins (Rv) reduce NETS and improve NETs clearance in a model of sepsis by Staphylococus aureus, a known trigger of NETosis (Chiang N et al. Blood 139 (8): 1222, 2022). We previously reported that targeting pro-resolution mechanisms with Rv improves SCD vasculopathy and organ damage in humanized sickle mice. Here, we studied 23 adult patients with SCD, followed by the Comprehensive center for hemoglobinopathies and rare anemias, University of Verona and AOUI Verona from January 2019 to December 2021. For each patient the presence/absence of concomitant rheumatological condition such as rheumatoid arthritis, other inflammatory arthropathies, immune-mediated dermatological conditions, Sicca syndrome and Raynaud's phenomenon, were assessed. Eight age, and ethnicity matched healthy controls were analyzed. Blood was collected for hematological and biochemical assay as part of the standard clinical care for these patients. Additional blood was collected for research studies on whole blood and on plasma cytokines. SCD patients display significant increase in tumor- necrosis-factor (TNF)- α (p = 0.011) and interleukin (IL)-10, suggesting both active inflammatory state and an upregulated counterregulatory mechanism to limit inflammation. We observed that antinuclear antibodies (ANA), but not extractable nuclear antibodies (ENA), were significantly increased in SCD patients (provide specific data here). Previous reports have reported the presence of this type of autoantibodies in the absence of autoimmune clinical manifestations in patients with SCD (Toly-Ndour C et al J Rheumatol 38: 302, 2011). ANA+ SCDsubjects (defined by a cell nuclei homogenous pattern, and positive dilution in the 1:80 to 1: 160 range) had a higher inflammatory and hemolytic status, as demonstrated by increased WBC and neutrophil counts and LDH values compared to ANA- subjects. NETosis plays a key role in modification and externalization of autoantigens involved in production of autoantibodies such as ANA. Here, we found basal NETosis was higher, though not significant, in ANA+ SCD subjects compared to ANA-SCD patients. This was associated with lower expression of receptors for RvD1 and D2, namely ALX, GPR32/DRV1, and GPR18/DRV2 on PMN, monocytes, and lymphocytes from ANA+ SCD patients when compared to ANA- SCD subjects, who were also characterized by relatively low LDH compared to ANA+ SCD patients. Exogenous treatment of SCD neutrophils with RvD1 and D4 significantly dampened NETs release and enhanced NETs clearance by macrophages. RvD4 along with other pro-resolving mediators also stimulated ex vivo clearance of P. aeruginosa and S. aureus by SCD neutrophils. Our findings provide a novel link between autoimmunity and neutrophil-mediated vasculopathy in SCD and highlight the importance of Rv and their immune-pro-resolution effects in limiting disease progression in SCD but also to modulate the host response to infections and sepsis, which is altered in SCD.

Clinical implications of autoantibodies to extractable nuclear antigens in rheumatoid arthritis patients in tertiary care hospital in Riyadh, Saudi Arabia

The purpose of this study was to assess the prevalence of autoantibodies against extractable nuclear antigens (ENAs), anti-Ro/SSA, anti La/SSB, anti Jo-1, ribo-nucleoproteins (anti UI-RNP) and antibodies to Smith (anti-Sm) in rheumatoid arthritis (RA) patients and to detect the relationship between the existence of these autoantibodies and clinical presentation, radiological damage, and disease activity markers. The study, included 57 RA patients and 35 normal controls, was conducted in Al-Quwayiya General Hospital. Sera were obtained from patients and controls to carry out Hs-CRP, ESR, RF factors, ANA and ACPA IgG. Anti-Sm, anti-U1-RNP, anti-Ro/SSA, anti-La/SSB, and anti-Jo-1 were measured using the Alegria® assay. ESR was 23.8±6.5, while CRP was 16.19±7.15 in RA patients. RF was detected in 23 (40.35%) patients and ACPA in 54 (94.73%), while ANA was positive in 14 (24.56%) cases. Anti-Ro/SSA was detected in 8 (14.03%) patients, anti-La/SSB in 3 (5.26%), anti-Jo-1 was found in 2 cases (3.50%), and anti-RNP in 1 (1.75%). Anti-Ro/SSA had a significant negative relationship with sex (r=-0.220, P=0.001), but a positive correlation was observed with sicca symptoms (r=0.149, P=0.02). Anti-La/SSB antibodies correlated positively with swollen joint count (r=0. 0.225, P=0.001), tender joint count (r=0.219, P=0.001) and ANA (r=0.367, P < 0.001). Anti-Jo-1 antibodies showed a significant positive correlation with interstitial lung disease (r=-0.429, P≤0.001). Anti-Ro/SSA had a significant positive correlation with RF titer (r=0.259, P < 0.001) and ANA (r=0.498, P < 0.001). Anti-La/SSB had significant positive correlation with ANA (r=0.372, P < 0.001). Anti-Jo-1 showed a significant positive correlation with RF titer (r=0.141, P < 0.040) and ANA (r=0.249, P < 0.001). Anti-RNP showed a significant positive correlation with ACPA titre (r=0.288, P < 0.001) and ANA (r=0.159, P < 0.018). We conclude that ENA autoantibodies are crucial and need to be correlated with clinical diagnosis and other serological testing for early diagnosis and intervention of the RA.

