Overlap Connective Tissue Disease Research Articles

P23 A case of visceral leishmaniasis presenting as seropositive erosive rheumatoid arthritis in an immunocompromised patient

Abstract Introduction Visceral leishmaniasis (VL) is a potentially fatal parasitic infection occurring primarily in the tropics, subtropics, and southern Europe. A strong humoral response can be observed in VL due to polyclonal activation of B-lymphocytes, and it can also result in the production of rheumatoid factor (RF), anti-CCP and anti-nuclear antibodies. We present this case here of visceral leishmaniasis presenting as seropositive RA on the background of HIV and hepatitis B infection. Case description We present a case of a 46-year-old Caucasian male with a two-year history of skin nodules, symmetrical arthralgia and weight loss. He was diagnosed with HIV a decade ago which was well controlled with bictegravir, emtricitabine and tenofovir alafenamide. He received pulmonary tuberculosis (TB) treatment in 2012 and had chronic e-antigen-positive hepatitis B. He previously resided in Ukraine and travelled frequently to Crimea and the Middle East. There was no history of Raynaud’s, chest pain, shortness of breath, sicca symptoms, mouth ulcers, genital ulcers, hair loss or photosensitivity. On examination, he was cachectic with generalised lymphadenopathy and multiple subcutaneous (1-2cm, firm, mildly tender, non-ulcerating) forearm nodules. There was synovitis on two joints but no tenosynovitis or joint deformity. Initial investigations revealed pancytopenia, hyperuricemia, proteinuria, positive RF (>200 IU/ml) and anti-CCP, positive ANA and anti-Ro antibody and erosion of proximal phalanx of the big toe bilaterally. His CD4 count was 166 (33%) with undetectable HIV viral load. Imaging showed lymphadenopathy and splenomegaly (17.5cm). A diagnosis of rheumatoid arthritis with possible connective tissue disease overlap was made and he was initiated on hydroxychloroquine. Because of systemic symptoms and atypical skin nodules, further investigation was undertaken including lymph node, bone marrow and skin biopsies, all of which confirmed a diagnosis of leishmaniasis. Blood PCR was positive for L. donovani complex, and serological analysis showed direct agglutination test and k39 Ag positivity. Treatment was initiated by the infectious diseases team initially with amphotericin B 40 mg/kg monotherapy, later on further amphotericin B 30 mg/kg and miltefisone. He responded well as evidenced by reduced splenomegaly, resolution of skin nodules and improvement in cytopenia. His joint symptoms also improved except for the recurrence of ankle pain for which he received intra-articular steroids. Discussion It has been widely reported in literature that leishmaniasis can trigger autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosis. There have also been multiple studies confirming the presence of rheumatoid factor, anti-CCP and ANA in patients with leishmaniasis without any presence of symptomatic autoimmune disease. The mechanisms involved in the pathophysiology of autoantibody productions are not yet fully understood. There is some evidence that these are related to activation of polyclonal B cells due to a decreased regulatory T cell activity. Another possible mechanism would be production of autoantigen in response to cross reaction between the parasite and the hoarse tissue antigens. There have been multiple case reports of leishmaniasis in patients with rheumatoid arthritis who were taking anti-TNF biologics. This represents the reactivation of leishmaniasis due to immunosuppression. There has been a long-known link between HIV infection and leishmaniasis. Our patient was a known case of HIV. Interestingly, not only did he have significantly positive rheumatoid factor, anti-CCP, ANA and anti-Ro antibodies, but he also had active synovitis on his joints and even erosions were seen on the X-ray. He fulfilled the criteria for rheumatoid arthritis. Our case was unique in the sense that this is a case of visceral leishmaniasis in an HIV patient who presented with rheumatoid arthritis. Skin nodules in this patient were appearing similar to rheumatoid nodules. Later on, the biopsy confirmed that these were due to leishmaniasis. It is also a challenge to manage RA in patients with HIV especially when have already an opportunistic infection like leishmaniasis. A high prevalence of hyperuricemia in HIV infection has been reported in multiple studies. Our case did have raised urate but his disease was not consistent with gout clinically. Key learning points • This is a rare case showing seropositive erosive RA coexisting with VL in an HIV patient, underscoring the link between autoimmune diseases and chronic infections. Chronic infections are always considered an important differential in inflammatory arthritis or connective tissue disease especially when they present with systemic features of fever, weight loss and organomegaly. • Although this disease is considered rare in the Western hemisphere, in the diverse, multiethnic and immigrant UK population this should be considered an important differential diagnosis. Another key element in clenching these diagnoses is detailed travel history. Multidisciplinary approach is key in managing such difficult cases. Our case was managed jointly by the rheumatology, dermatology and infectious disease teams, and the national leishmaniasis multidisciplinary team from University College London Hospitals. • It is important to do a holistic assessment for these patients and get help from other specialities especially in such challenging cases.

The Relationship Between Anti-SSA-52 and Interstitial Lung Disease.

