Atypical Autoantibodies Research Articles

Diagnostic and prognostic scoring systems for autoimmune hepatitis: a review.

Auto-immune hepatitis (AIH) is a rare condition which primarily affects young women. Several diagnostic scoring systems exist based on clinical, biochemical, immunologic and histologic characteristics of AIH. Additionally, prognostic parameters can be identified. The purpose of this literature review is to compare the clinical value, strengths and limitations of these diagnostic and prognostic scoring systems. A literature search was performed in two databases and selected based on diagnostic and prognostic criteria. Only studies concerning AIH in adults were included. The backbone of scoring systems remains the revised AIH criteria published in 1999 and the simplified from 2008. The revised system shows a higher sensitivity, lower specificity and lower diagnostic accuracy compared to the simplified. Limitations to these scoring systems include limited diagnostic accuracy in acute or fulminant liver failure, insufficient inclusion of atypical auto-antibodies and lacking diagnostic power in presence of overlap syndromes. Concerning these overlap syndromes, the Paris criteria show a higher diagnostic accuracy compared to the scoring systems for AIH. Presently, no clinical prognostic scoring systems are available. However, a first system based on response to treatment accurately predicts long-term survival in AIH. Diagnostic scoring systems are useful in diagnosing AIH and have complementary value. However, they are no substitute for the gold standard of appropriate clinical assessment and are mostly useful in defining cohorts for research purposes. An evolution towards a more dynamic scoring system, using prognostic parameters and the progression of typical features, seems more valuable than the current diagnostic systems.

Artemisinin therapy and severe delayed haemolysis

In April, 2012, a 32-year-old white man came to our hospital with fever, lethargy, dyspnoea, and bilateral ankle oedema. He had spent the last 4 months in Togo and had not taken malaria prophylaxis. 15 days previously, he had developed fever and lethargy, and had attended a clinic at which Plasmodium falciparum malaria was diagnosed, with an initial parasitaemia of 1650 para sites per μL. His haemoglobin (Hb) was 128 g/L. He was given 160 mg intramuscular artemether daily for 3 days, followed by a 3-day course of oral dihydroartemisinin/piperaquine, with a good symptomatic response. 2 days later, he had a recurrence of fever, in addition to dyspnoea and ankle swelling. A blood fi lm showed no malaria parasites, but his Hb was 108 g/L. During the next 3 days he deteriorated and was transferred to hospital in Lome. A blood fi lm was again negative for malaria parasites, but the Hb had dropped to 70 g/L. He was prescribed intravenous (IV) ofl oxacin with oral doxycycline and was fl own to London. On arrival at this hospital he was febrile at 38·5°C, tachycardic, clinically anaemic, and jaundiced, had hepato splenomegaly, and was passing dark brown urine. Urinalysis confi rmed moderate haemoglobinuria. His Hb was 41 g/L with a mean corpuscular volume of 83 fL, anisocytosis and mild polychromasia, platelets of 112×109/L, and a white cell count of 4·2×109/L. Reticulocyte count was 5%, haptoglobin <100 mg/L, and direct agglutinin test was negative. Bilirubin was 35 μmol/L. Urea, electrolytes, and liver function tests were within normal limits. Lactate dehydrogenase was raised at 28·17 μkat/L, glucose-6-phosphate dehydrogenase activity was normal at 0·14 nkat/g haemoglobin, haemo globinopathy screen was negative, and iron, folate, and vitamin B12 values were normal. A rapid diagnostic test detecting histidine-rich protein 2 from P falciparum was positive. In-house nested PCR detected P falciparum DNA. However, thick and thin blood fi lms were consis tently negative. A comprehensive infection screen was negative. A fl uorodeoxyglucose positron emission tomography scan was unremarkable. Bone marrow biopsy showed pro nounced erythroid hyperplasia that was consistent with rapid red cell turnover. There was no evidence of any infi ltrative process, haemophagocytosis, or macrophage activation, and perforin expression was normal. No cold antibodies or other atypical auto antibodies or alloanti bodies were detected. A diagnosis of artemisinin induced haemolysis was made, on the basis of having excluded other potential causes of haemolysis. The patient received four blood transfusions over the next 6 days, with evidence of continuing severe intra vascular haemolysis (appendix). On the 7th day after admission, his fever stopped and haemolysis spon taneously resolved. He was discharged home and made a full recovery without further transfusion or treatment and remained well when last followed up in December, 2012. Artemisinin combination therapy has recently become the recommended fi rst-line treatment for both complicated and uncomplicated malaria in endemic areas, and is increasingly used in both Europe and the USA. Artemisinin derivatives are especially valuable for severe malaria because of the rapid rates of parasite clearance, and data from large clinical trials have shown the superiority of IV artesunate over IV quinine. Although the safety profi le of oral and parenteral artemisinins seems excellent in reported clinical trials, severe delayed haem olysis is emerging as a problem in European patients treated with parenteral artemisinins. 10% of patients (seven of 68) treated with IV artesunate in a recent Dutch and Belgian series developed severe haemolysis, with a median lowest Hb of 38 g/L occurring 7–31 days after treatment. Haemolysis persisted for up to 7 weeks. A second European series of 25 patients reported a similar syndrome, with 24% (6/25) developing profound haemo lytic anaemia 14–31 days after IV artesunate. Four additional cases have now been reported from other European centres, and despite extensive investigation in most of these cases, alternative explanations for haemolysis have not been identifi ed. As artemisinin-based therapy becomes the standard of care for severe imported malaria, caution must be taken to monitor for the increasingly recognised and serious com pli cation of severe delayed haemolysis.