British Association of Dermatologists guidelines for the management of people with cutaneous lupus erythematosus 2021.

The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of cutaneous lupus erythematosus (CLE) in the presence or absence of systemic lupus erythematosus (SLE) in adults, young people and children. The document aims to: offer an appraisal of all relevant literature up to December 2020, focusing on any key developments address important, practical clinical questions relating to the primary guideline objective. provide guideline recommendations and if appropriate research recommendations.

Non-organ-specific autoimmunity in adult 47,XXY Klinefelter patients and higher-grade X-chromosome aneuploidies.

Current literature regarding systemic autoimmune diseases in X-chromosome aneuploidies is scarce and limited to case reports. Our aim was to evaluate the frequency of anti-nuclear (ANAs), extractable nuclear (ENA), anti-double-stranded DNA (dsDNAs), anti-smooth muscle (ASMAs) and anti-mitochondrial (AMAs) antibodies in a large cohort of adults with Klinefelter's syndrome (KS, 47,XXY) and rare higher-grade sex chromosome aneuploidies (HGAs) for the first time. Sera from 138 X-chromosome aneuploid patients [124 adult patients with 47,XXY KS and 14 patients with HGA (six children, eight adults)] and 50 age-matched 46,XY controls were recruited from the Sapienza University of Rome (2007-17) and tested for ANAs, ENAs, anti-dsDNAs, ASMAs and AMAs. Non-organ-specific immunoreactivity was found to be significantly higher in patients with 47,XXY KS (14%) than in the controls (2%, p=0.002). Among all the antibodies investigated, only ANAs were observed significantly more frequently in patients with 47,XXY KS (12.1%) than in the controls (2%, p=0.004). No anti-dsDNA immunoreactivity was found. Stratifying by testosterone replacement therapy (TRT), non-organ-specific autoantibody frequencies were higher in TRT-naive (p=0.01) and TRT-treated groups than in controls. No patients with HGA were found positive for the various autoantibodies. Non-organ-specific autoantibodies were significantly present in 47,XXY adult patients. Conversely, HGAs did not appear to be target of non-organ-specific immunoreactivity, suggesting that KS and HGAs should be considered as two distinct conditions. The classification and diagnosis of systemic autoimmune diseases is frequently difficult. To support a correct clinical evaluation of KS disease and to prevent eventual secondary irreversible immune-mediated damages, we highlight the importance of screening for non-organ-specific autoimmunity in Klinefelter's syndrome.

Coexisting systemic and organ-specific autoimmunity in MOG-IgG1-associated disorders versus AQP4-IgG+ NMOSD

Aquaporin-4 (AQP4) neuromyelitis optica spectrum disorder (NMOSD) has been demonstrated to be associated with non-organ and organ-specific autoantibodies (antinuclear antibody, extractable nuclear antibody, double-stranded DNA, muscle acetylcholine receptor antibody) and systemic autoimmune diseases. In this study, we evaluated whether a similar association with non-organ and organ-specifc autoantibodies occurs in patients with MOG-IgG1-associated disorders. We determined that MOG-IgG1 was not strongly associated with these organ and non-organ-specific autoantibodies. Systemic lupus erythematous (SLE) was significantly associated with AQP4-IgG+ NMOSD and not with MOGAD (p = 0.037). These findings suggest differences in co-existing systemic and organ-specific autoimmunity between MOGAD and AQP4-IgG+ NMOSD.