The aims of this study were to assess whether a relationship between anti-SSA-52 and interstitial lung disease (ILD) can be further defined, and to enhance screening, detection, and potentially guide treatment. A historical cohort study of 201 patients was conducted at a single tertiary care center between January 1, 2016 and December 31, 2020. All included patients were anti-SSA-52 antibody positive. Chart review was performed for laboratory values, symptoms, pulmonary function tests, treatment, and imaging. Chest computed tomographies were reviewed by chest radiologists. Among anti-SSA-52 antibody-positive patients, ILD was found in 125 (62.2%) compared with 76 (37.8%) with no ILD (p = 0.001). For those with ILD, 78 (62.4%) were diagnosed with connective tissue disease (CTD)-associated ILD, 28 (22.4%) were diagnosed ILD only, and 19 (15.2%) met the criteria for interstitial pneumonia with autoimmune features. In patients with CTD-ILD, 18 (23.0%) had their ILD diagnosis made over 6 months before a CTD diagnosis, and an additional 43 (55.1%) had their ILD and CTD diagnosed within 6 months of each other (p < 0.001). Common computed tomography patterns were nonspecific interstitial pneumonia/organizing pneumonia overlap in 44 (35.2%), 25 (20.0%) nonspecific interstitial pneumonia, and 15 (12%) usual interstitial pneumonia. Twenty-eight (35.9%) had antisynthetase syndrome, followed by 16 (20.5%) with dermatomyositis, 10 (12.8%) with CTD overlap, and 6 (7.7%) with systemic scleroderma. There was a significant association between anti-SSA-52 antibodies and ILD across a wide spectrum of rheumatological diagnoses. A significant portion of patients were diagnosed with ILD either at the same time or before their CTD diagnosis. Further study will be needed to assess effective treatment and response.

EP05 COVID-19 and the biliary tree: atypical manifestations of disease during the pandemic

Case report - IntroductionCOVID-19, the infectious disease caused by the novel coronavirus SARS-CoV-2, and first described in Wuhan, China in December 2019, has affected more than 19 million patients worldwide and resulted in more than 700,000 deaths at the time of writing1. Patients with rheumatic diseases and those receiving immunosuppressive treatment are felt to be at greater risk of complications from this illness, though registry and trial data should help refine our understanding of these risks. We hereby describe a case of COVID-19 complicating an unusual rheumatic illness, resulting in severe multi-system disease and premature death.Case report - Case descriptionA 69 year-old male presented to rheumatology and haematology with symmetrical polyarthritis, thrombocytopenia (18 x 109/L), eosinophilia (25.4 x 109/L), raised C-reactive protein (CRP, 43 mg/L), positive rheumatoid factor (>200), antinuclear antibody (ANA) and anti-Ro. Bone marrow biopsy did not demonstrate evidence of haematological malignancy. Seropositive rheumatoid arthritis and connective tissue disease overlap were diagnosed, and treatment with Prednisolone 60mg daily was initiated. Despite rituximab and intravenous immunoglobulins, thrombocytopenia deteriorated on reducing corticosteroids, however the addition of mycophenolate mofetil (MMF) allowed gradual prednisolone tapering to 3mg daily. Hydroxychloroquine was briefly added but discontinued due to headaches. MMF was discontinued after he developed fungal pneumonia followed by jaundice. Liver biopsy was consistent with drug-induced cholestasis, attributed to co-amoxiclav, and his liver function tests (LFTs) improved on ursodeoxycholic acid. Following a further deterioration in thrombocytopenia, hyperferritinaemia and new onset erythema nodosum, he had a repeat bone marrow examination. This demonstrated large areas of fibrosis and granulomatous inflammation with a dense, pleomorphic T-cell infiltrate, but no haemophagocytosis. Haematologists felt this was reactive and prednisolone dose was increased to 10mg daily.Six months later he developed cholangitis. Magnetic resonance cholangiopancreatography (MRCP) demonstrated a tight 4cm stricture of the distal common bile duct (CBD) within the head of pancreas, which was diffusely swollen without any clear focal mass. Serum amylase was mildly elevated (316 units/L). Concurrent CT thorax, abdomen and pelvis demonstrated bilateral ground-glass changes within the lungs, and a SARS-CoV-2 nasopharyngeal PCR test was positive, though he had no respiratory symptoms or oxygen requirement at that stage.Sadly, four days after the CT scan and before a planned endoscopic retrograde cholangiopancreatography (ERCP) could be performed, he became markedly hypoxic with plain chest x-ray features suggestive of COVID-19 pneumonia. Despite medical management, including doubling of his prednisolone dose, he rapidly deteriorated and died.Case report - DiscussionThis case highlights an unusual presentation of COVID-19 in a patient with a complex background of inflammatory arthritis with immune-mediated thrombocytopenia. At the time of his final illness, these conditions were managed with steroid monotherapy. Based on the COVID-19 risk matrix recommended by the British Society for Rheumatology, he was not identified as a patient requiring shielding.Cholangitis was the major problem precipitating his final admission to hospital, and at the time of admission he had no respiratory symptoms. One week prior to this admission, his father-in-law had died of COVID-19 pneumonia, though they had not been in recent direct contact. Interstitial lung changes were incidentally noted on a CT performed to identify the cause of cholangitis, which prompted the nasopharyngeal PCR that detected SARS-CoV-2. This occurred prior to widespread routine testing of hospital inpatients for SARS-CoV-2 by PCR. Unfortunately he then rapidly developed COVID-19 pneumonia and died before the underlying cause of cholangitis could be definitively identified, though an MRCP demonstrated an obstructed CBD within a diffusely swollen pancreas, where a differential diagnosis of pancreatic malignancy or autoimmune pancreatitis was suggested by the reporting radiologist. There are emerging case reports of COVID-19 resulting in significant pancreatic injuryand a further recent laboratory analysis has suggested that ACE2 receptors, which are utilised by SARS-CoV-2 to gain entry to host cells, are highly expressed on cholangiocytes at a comparable level to type II alveolar cells. Whilst the ultimate cause of cholangitis will remain unknown in this patient, this case highlights the potential for atypical presentations and extra-pulmonary manifestations of COVID-19. Case report - Key learning points COVID-19 is a multi-system illness which can cause significant extra-pulmonary as well as pulmonary pathology, with emerging reports that the biliary tract and pancreas are frequently affected.Evidence to inform accurate prediction of which patients with rheumatic diseases are at highest risk of acquiring severe COVID-19 disease remains insufficient, with current shielding guidelines based on expert consensus.This case highlights the importance of widespread testing for COVID-19 in hospital patients, as not all patients carrying the SARS-CoV-2 virus will demonstrate classical respiratory features of the disease at the point of admission.