The Overlap of Sjögren’s Syndrome with Other Systemic Autoimmune Diseases

To analyze the main diagnostic problems caused by the overlap between Sjögren's syndrome (SS) and other systemic autoimmune diseases (SAD). We performed a MEDLINE search for articles published between January 1966 and December 2005 that specifically analyzed the overlap between SS and other SAD. We identified a list of diagnostic problems in patients with primary SS who had features considered typical of other SAD. Clinically, the main diagnostic problems occur in SS patients presenting with arthritis, Raynaud phenomenon, cutaneous features (subacute cutaneous lupus erythematosus, purpura, livedo reticularis, erythema nodosum), interstitial pulmonary disease, and cytopenias (leukopenia, thrombocytopenia). Immunologically, antiphospholipid antibodies (aPL) and antineutrophil cytoplasmic antibodies (ANCA) are the most frequent atypical autoantibodies found in primary SS, with a prevalence ranging between 10 and 20%. However, coexisting antiphospholipid syndrome or systemic vasculitis is only detected in around 10% of SS patients with aPL or ANCA. Anti-DNA and anticentromere antibodies have a prevalence of 5 to 10%, but are more closely related to clinical and/or laboratory data suggestive of associated systemic lupus erythematosus and limited systemic sclerosis, respectively, leading to the fulfillment of classification criteria for these diseases in more than 25% of cases. The wide variety of clinical and immunological manifestations of patients with primary SS often overlap with other SAD, making the differentiation between primary SS, SS associated with SAD, and SS-like presentations of some other SAD difficult. This overlap suggests that the current classification criteria are useful in differentiating between autoimmune and non-autoimmune processes but fail to clearly differentiate among SAD.

Atypical Autoantibodies in Patients with Primary Sjögren Syndrome: Clinical Characteristics and Follow-Up of 82 Cases

To analyze the clinical characteristics, follow-up, and fulfillment of classification criteria for other systemic autoimmune diseases (SAD) in patients with primary Sjögren syndrome (SS) and atypical autoantibodies. We studied 402 patients diagnosed with primary SS seen consecutively in our Department since 1994. We considered anti-DNA, anti-Sm, anti-RNP, anti-topoisomerase1/Scl70, anticentromere (ACA), anti-Jo1, anti-neutrophil cytoplasmic antibodies (ANCA), anticardiolipin antibodies (aPL), and lupus anticoagulant as atypical autoantibodies. The patients were prospectively followed after inclusion into the protocol, focusing on the development of features that might lead to the fulfillment of classification criteria for additional SAD. As a control group, we selected an age-sex-matched subset of patients with primary SS without atypical autoantibodies. Eighty-two (20%) patients showed atypical autoantibodies (36 had aPL, 21 anti-DNA, 13 ANCA, 10 anti-RNP, 8 ACA, 6 anti-Sm, 2 anti-Scl70, and 1 anti-Jo-1 antibodies). There were 77 (94%) women and 5 (6%) men, with a mean age of 57 years. Patients with atypical autoantibodies had no statistical differences in the prevalence of the main sicca features, extraglandular manifestations (except for a higher prevalence of Raynaud's phenomenon, 28% versus 7%, P=0.001), immunological markers, and in the fulfillment of the 2002 classification criteria, compared with the control group. After a follow-up of 534 patient-years, 13 (16%) of the 82 patients with atypical autoantibodies developed an additional SAD (systemic lupus erythematosus in 5 cases, antiphospholipid syndrome in 4, limited scleroderma in 3, and microscopic polyangiitis in 1) compared with none in the control group (P<0.001). This study shows an immunological overlap (defined by the presence of autoantibodies considered typical of other SAD) in 20% of our patients with primary SS. However, the clinical significance of these atypical autoantibodies varies widely depending on the autoantibodies detected, with a broad spectrum of prevalence and clinical patterns of disease expression, and a specific predilection for association with some SAD in preference to others.