Appropriateness of laboratory tests in the diagnosis of inflammatory rheumatic diseases among patients newly referred to rheumatologists.

Autoantibody tests are commonly ordered when screening for rheumatic diseases. Rheumatoid factor (RF) and antinuclear antibody (ANA) have low positive predictive values in general practice. Overuse of diagnostic tests can result in an increase in unnecessary referrals, patient anxiety, and further costs. The objective was to evaluate the utilization patterns, appropriateness, and associated costs of tests including ANA, extractable nuclear antibodies (ENA), anti-double stranded DNA (anti-dsDNA), RF, and HLA-B27 in patients referred to rheumatologists. A review was conducted of consecutive referrals (accepted and rejected) using university rheumatologists' practices over one year. Inappropriate investigations, and associated costs were analyzed. Tests were considered appropriate if at least one criterion for a specific disease was provided. Of 638 referrals the most common reported reasons for referral were: spondyloarthropathies (SpA), rheumatoid arthritis (RA), and lupus (SLE). Prior to referral: 61% had undergone ANA testing at least once, ANA was repeated in one third; 19% had ENA and 21% had anti-dsDNA. 20% had ANA testing with no clinical indication. Half of ENA and anti-dsDNA testing was in the context of a negative ANA. RF was requested in 65% and in close to one third, there was no clinical suspicion of inflammatory arthritis. Despite the recommendations by CRA Choosing Wisely Campaign, at least 50% of laboratory investigations, including RF, ANA, ENA, and anti-dsDNA, are inappropriately ordered. More selective ordering of the above tests would lead to marked cost reduction.

EP10 A rare cause of lobular panniculitis

Abstract Background Weber-Christian disease is a rare inflammatory disorder of the subcutaneous fatty tissue. It is characterised by painful relapsing, subcutaneous nodules occurring preferentially at the upper arm, thigh and trunk regions. The disease is often accompanied by recurrent temperatures and constitutional symptoms. Methods We aimed to increase awareness regarding clinical presentation, diagnosis, and treatment of this rare disorder. Results A 65 year old female had been investigated thoroughly within a period of 7 years by a number of dermatology and rheumatology departments of North West hospitals. Symptoms started after mastitis with skin rash in form of macular blanching on upper abdomen and episodes of fever ranging between 38 and 40 degree Celsius, fatigability and arthritis. C-reactive protein was 300 mg/l, Erythrocytes Sedimentation Rate 150 mm/H and haemoglobin 95 g/L, positive lupus anticoagulant and negative anti-nuclear antibodies as well as extractable nuclear antibodies and normal complement levels C3 and C4 . Investigations results showed no evidence of infection, malignancy, vasculitis or connective tissue disease. PET scan revealed subcutaneous fat inflammation with increased uptake in mediastinum fat, initial skin biopsy showed lobular panniculitis with mild dermatitis suggestive of lupus profundus. Symptoms and inflammatory markers responded well to steroids however all tried DMARDs (methotrexate, azathoprime, hydroxychlorquine and mycophenolate) as well as dapsone and colchicine were not successful. In addition, 2 doses of rituximab were also ineffective in controlling her disease. Following a required excessive steroid therapy she developed cataract, osteopenia, and diabetes and became cushingoid. Repeated biopsy from the skin showed mixed inflammatory lobular pannicuilitis with neutrophils, lymphocytes and histiocytic. As per Dermatology Multi-Disciplinary Team the diagnosis of Weber-Christian disease was raised. As her condition continued to be very active she was also referred to London, where treatment with anakinra was organised. Conclusion The diagnosis of Weber-Christian disease depends on the presence of relapsing fever, systemic inflammation and panniculitis and prognosis varies depending on the response to steroids or DMARDs. For diagnosis you need to exclude all likely differential diagnoses of lobular panniculitis, like infections, certain malignancies, alpha-1-antitrypsin deficiency, pancreatitis and systemic lupus erythematosus. In conclusion, the patient has symptoms and signs as well as investigation results in keeping with Weber-Christian disease. Due to the rare nature of this disease the patient went through, multiple rheumatology and dermatology reviews and investigations and treatment trials over a period of 7 years prior to the correct diagnosis being reached. We believe reporting this case would raise awareness and improve on future patients journeys and care. Disclosures T. mudawi None. C. Amoasii None. A. Clewes None.