An autoimmune storm: A case based literature review of successful management of lupus-polymyositis overlap syndrome complicated by multiple organ failure

Overlap syndromes of Connective tissues diseases is a rare and under-studied disorder. This syndrome can be complicated by multiple life-threatening complications like hepatitis, pancreatitis, macrophage activation syndrome and Acute Respiratory Distress syndrome. We report a 22-year-old Hispanic male with no remarkable past medical history who presented to the hospital with abdominal pain, myalgia, arthralgia, and persistent fever for two weeks and was found to have tachycardia, pancytopenia, transaminitis and an elevated lipase. The patient was initially evaluated for acute pancreatitis and hepatitis due to binge drinking and presumptive viral infection. Infectious work up was unrevealing, and the patient continued to deteriorate. The autoimmune panel came back significant for highly elevated Antinuclear Antibody (ANA) and Anti Double Stranded DNA antibody (dsDNA), low complement, high inflammatory markers, ferritin, elevated Creatine Kinase (CK), positive Anti Mi 2 antibody, low Natural Killer (NK) cell activity and elevated CD25. Patient was subsequently diagnosed with Lupus- Polymyositis overlap syndrome. Acute lupus flare was considered as the trigger for pancreatitis and hepatitis. The hospital course was complicated by Acute Respiratory Distress Syndrome (ARDS) due to Lupus pneumonitis, encephalopathy, and Macrophage Activation Syndrome (MAS). Patient was treated successfully with steroid pulse therapy, Cyclophosphamide, plasmapheresis, artificial ventilation, and extracorporeal membrane oxygenation (ECMO). We believe that this case is unique as it represented a diagnostic challenge as the Lupus-Polymyositis overlap syndrome is a rare entity, and it initially manifested in an extensively complicated pattern which is unusual. Moreover, this case was not only a diagnostic challenge but also a treatment conundrum due to multiple life-threatening complications the patient had during this hospitalization. In this review, we intend to discuss the management of this challenging and rarely reported connective tissue disease overlap syndrome.