The evaluation of cellular immune function in elderly patients with systemic lupus erythematosus.

Background/AimsTo evaluate cellular immune function in systemic lupus erythematosus (SLE) patients over 60 years old, the association between antinuclear antibody (ANA) titers and the ratio of CD4+ /CD8+ was analyzed in this study. The distribution of ANAs and extractable nuclear antibodies (ENAs) in a healthy elderly population was also investigated.MethodsSerum ANA titers were assayed by indirect immunofluorescence (IIF) and the CD4+ /CD8+ T-cell ratio was determined by flow cytometry in 76 SLE patients and 30 healthy control individuals. IIF of cytoplasm and nuclear and nucleolar staining were performed on samples taken from 286 healthy elderly individuals. ENA levels were determined using a strip enzyme immunoassay among patients that tested positive for ANAs.ResultsANA titers were negative in the 30 control individuals, but were positive in the 76 SLE patients. Based on ANA titers, the SLE patients were stratified to low (≤ 1:320), medium (1:640 to 1:1,280), and high (≥ 1:2,560) titer groups. The average CD4+ /CD8+ ratio of the SLE group was significantly lower than that of the control group. Among the 286 healthy elderly volunteers, 59 (20.63%) tested positive for ANAs. A homogeneous pattern was present in 47.46% of those 59 patients and a granule pattern in the karyoplasm was present in 33.90%. Furthermore, of the 59 patients, ENAs immunoassay was positive in 18 (30.51%); Sjogren syndrome-related antigen A (SSA)/52 kd and Sjogren syndrome antigen B (SSB)/La were the two major antibodies.ConclusionsThe significantly lower CD4+ /CD8+ ratio among SLE patients over 60 years old is associated with deregulated immune responses and the development of SLE. A low ANA titer (1:160) is common in healthy elders, emphasizing the importance of considering age when determining if the evaluation of ANA titers is to be included in autoimmune disease diagnosis.

Juvenile systemic lupus erythematosus in Nigeria.

Juvenile systemic lupus erythematosus (JSLE) is a complex multisystemic autoimmune disorder of unknown cause. It accounts for about one in five cases of SLE. The tendency for SLE to run a fulminant course when it starts in childhood has made JSLE a potentially more severe disease than adult SLE. Reports of JSLE from sub-Saharan Africa are scanty in spite of the increasing reports of adult SLE. We conducted a 4-year retrospective study of JSLE cases seen at the Lagos State University Teaching Hospital between January 2010 and December 2014. Out of the 12 patients studied, eight were girls and four were boys. All patients had positive antinuclear antibody and extractable nuclear antibody tests. Anti-dsDNA antibody was positive in 10 patients. Eight patients had renal disease while four patients had neuropsychiatric manifestations. Haematological abnormalities and constitutional symptoms were present in all patients. Patients were treated with pulse methylprednisolone, oral prednisolone, hydroxychloroquine and azathioprine. Three patients also received rituximab. In conclusion, JSLE exists in Nigeria and exhibits clinical and immunological characteristics similar to its pattern in other parts of the world. It is, however, diagnosed late and is possibly being underdiagnosed as there is no paediatric rheumatologist in the country.

Ultrasound of the salivary glands is a strong predictor of labial gland biopsy histopathology in patients with sicca symptoms.

The international classification criteria for Sjögren's syndrome necessitate the presence of either extractable nuclear antibody or a characteristic focal inflammatory infiltrate in a minor salivary gland. Thus, patients who are extractable nuclear antibody-negative will need to have a labial salivary gland biopsy, which is an invasive procedure associated with morbidity. The aim of this study was to evaluate the viability of ultrasound imaging of the major salivary glands as a predictor of the histology to explore whether ultrasound can help in stratifying Sjögren's patients and reduce the need for biopsy. The records of 85 patients suspected of having Sjögren's syndrome and who have had biopsy and ultrasound were analysed retrospectively. The histology and the ultrasound were reported by experts independently. The reporting was impartial as the examiners were blinded to the results of the other investigations and to the diagnosis. Out of the 85 patients, 34 had positive ultrasound, 29 of whom also had positive histology. Fifty-one patients had negative ultrasound, of whom 49 were also negative for histological features of Sjögren's syndrome. The results show that the ultrasound had a positive predictive value of 85% and a striking negative predicative value of 96% of the histology results. The overall concordance between the ultrasound and the histology was 91% (Kappa = 0.826). Our study shows that potentially the ultrasound has a role in stratifying patients who are extractable nuclear antibody-negative and can help to prioritize the biopsy for those who have sonographic evidence of SS.

The value of autoantibody testing in a central triage system

The referral of patients with positive anti-nuclear antibody (ANA) tests to specialists has been criticised as an inappropriate use of tertiary care resources. On the other hand, an accurate and timely diagnosis in patients with a positive ANA and protean symptoms can lead to improved health outcomes while reducing health care costs. In order to address this apparent paradox, we studied the serological profiles and clinical diagnoses of patients referred to rheumatologists through a regional triage system because of a positive ANA or extractable nuclear antibody (ENA) test. As an approach to informing an evidence based approach to triage, the primary objectives were to document the most common ANA specificities, the presence of anti-dense fine speckled (DFS70) antibodies and the specialist’s clinical opinion. The spectrum of autoantibody specificities was wide with anti-Ro52/TRIM21, which has been established as a biomarker for SARD, being the most common autoantibody detected. In addition, some referred patients had only antibodies to DFS70, the majority of which did not have clinical evidence for a definite diagnosis of a SARD. This study implies that there is value in determining autoantibody specificity in a rheumatology triage service by providing a general guideline to referrals that require urgent versus less urgent attention.

Polynesian Variant Of Idiopathic Multicentric Castleman Disease

Multicentric Castleman Disease (MCD) is an uncommon non-clonal lymphoproliferative disease that traditionally has high morbidity and carries a poor prognosis, with median survival of 26-30 months. There has been growing interest in using interleukin-6 (IL-6) as a therapeutic target due to its role in the pathogenesis of MCD. In our practice, we noted a high number of Polynesian patients with idiopathic MCD (iMCD) and their prognosis appeared good. We therefore carried out a retrospective review. Via email survey, laboratory audit and our local database we identified 13 patients with MCD. Twelve patients were HIV and HHV8 negative hence classified as having iMCD; one patient was positive for HIV and HHV8.Of the twelve patients with iMCD (five females, seven males), the median age at diagnosis was 53 (41 - 70). Eleven patients had plasma cell variant; one patient's MCD subtype was not available. 83.3% (10 of 12 patients) were of Polynesian decent: New Zealand Maori (4), Samoan (3), and Niuean (3). Polynesian subjects had fewer general symptoms compared to literature: weight loss 40%, fever 20%; Skin lesions were observed in 60%, 60% had splenomegaly and 40% had polyarthrialgia related to MCD. There is a recognized association between autoimmune disease and MCD. In our series, 6 of the 12 patients had some form of autoantibodies, including antinuclear antibodies, extractable nuclear antibodies and anti-cardiolipin antibodies; however only 2 patients had confirmed autoimmune diseases, with Grave's disease in one and concurrent autoimmune haemolytic anaemia and coeliac disease in another patient. The median baseline gammaglobulin (IgG) was 61g/L (12- 96), C-reactive protein (CRP) was 105mg/L (39 - 219) and hemoglobin (Hb) was 89g/L (50 - 118), excluding one Polynesian patient who was an outlier with a CRP of 1 and Hb of 140. We traced pre-diagnosis electronic records of biochemical markers, such as total protein and total globulin levels, an indirect marker for hypergammaglobulinaemia. We could not find a normal value amongst the Polynesian patient group prior to the diagnosis, abnormalities were noted up to 6 years pre-diagnosis. Despite the biochemical derangement of most patients, performance status was high and 80% of the Polynesian patients remained at work. The mean duration of disease after tissue diagnosis was 5.3 years whereas the mean duration of biochemical evidence of disease presence was 9.2 years.Various therapies including corticosteroid (dexamethasone or prednisone), Rituximab and chemotherapeutic agents were used with mixed but mostly non-durable response until 2009 when those needing treatment were given targeted treatment to block IL-6 with Tocilizumab (6) or Siltuximab (2 in a randomized double-blind placebo controlled study; results will be presented separately). Tocilizumab was administered as an intravenous infusion (at 8mg/kg) in a 3-4 weekly cycle. We used CRP as a measure of the response to treatment. By aiming for a low CRP (i.e. less than 20mg/L) rather than a normal CRP value, at the end of each cycle, we were able to increase the time interval between treatment cycles and therefore rationalize treatment frequency. The median duration of therapy was 19 months during which we saw normalization of Hb in 6/6 of patients, their median hemoglobins increasing from 87g/L (69 - 140) to 133g/L (118 - 157). There were significant improvement of IgG from 65g/L (42 - 96) to 32g/L (17 - 59); CRP from 86mg/L (39 - 160) to 4mg/L (1 - 23). Treatment was stopped in 2/6 patients with subsequent relapse, and response to tocilizumab retreatment. There were three deaths in the entire patient group, only 1/10 Polynesian, and all three patients died before IL-6 specific therapy became available.Because most patients had high levels of IgG, we reviewed all patients tested at North Shore Hospital in the past 3 years with a polyclonal increase of IgG>35g/l and identified 3 further patients, all Polynesian, with blood test consistent with iMCD. Clinical follow-up on these patients was not available.Our review demonstrates a disproportionately large group of Polynesians with iMCD, with distinctively favourable disease outcome. iMCD shows promising response to IL-6 targeted therapy. Based on the chronicity of the IgG elevation and the genetic association, we speculate that the up-regulation of IL-6 could be related to a defect in IL-6 regulation. Similar clinical cases have also been described in Japan. Disclosures:No relevant conflicts of interest to declare.