Cardiac Imaging for Overlap Connective Tissue Disease Myocarditis

Cardiac Imaging for Overlap Connective Tissue Disease Myocarditis

13. Idiopathic inflammatory myopathy, everything it should not be: asymmetrical, normal CK, high fever

IntroductionMyositis can be infective, metabolic or immune-mediated. Idiopathic inflammatory myopathy, which is immune-mediated, tends to be subacute, with symmetrical symptoms, overlap clinical features and positive autoimmune serology. We present a case of acute onset lower limb seronegative inflammatory myopathy with a normal creatinine kinase (CK), a marked acute phase response that responded promptly to immunomodulatory therapy.Case descriptionA 68-year-old man presented with a 2-week history of lower limb pain with subjective weakness, on a background of well-controlled type 2 diabetes mellitus and hypertension. He was admitted with worsening symptoms of marked left thigh pain, night sweats, and fevers.On admission, he had swinging pyrexia (above >39 °C) while remaining haemodynamically stable. He had focal tenderness over the left anterolateral thigh, with a good range of movement, normal power and no signs of focal collection or cellulitis. There were no extra-muscular features to suggest systemic infection or overlap connective tissue disease.Bloods showed C-reactive protein (CRP) 225, normal CK 212 and negative blood cultures. X-rays knee, femur and pelvis were normal. Magnetic resonance imaging (MRI) on T2, fat-suppressed STIR sequences demonstrated increased signal/oedema both thighs throughout the anterior muscle compartment and along the fascial plane, notably most severe in the left vastus lateralis. He was treated empirically for infective myositis. Despite 14 days of broad-spectrum antibiotics, he remained febrile with persistently elevated CRP. There was no focal collection, lymphadenopathy or occult malignancy on CT abdomen and pelvis. Trans-oesophageal echocardiogram showed no evidence of infective endocarditis but revealed incidental moderate aortic stenosis.The patient described persistent now bilateral thigh pain with continued normal CK and high CRP. Full autoimmune screen (ANA, ANCA, ACE and complement studies) was negative. Despite negative nuclear and cytoplasmic HEp-2 immunofluorence, extended myositis immunoblot was negative. Muscle biopsy from the left vastus lateralis demonstrated inflammation within the perimysium and perivasculature. In view of biopsy findings and no response to anti-microbial therapy, prednisolone (0.5mg/kg) with significant clinical response (resolution of fever and pain) with concurrent normalisation in CRP. The patient remains in remission following steroid reduction with no additional immunomodulatory therapy required.DiscussionWe report a case of idiopathic inflammatory myopathy presenting with predominantly asymmetrical symptoms, normal CK, marked inflammatory response and negative myositis autoantibodies. Diagnosis was confirmed on MRI and muscle biopsy. The normal CK can be explained by the histology demonstrating inflammation in perivascular regions and around muscle fibres, rather than inflammation or necrosis in the muscle fascicles and fibres themselves. Idiopathic inflammatory myopathy including sporadic inclusion-body myositis, dermatomyositis, overlap CTD myositis and polymyositis/necrotising myopathy subsets are distinguishable based on clinical features, autoantibodies, MRI and biopsy features. The table below summarises the atypical aspects of this case. Differential diagnoses for this case include atypical infection, sarcoid myopathy and amyloid myonecrosis secondary to diabetes. Table: Features of typical idiopathic inflammatory myopathy compared with this atypical case.Idiopathic inflammatory myopathiesOur patient- typical featuresOur patient- atypical featuresSymptomsPain, fever, weakness.Pain and fever.Normal power.Clinical distributionSymmetrical, proximal muscle groups.Predominantly asymmetrical (worse on left), only in thighs.AntibodiesMyositis associated autoantibodiesSeronegativeMuscle enzymesElevated CKNormal CK.Inflammatory markersNormal to slightly elevated CRPMarkedly raised CRP and WCC.MR imaging resultsFocal muscle oedema in affected musclesDiffuse and speckled muscle oedemaKey learning pointsEarly idiopathic inflammatory myopathy can have inflammation around the muscle fascicles in the perimysium. Normal CK does not rule out a diagnosis of idiopathic inflammatory myopathy.Idiopathic inflammatory myopathies can present atypically with fevers >39 °C, significantly raised inflammatory markers, and asymmetrical symptoms and MRI findings.In the absence of overlap features, normal CK and negative serology, MRI and biopsy can delineate the type of myositis and direct management.Conflicts of interestThe authors have declared no conflicts of interest.

Scurfy Mice Develop Features of Connective Tissue Disease Overlap Syndrome and Mixed Connective Tissue Disease in the Absence of Regulatory T Cells.

Due to a missense mutation in the Foxp3 gene, scurfy mice are deficient in functional regulatory T cells (Treg). The consequent loss of peripheral tolerance manifests itself by fatal autoimmune mediated multi-organ disease. Previous studies have outlined the systemic inflammatory disease and demonstrated production of anti-nuclear antibodies (ANA) in scurfy mice. However, specific autoantibody targets remained to be defined. ANA are immunological markers for several connective tissue diseases (CTD) and target a large number of intracellular molecules. Therefore, we examined scurfy sera for the presence of different ANA specificities and further assessed the organ involvement in these animals. Indirect immunofluorescence was used as a screen for ANA in the sera of scurfy mice and dilutions of 1/100 were considered positive. Addressable laser bead immunoassays (ALBIA) were used to detect specific autoantibody targets. Subsequent histological tissue evaluation was verified by hematoxylin and eosin (H&E) staining. In our study, we observed that nearly all scurfy mice produced ANA. The most prevalent pattern in scurfy sera was nuclear coarse speckled, also known as the AC-5 pattern according to the International Consensus on ANA Patterns. U1-ribonucleoprotein (U1RNP) was found to be the most common target antigen recognized by autoantibodies in scurfy mice. Additionally, scurfy mice exhibited a mild myositis with histological characteristics similar to polymyositis/dermatomyositis. Myopathy-specific autoantibody profile revealed significantly increased levels of anti-SMN (survival of motor neuron) as well as anti-Gemin3 antibodies in scurfy sera. Overall, we demonstrate that the impaired peripheral tolerance in the absence of regulatory T cells in scurfy mice is associated with features of mixed connective tissue disease (MCTD). This includes, along with our previous findings, very high titers of anti-U1RNP antibodies and an inflammatory myopathy.