A woman with ataxia, nystagmus and headache

past medical history, she was not taking any medicationand had recently moved to the UK. She was apyrexial and hercardiovascular observations were stable. Neurological examina-tion revealed bilateral horizontal gaze-evoked nystagmus andsymmetrical finger–nose, heel–shin and gait ataxia with dysdi-adochokinesia. Her haematological and biochemical parameterswere normalexceptforaslightlyraisederythrocytesedimentationrate (ESR=34mm/h). Angiotensin converting enzyme, carcino-embryonic antigen, CA-125, CA-199 and vitamin D levels werenormal. Antinuclear antibodies, extractable nuclear antigens andanti neutrophil cytoplasmic antibodies were negative. Serum elec-trophoresis testing for immunoglobulins was normal. A malariascreen was negative. Treponemal antibody and toxoplasma IgGwere negative. Virology investigations are described in Table 1.Generalised cerebellar atrophy was observed on a head CT. AnMRI showed T2 hyperintensity within the right middle cerebellar

Successful living related kidney transplantation for end-stage renal failure caused by orellanine syndrome

A 43-year-old previously healthy man presented with a 10-day history of feeling unwell, nausea, vomiting, diarrhoea, myalgia and fever. He had not passed urine for 2 days. He was not taking any medications and denied taking recreational or ‘over the counter’ drugs. On examination, he was dehydrated. Blood pressure was 150/90 mmHg. Systemic examination was otherwise normal. Initial blood/serum tests were as follows: creatinine 2650 μmol/l, urea 50 mmol/l, potassium 6.7 mmol/l, sodium 128 mmol/l, C-reactive protein 30 mg/l, normal liver function tests and haemoglobin 14.4 g/dl. Urine microscopy revealed haematuria and leukocyturia but no proteinuria or casts. Chest X-ray showed congested lung fields. Renal ultrasound showed echogenic but normal sized kidneys with no evidence of obstruction. Anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, extractable nuclear antibodies, anti-glomerular basement membrane antibodies and myeloma screen were negative. Kidney biopsy performed 3 days after admission showed normal glomeruli, severe interstitial nephritis with a predominantly lymphocytic infiltrate and moderate degree of tubular necrosis. Staining for immunoglobulins and complement was negative. Electron microscopy showed no glomerular deposits. The patient was commenced on haemodialysis from the day of admission. As the aetiology of this patient’s acute kidney injury (AKI) was still unknown, history was revisited. He accepted eating raw wild mushrooms whilst on a backpacking trip in the mountains of north Wales in the UK, …