Overlap Syndromes in Inflammatory Myopathies

Purpose of Review This review discusses the epidemiology, evaluation and treatment of overlap inflammatory myopathy syndromes. Recent findings Evaluation of overlap myopathy in systemic sclerosis (SSc) has shown that the disease is often heterogeneous with variable presentation, histopathology, and response to therapy. These differences have shown to be important in management, specifically with the response to immunosuppression. Inflammation and necrosis are features suggestive of a positive response, whereas fibrosis and neurogenic atrophy are also common and may be less responsive to therapy. Summary Inflammatory myopathy associated with overlap connective tissue disease is often associated with greater morbidity, and there are few studies to guide treatment. Treatment is often tailored to the patient based on severity of muscular and concomitant extramuscular disease. While further research is needed to better understand treatment of overlap syndromes, the absence of consensus criteria remains a limiting factor.

The association of low complement with disease activity in systemic sclerosis: a prospective cohort study.

BackgroundIn some rheumatic diseases such as systemic lupus erythematosus (SLE), low serum complement (‘hypocomplementaemia’) is a feature of active disease. However, the role of hypocomplementaemia in systemic sclerosis (SSc) is unknown. We sought to determine the frequency, clinical associations and relationship to disease activity of hypocomplementaemia in SSc.MethodsThe study included 1140 patients fulfilling the 2013 American College of Rheumatology criteria for SSc. Demographic, serological and clinical data, obtained prospectively through annual review, were analysed using univariable methods. Linear and logistic regression, together with generalised estimating equations, were used to determine the independent correlates of hypocomplementaemia ever, and at each visit, respectively.ResultsAt least one episode of hypocomplementaemia (low C3 and/or low C4) occurred in 24.1 % of patients over 1893 visits; these patients were more likely to be seropositive for anti-ribonucleoprotein (OR = 3.8, p = 0.002), anti-Ro (OR = 2.2, p = 0.002), anti-Smith (OR = 6.3, p = 0.035) and anti-phospholipid antibodies (OR = 1.4, p = 0.021) and were more likely to display features of overlap connective tissue disease, in particular polymyositis (OR = 16.0, p = 0.012). However, no association was found between hypocomplementaemia and either the European Scleroderma Study Group disease activity score or any of its component variables (including erythrocyte sedimentation rate) in univariate analysis. Among patients with SSc overlap disease features, those who were hypocomplementaemic were more likely to have digital ulcers (OR = 1.6, p = 0.034), tendon friction rubs (OR = 2.4, p = 0.037), forced vital capacity <80 % predicted (OR = 2.9, p = 0.008) and lower body mass index (BMI) (OR for BMI = 0.9, p < 0.0005) at that visit, all of which are features associated with SSc disease activity and/or severity.ConclusionsWhile hypocomplementaemia is not associated with disease activity in patients with non-overlap SSc, it is associated with some features of increased SSc disease activity in patients with overlap disease features.

The Clinical Features of Myositis-Associated Autoantibodies: a Review.

The idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases traditionally defined by clinical manifestations including skeletal muscle weakness, skin rashes, elevated skeletal muscle enzymes, and neurophysiological and/or histological evidence of muscle inflammation. Patients with myositis overlap can develop other features including parenchymal lung disease, inflammatory arthritis, gastrointestinal manifestations and marked constitutional symptoms. Although patients may be diagnosed as having polymyositis (PM) or dermatomyositis (DM) under the IIM spectrum, it is quite clear that disease course between subgroups of patients is different. For example, interstitial lung disease may predominate in some, whereas cutaneous complications, cancer risk, or severe refractory myopathy may be a significant feature in others. Therefore, tools that facilitate diagnosis and indicate which patients require more detailed investigation for disease complications are invaluable in clinical practice. The expanding field of autoantibodies (autoAbs) associated with connective tissue disease (CTD)-myositis overlap has generated considerable interest over the last few years. Using an immunological diagnostic approach, this group of heterogeneous conditions can be separated into a number of distinct clinical phenotypes. Rather than diagnose a patient as simply having PM, DM or overlap CTD, we can define syndromes to differentiate disease subsets that emphasise clinical outcomes and guide management. There are now over 15 CTD-myositis overlap autoAbs found in patients with a range of clinical manifestations including interstitial pneumonia, cutaneous disease, cancer-associated myositis and autoimmune-mediated necrotising myopathy. This review describes their diagnostic utility, potential role in disease monitoring and response to treatment. In the future, routine use of these autoAb will allow a stratified approach to managing this complex set of conditions.

Redefining dermatomyositis: a description of new diagnostic criteria that differentiate pure dermatomyositis from overlap myositis with dermatomyositis features.

Dermatomyositis (DM) is a major clinical subset of autoimmune myositis (AIM). The characteristic DM rash (Gottron papules, heliotrope rash) and perifascicular atrophy at skeletal muscle biopsy are regarded as specific features for this diagnosis. However, new concepts are challenging the current definition of DM. A modified Bohan and Peter classification of AIM was proposed in which the core concept was the inclusion of the diagnostic significance of overlap connective tissue disease features. In this clinical classification, a DM rash in association with myositis in the absence of overlap features indicates a diagnosis of pure DM. However, overlap features in association with myositis allow a diagnosis of overlap myositis (OM), irrespective of the presence or absence of the DM rash. Perifascicular atrophy may be present in both pure DM and OM. Recently, the presence of perifascicular atrophy in myositis without a DM rash was proposed as diagnostic of a novel entity, adermatopathic DM. We conducted the present study to evaluate these new concepts to further differentiate pure DM from OM.Using the modified Bohan and Peter classification, we performed a follow-up study of a longitudinal cohort of 100 consecutive adult French Canadian patients with AIM, including 44 patients with a DM phenotype, defined as a DM rash, and/or DM-type calcinosis, and/or the presence of perifascicular atrophy on muscle biopsy. A detailed evaluation was performed for overlap features, the extent and natural history of the DM rash, adermatopathic DM, DM-specific and overlap autoantibodies by protein A immunoprecipitation on coded serum samples, and associations with cancer and survival.Two distinct subsets were identified in patients with a DM phenotype: pure DM (n = 24) and OM with DM features, or OMDM (n = 20). In pure DM, the DM rash was a dominant finding. It was the first disease manifestation, was always present at the time of myositis diagnosis, and was associated with a high cutaneous score and chronicity. Concurrent heliotrope rash and Gottron papules (positive predictive value [PPV] 91%), as well as the V-sign and/or shawl sign (PPV 100%), were diagnostic of pure DM. Anti-Mi-2, anti-MJ, and anti-p155 autoantibodies were present in 50% of pure DM patients and were restricted to this subset (PPV 100%). Cancer was present in 21% of pure DM patients. The 15-year survival was excellent (92%).In contrast, in patients with OMDM, the first manifestation was proximal muscle weakness or other skeletal muscle-related complaints. The DM rash appeared at diagnosis or at follow-up, was associated with a low cutaneous extent score and was transient. Adermatopathic DM, which was absent in pure DM, was highly predictive (PPV 100%) of OMDM. Overlap autoantibodies (including anti-Jo-1, anti-PL-7, anti-PM-Scl, anti-U1RNP, and/or anti-U5-RNP) were found in 70% of OMDM patients. OMDM was not associated with cancer, but the 15-year survival was significantly decreased (65%).Perifascicular atrophy occurred as commonly in OMDM (n = 6/20, 30%) as in pure DM (n = 4/24, 17%) patients. These 6 OMDM patients had adermatopathic DM at myositis diagnosis, and only 1 of them developed a DM rash at follow-up, emphasizing the lack of specificity of perifascicular atrophy for pure DM.In conclusion, using the modified Bohan and Peter classification of AIM allowed identification of OMDM, a new clinical subset of OM. Furthermore, identification of OMDM allowed recognition of pure DM as a new entity that was distinct from OMDM or from OM without DM features. However, the absolute specificity of a DM rash and perifascicular muscle atrophy for the diagnosis of pure DM was lost. The distinctive clinical manifestations and autoantibody profiles presented are proposed as diagnostic criteria to differentiate pure DM from OMDM.

SP0056 Raynaud's Phenomenon and Systemic Sclerosis

Systemic sclerosis has high mortality and morbidity and is diverse in clinical manifestations. In approaching management it is important to consider baseline assessment that must include confirmation of diagnosis, ascertainment...

Plain radiography is effective for the detection of calcinosis cutis occurring in association with autoimmune connective tissue disease

Studies on the radiological findings of calcinosis cutis in patients with autoimmune connective tissue disease (ACTD) are limited. To describe imaging findings and radiological patterns of calcinosis cutis occurring with ACTD. We retrospectively reviewed the cases of 37 patients with imaging studies assessing for calcinosis cutis associated with ACTD at our institution between 1996 and 2009. A formal blinded review of available images (i.e. radiographs, computed tomography scans) for all 37 patients was performed by radiologists. Of 37 patients, 30 (81%) were female. The mean age at diagnosis of calcinosis cutis was 43·4years. Patients had the following ACTDs: dermatomyositis (n=17) with classic (n=9), juvenile (n=7) and amyopathic (n=1) subtypes; systemic sclerosis with limited cutaneous scleroderma (n=8); undifferentiated connective tissue disease (n=4); mixed connective tissue disease (n=3); systemic lupus erythematosus (n=2); lupus panniculitis (n=1); overlap connective tissue disease (n=1); and polymyositis (n=1). Plain radiographs detected calcinosis in all 37 patients; a nodular pattern of calcification was most commonly observed (31/37; 84%). Two or more morphological patterns of calcification were present in 19 patients (51%). In general, individual patterns were not specific to a particular ACTD subtype. Radiography detected calcinosis in all patients and is recommended for initial imaging of calcinosis. Multiple morphological patterns of calcification were observed across ACTD subtypes. Further studies should correlate radiological studies with treatment of calcinosis and underlying ACTD.