Patient With a Rash, Abdominal Pain, and Weight Loss

A 49-YEAR-OLD MAN PRESENTS WITH RIGHT ILIAC FOSSA PAIN OF 36 HOURS’ duration. He reports loss of appetite, weight loss, and increasing lethargy over the preceding 10 months with intermittent constipation but no other symptoms. He describes asymmetric altered sensation in his distal lower limbs with left worse than right. The patient smokes, has a history of illicit amphetamine and cannabinoid use, and acquired tattoos in a correctional facility. Past medical history is remarkable for an idiopathic splenic infarction 6 months ago. On physical examination, he is cachectic and he has right iliac fossa tenderness and percussion tenderness. He has a demarcated, erythematous maculopapular rash across his torso and limbs (FIGURE 1). Neurological examination reveals an asymmetric lower limb sensory neuropathy. Laboratory findings include leukocytosis (whitebloodcells, 16 900/μL), elevated inflammatorymarkers (C-reactiveprotein,109g/L; erythrocyte sedimentationrate, 27 mm/h), elevated rheumatoid factor (269 IU/L), low C3 and C4 (0.24 and 0.05 g/L, respectively), and a low titer of atypical perinuclear antineutrophil cytoplasmic antibody(ANCA),not selective foreitherproteinase3ormyeloperoxidase.Doublestranded DNA and extractable nuclear antibodies are negative. Cryoglobulins and serology for human immunodeficiency virus, hepatitis B, and hepatitis C are negative. Renal function is normal with normal urinary sediment. Abdominal computed tomographyrevealsmild thickeningof theascendingcolonandthepreviouslydocumented splenic infarction (FIGURE 2). What Would You Do Next?

Levodopa-induced breathing, cognitive and behavioral changes in Parkinson’s disease

A 78-year-old male, already affected by Parkinson’s disease (PD) for the last 9 years, is the focus of this report. At diagnosis, after a good response to acute dopaminergic challenge, he was started on therapy with levodopa/Carbidopa 100 mg three times/day. At the age of 77, the patient developed daily recurrent respiratory disturbances and confused state, lasting from 2 to 4 h, which required assistance. In one of these episodes, the most severe, he was admitted to our clinic. On admission, he was confused and irritable with visual hallucinations, and dysphonic with irregular breathing as well as signs due to parkinsonism. Four hours later, the patient returned to a normal state: well-oriented, quiet and cooperative, without abnormal movements and with regular breathing. Laboratory tests, performed to exclude systemic causes, showed only a mild kidney insufficiency. Blood tests, including complete blood count, serum electrolytes, glucose, vitamin B12, vitamin E, antinuclear antibodies, lactate dehydrogenase, serum immunofixation, extractable nuclear antibody, paraneoplastic panel and angiotensinconverting enzyme concentrations, were negative or within normal limits. Thyroid, coagulation, and D-dimer and ECG were normal. Chest X-rays and CT were unremarkable. An MRI exam showed a diffused leukoencephalopathy and mild atrophy. At this point, a polygraphic exam during a levodopa challenge test was performed. Fifty minutes after the administration of 300 mg levodopa/Carbidopa, the patient presented irregular breathing and confusion. Ten minutes thereafter, the patient became agitated and uncooperative (see video). This condition lasted 4 h, and then progressively agitation and confusion decreased and breathing became regular. The polygraphy recording did not show EEG, O2-saturation and heart rate modifications, but an irregular respiratory rhythm (Fig. 1). Levodopa therapy was reduced and the episodes disappeared, although increases in bradykinesia and rigidity were observed. In PD, an underlying pulmonary dysfunction of both restrictive, partially responsive to levodopa, and obstructive type, in which levodopa induces significant variations in peak expiratory flow and upper-airway obstruction ratios, has been reported [1]. On the other hand, an acute onset of breath disorders has been described in PD in both onand off-condition [2]. To our knowledge, in on-condition, five cases of levodopa-induced respiratory disorders have been reported [3–6] (Table 1). In all patients, the decrease of dopaminergic therapy resulted in a reduction of the episodes, except for the one in which the treatment with tiapride was effective. Electronic supplementary material The online version of this article (doi:10.1007/s00415-011-6119-5) contains supplementary material, which is available to authorized users.

Risk factors for ANA positivity in healthy persons.