T-regs in autoimmune hepatitis-systemic lupus erythematosus/mixed connective tissue disease overlap syndrome are functionally defective and display a Th1 cytokine profile

Autoimmune hepatitis (AIH), a severe hepatopathy characterized by hypergammaglobulinaemia, autoantibodies and interface hepatitis, is occasionally associated with systemic autoimmune manifestations [systemic lupus erythematosus (SLE); mixed connective tissue disease (MCTD)]. In both AIH and SLE/MCTD numerical and/or functional impairment of regulatory T-cells (T-regs) is believed to favour autoimmunity. To investigate whether immune-tolerance breakdown profiles differ in patients with AIH and SLE/MCTD, isolated AIH or systemic autoimmunity, we studied phenotypic and functional features of T-regs in 10 patients with AIH-SLE/MCTD, 22 with AIH, 12 with SLE and 20 healthy subjects. Compared to health, CD4posCD25pos cells were decreased in number and expressed high levels of the CD127 activation marker in all three disease groups; in AIH-SLE/MCTD and in SLE they displayed low levels of FOXP3. In AIH-SLE/MCTD, they also contained a high proportion of IFNγ positive cells, indicating a Th1 profile. Similarly, in AIH-SLE/MCTD, CD4posCD25posCD25high T-regs were reduced in number and contained an increased proportion of activated CD127pos and IFNγpos cells. Such skewing towards a Th1 profile was also present at effector level, as a high frequency of IFNγ-producing cells was observed within AIH-SLE/MCTD CD4posCD25neg responder cells. Impairment in suppressor function both of CD4posCD25pos cells and CD4posCD25posCD127neg T-regs was observed in all three autoimmune conditions, but while addition of CD4posCD25posCD127neg T-regs decreased CD4posCD25neg responder cell proliferation in healthy subjects and partially in AIH patients, it had no effect in AIH-SLE/MCTD and SLE patients.In conclusion, in AIH-SLE/MCTD T-regs display a distinctive phenotypic and functional signature, characterized by marked activation, elevated IFNγ production and by a profound impairment of suppressive function, suggesting that multiple autoimmune manifestations may derive from a complex defect of immune-regulation.

Calcinosis Cutis Occurring in Association With Autoimmune Connective Tissue Disease

To describe characteristics and treatment of patients with calcinosis cutis in the clinical setting of autoimmune connective tissue disease (ACTD). Retrospective study. Tertiary referral center. Seventy-eight patients with calcinosis cutis and ACTD between 1996 and 2009. Clinical features, treatments, and outcomes of patients with calcinosis cutis in the clinical setting of ACTD. Of 78 patients (mean age at onset of calcinosis cutis, 40.1 years), 64 (82%) were female. The following diseases were associated with calcinosis cutis: dermatomyositis (n = 30) with classic (n = 15), juvenile (n = 14), and amyopathic (n = 1) subtypes; systemic sclerosis with limited cutaneous scleroderma (n = 24); lupus panniculitis (n = 4); systemic lupus erythematosus (n = 2); mixed connective tissue disease (n = 4); overlap connective tissue disease (n = 6); undifferentiated connective tissue disease (n = 6); polymyositis (n = 1); and rheumatoid arthritis (n = 1). Therapy for calcinosis cutis consisted of medical treatment alone (n = 19), surgical therapy alone (n = 11), combined medical and surgical treatment (n = 17), no treatment (n = 30), and unknown (n = 1). Diltiazem hydrochloride was the most commonly used medical therapy, with 9 of 17 patients having a partial response. Twenty-eight patients had surgical excision of 1 or more lesions of calcinosis cutis: 22 had a complete response, 5 had a partial response, and 1 had no response. Dermatomyositis and systemic sclerosis were the most common ACTDs associated with calcinosis cutis. Although no treatment was uniformly effective, surgical excision of symptomatic lesions and medical treatment with diltiazem provided benefit for some patients.

Detection of serum anti-B/B' UsnRNP antibodies in patients with connective tissue diseases by immunoblotting