IntroductionThe finding of antinuclear antibody (ANA) positivity in a healthy individual is usually of unknown significance and in most cases is benign. However, a subset of such individuals is at risk for development of autoimmune disease. We examined demographic and immunological features that are associated with ANA positivity in clinically healthy persons to develop insights into when this marker carries risk of progression to lupus.MethodsBiological samples from healthy individuals and patients with systemic lupus erythematosus (SLE) were obtained from the Dallas Regional Autoimmune Disease Registry (DRADR). Measurements carried out on serum samples included ANA, extractable nuclear antibodies (ENA) and autoantibody profiling using an array with more than 100 specificities. Whole blood RNA samples from a subset of individuals were used to analyze gene expression on the Illumina platform. Data were analyzed for associations of high ANA levels with demographic features, the presence of other autoantibodies and with gene expression profiles.ResultsOverall, ANA levels are significantly higher in females than in males and this association holds in patients with the autoimmune diseases lupus and rheumatoid arthritis (RA) as well as in healthy controls (HC). Age was not significantly associated with ANA levels and the elevated ANA values could not be explained by higher IgG levels. Another autoantibody, anti- cyclic citrullinated peptide (CCP), did not show gender dimorphism in rheumatoid arthritis (RA) or healthy individuals. The autoantigen array showed significant elevations of other autoantibodies in high ANA HCs. Some of these autoantibodies were directed to antigens in skin and others were related to autoimmune conditions of kidney, thyroid or joints. Gene expression analyses showed a greater prevalence of significantly upregulated genes in HCs with negative ANA values than in those with significant ANA positivity. Genes upregulated in high ANA HCs included a celiac disease autoantigen and some components of the Type I interferon (IFN) gene signature.ConclusionsRisks for ANA positivity include female gender and organ-specific autoimmunity. Upregulation of skin-specific autoantibodies may indicate that early events in the break of tolerance take place in cutaneous structures. Some of these changes may be mediated by Type I IFN. Blood profiling for expressed autoantibodies and genes has the potential to identify individuals at risk for development of autoimmune diseases including lupus.

Treatment of Recalcitrant Generalized Morphea With Infliximab

A 66-year-old white woman with a history of hypertension and degenerative arthritis was seen in July 2003 by her primary care physician (PCP) for erythematous and sclerotic patches on her trunk. A skin biopsy specimen taken by the PCP at that time was interpreted (by an outside pathology laboratory) to indicate granuloma annulare. The patient began treatment with systemic corticosteroids and ceased taking her antihypertensive medication. However, her cutaneous symptoms continued to progress, and she was referred to our clinic in January 2004. At that time, the patient denied any illnesses prior to her skin eruption and noted that the only change in her medications was from lisinopril to valsartan. A review of systems found no shortness of breath, dysphagia, worsening of chronic joint symptoms, or Raynaud phenomenon. The patient was noted to have extensive white sclerotic patches and a few eczematous inflammatory patches on the upper chest, breasts (excluding the areola), upper abdomen, flanks, and proximal extremities (Figure 1). Her skin was firm and sclerotic on palpation. No sclerodactyly was present. A skin biopsy specimen was obtained. Light microscopic examination revealed a striking pandermal sclerosing reaction. The collagen bundles were of wider caliber and oriented parallel to the long axis of the epidermis. In addition, the overlying epidermis was attenuated with prominent hyperkeratosis. The subjacent papillary dermis had a hyalinized appearance with vascular dropout. The findings were compatible with an overlap between morphea and lichen sclerosus et atrophicus (LS&A). In situ hybridization studies demonstrated focal staining of the endothelium for cytomegalovirus (CMV) and tumor necrosis factor (TNF) RNA transcript expression. Direct immunofluorescence showed deposits of C5b-9 within the microvasculature most compatible with a humorally mediated microangiopathy syndrome (Figure 2). Serologic studies revealed positive anti-CMV IgM and IgG. However, the findings of antinuclear antibody assays, extractable nuclear protein antibody tests, an interstitial lung battery, complete blood cell count, and comprehensive chemical analysis were all within normal limits, as was the erythrocyte sedimentation rate. The patient was also found to be very hypertensive and resumed taking antihypertensive medications along with class 1 topical corticosteroids. Figure 1. Eczematous inflammatory patches.