To investigate the reliability of the immunoblot method in the detection of serum immunoreactivity towards the B/B' polypeptides of U small nuclear ribonucleoproteins (UsnRNP) and to assess the significance of these antibodies in connective tissue disease (CTD) patients. We tested the sera of 348 patients with CTD (101 SLE, 51 systemic sclerosis, 53 primary Sjögren's syndrome, 27 poly/dermatomyositis, 15 rheumatoid arthritis and 101 overlap CTD), of 31 matched healthy subjects and 13 patients with primary Epstein-Barr virus (EBV) infection with high titre of IgG anti-EBV antibodies. IgG anti-UsnRNP antibodies were determined by immunoblotting on nuclear extract from Raji cells (an EBV-immortalised human B lymphoid cell line) and Jurkat cells (a human T lymphoid cell line). Anti-dsDNA antibodies were detected by indirect immunofluorescence on Crithidia luciliae and anti-ENA by counterimmunoelectrophoresis. Anti-dsDNA activity and avidity were measured in SLE sera by ELISA with Scatchard analysis. Results were statistically analysed by chi-square and Mann-Whitney tests. A high frequency of anti-B/B' antibodies was found in the sera of CTD patients, confined to SLE (54.4%) and overlap CTD with SLE features (55,2%). Anti-B/B' immune reactivity was closely associated with other anti-UsnRNP specificities, gel precipitating anti-nRNP and anti-P antibodies. Nine out of 15 (60%) anti-B/B' positive/anti-ENA negative lupus sera on Raji blots were confirmed to be positive also on Jurkat blots. The sera from patients with EBV infection provided, on Raji blots, completely different band patterns from those obtained with auto-immune sera. CONCLUSIONS. The Sm B/B' proteins are the predominant or, at least, the most frequently targeted antigens of the UsnRNP auto-immune response in SLE and "lupus-like" overlap CTD. Moreover, anti-B/B' is diagnostically specific for CTD with SLE features. Immunoblotting on human B lymphoid cells is a reliable method, in terms of sensitivity and specificity, for the detection of anti-Sm B/B' antibodies.

Malignancy in Myositis

Dermatomyositis is associated with an underlying malignancy in about 24% of cases. This association is also true for polymyositis but is less prominent. The malignancy is usually an adenocarcinoma of the ovary, lung, or gastrointestinal tract in Western countries and nasopharyngeal carcinoma in Southeast Asia, Southern China, and Northern Africa. Factors predictive of malignancy in myositis patients include more severe skin and muscle disease and the absence of overlap connective tissue disease features, such as interstitial lung disease. Anti-p155/140 antibodies have a strong predictive value for malignancy in adult patients. Patients with dermatomyositis or polymyositis require an evaluation for occult malignancy at the time of diagnosis and, in some cases, in the event of a subsequent recurrence. This paraneoplastic phenomenon may stem from an immune reaction to antigens expressed in both cancer cells and regenerating fibers in affected muscle.

ANCA-associated vasculitis in scleroderma: a case series of fourteen patients

Antimyeloperoxidase (MPO), perinuclear antineutrophil cytoplasmic antibodies (pANCA), and/or clinically evident vasculitis in patients with scleroderma have been reported only rarely. The clinical significance and prognosis of ANCA-associated vasculitis in systemic sclerosis is uncertain. To report a case and identify the clinical characteristics of scleroderma patients with ANCA-associated vasculitis. Patients with both vasculitis and scleroderma occurring between 1976 to 2006 were identified using an electronic diagnostic index. These diagnoses were confirmed by retrospective review of complete medical records. Clinical features and outcomes recorded included age at vasculitis diagnosis, connective tissue disease (CTD) features, type of scleroderma (limited or diffuse); ANCA serology, vasculitic organ system manifestations; and death. Fourteen cases of scleroderma patients with ANCA-associated and/or small vessel vasculitis were identified. The majority (71%) were female, with mean age at vasculitis diagnosis 53 years. Seven patients (50%) had overlap CTD features, and the majority (79%) had limited variant of scleroderma. All of the 10 patients tested were MPO and pANCA positive. Seven patients (50%) had glomerulonephritis, 11 (79%) pulmonary involvement including 3 with pulmonary-renal syndrome, 6 skin purpura, and 5 mononeuritis multiplex and/or peripheral neuropathy. Six patients (43%) died during followup to 2008. The presence of pANCA-associated small vessel vasculitis is a rarely reported complication of scleroderma. It occurs most commonly in women with limited scleroderma and most commonly includes pulmonary and/or renal involvement, including severe organ-threatening manifestations and death. Further studies are needed to clarify the role and clinical impact of ANCA in scleroderma patients with and without vasculitis.

A 32‐year‐old woman with arthralgias and severe hypotension

A 32‐year‐old woman with arthralgias and severe hypotension

Leg ulcer progression caused by topical anesthesia with EMLA® cream

While treating a 63-year-old woman with leg ulcerations, we observed an unusual phenomenon. A wound débridement was planned to remove adherent necrotic material. After topical anesthesia with a lidocaine-prilocaine mixture (EMLA cream) a hemorrhagic,livid margin area developed around the ulcer 90 minutes after application. The area turned necrotic over days and the center was débrided. A more detailed history revealed that similar necrosis had occurred previously when EMLA cream had been employed. We interpreted the current event,as well as the past episodes,as a pathological reaction of the small cutaneous blood vessels to EMLA cream. The history also revealed an overlap connective tissue disease with microvascular impairment. After exposure to the topical anesthetics, the pre-damaged cutaneous blood vessels presumably produced a critical ischemia with subsequent necrosis. Based on this case, we recommend careful use of EMLA cream with frequent monitoring for necrosis when treating patients with a known disorder of microcirculation.