Antineutrophil cytoplasmic antibody-associated vasculitis with initial gastrointestinal symptoms: case series and literature review.

Wegener Granulomatosis Mimicking Inflammatory Bowel Disease in a Pediatric Patient

Objective To investigate the clinical and pathological features of patients with a combination of Sjogren's syndrome (SS) and antineutrophil cytoplasmic antibody (ANCA) associated vasculitis with renal involvement. Methods By searching the Peking Union Medical College Hospital medical database and literature between January 1990 and June 2017, patients had a combination of SS and ANCA associated vasculitis with renal involvement were included. Data of clinical information, autoimmune antibodies, renal manifestations and renal pathology were retrieved and analyzed. Results Eighteen patients were enrolled: 4 from our hospital and 14 from literature. SS was diagnosed no later than ANCA associated vasculitis in all the patients, among which 83.3%(15/18) of patients had extra-glandular and extra-renal organs involved. All the patients were tested positive for myeloperoxidase (MPO)-ANCA, and only two were protein 3 (PR3)-ANCA positive concurrently. The positivity rates of antinuclear antibody (ANA), rheumatoid factor (RF), anti-SSA antibody, and anti-SSB antibody were 83.3%(15/18), 55.6%(10/18), 77.8%(14/18), and 38.9%(7/18), respectively. The renal manifestations were characterized by renal insufficiency with a median serum creatinine of 174 μmol/L, hematuria, moderate proteinuria with a median 24 hour urine protein of 1.70 g, and necrotizing vasculitis with oligo-immune complex and varying degrees of interstitial damage in pathology. Conclusions A combination of Sjogren's syndrome and ANCA associated vasculitis with renal involvement is rare in clinical setting, and almost all of the patients are MPO-ANCA positive, with high probability of ANA positivity and extra-glandular involvement. Physicians should beware of ANCA associated glomerulonephritis in SS patients with inexplicable renal dysfunction and renal biopsy should be carried out in time. Key words: Sjogren's syndrome; Anti-neutrophil cytoplasmic antibody-associated vasculitis; Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis

In this study of antineutrophil cytoplasmic antibody (ANCA)-associated diseases, we determined the prevalence of other autoantibodies and the antigen specificities of ANCA. ANA were common, occurring in 7 of 36 (19%) patients with Wegener's granulomatosis, in 16 of 34 (47%) patients with microscopic polyarteritis, in 6 of 11 (55%) patients with segmental necrotising glomerulonephritis and in 8 of 18 (44%) of those with ANCA-associated systemic vasculitis without renal involvement. ANA were associated more often with pANCA and microscopic polyarteritis than with cANCA (P < 0.05). Patterns were speckled (n = 23), homogeneous (n = 10) or nucleolar (n = 4). Anticardiolipin antibodies were also common, occurring in 10 of 25 (40%) patients with Wegener's granulomatosis, in 8 of 14 (57%) patients with microscopic polyarteritis and in 6 of 18 (33%) of those with a systemic vasculitis. However, anticardiolipin antibodies did not correlate with the presence of ANCA in any of the disease groups. Anti-GBM antibodies were demonstrated in only 2 of 25 (8%) patients with Wegener's granulomatosis, in 1 patient with microscopic polyarteritis (1/14, 7%) and in 1 with segmental necrotising glomerulonephritis (1/11, 9%). All four patients with anti-GBM antibodies had either cANCA or pANCA. In the second part of the study, the target antigens of ANCA were determined in Wegener's granulomatosis, microscopic polyarteritis, systemic vasculitis, inflammatory bowel disease, rheumatoid arthritis and systemic lupus erythematosus (SLE). Of the 19 sera with cANCA, 13 (68%) were directed against proteinase 3; other antigens were myeloperoxidase (1/19, 5%), elastase and lactoferrin together (1/19, 5%), lysozyme (1/19, 5%) or unknown (3/19, 16%). Of the 12 (58%) sera from patients with Wegener's granulomatosis who had cANCA, 7 bound to proteinase 3. Antimyeloperoxidase antibodies were present in 14 of 45 (31%) sera with pANCA; other antigens were proteinase 3 (5/45, 11%), elastase (3/45, 78%), lactoferrin (1/45, 2%), cathepsin G (5/45, 11%) or unknown (17/45, 38%). Antimyeloperoxidase antibodies were common in microscopic polyarteritis (6/14, 43%) and systemic vasculitis (5/16, 31%). However, the majority of target antigens in systemic vasculitis and rheumatoid arthritis with pANCA were not determined. "Atypical" ANCA were present in four patients, one with inflammatory bowel disease (1/8, 13%) and three with SLE (3/15, 20%). The specificities were cathepsin G, cathepsin G plus lactoferrin, or unknown in two sera. A recent report has suggested that bactericidal/permeability-increasing protein may be the target in patients with inflammatory bowel disease.

A 44-year-old woman with a history of cocaine and heroin abuse presented with a painful, necrotic rash. Five weeks before presentation, the patient had experienced a cough and mild dyspnea. She was diagnosed with pneumonia, completed a 7-day course of ciprofloxacin and doxycycline, and her respiratory symptoms resolved. Three weeks before presentation, the patient had reported fevers, chills, diaphoresis, arthralgias, and myalgias, and developed a small erythematous lesion on her left breast. The lesion subsequently enlarged and became hemorrhagic. She simultaneously developed additional lesions on her chest, abdomen, arms, and back. The largest of these, located on her left arm, was 15 cm in diameter. All of the lesions were exquisitely tender. She was hospitalized at an outside hospital for 5 days and given a diagnosis of cocaine-induced vasculitis. Upon discharge, she was instructed to abstain from cocaine and was prescribed trimethoprim/sulfamethoxazole for a possible cellulitis involving the skin lesions. Ten days after discharge from the outside hospital, the patient presented to our institution for pain management and further evaluation. The rash had progressed since her earlier discharge. She had continued to use cocaine, heroin, and prescription opioids. She had last smoked cocaine 3 days before presentation and last used intranasal heroin 1 week before admission. She reported acquiring cocaine from a new supplier 2 weeks before her rash had begun. The patient had a history of nephrolithiasis and had undergone a cholecystectomy for gallstones. She had had 5 normal pregnancies. The patient had received ciprofloxacin, doxycycline, and trimethoprim/sulfamethoxazole in the weeks before her presentation. She also took combined oxycodone and acetaminophen for pain. She had no known drug allergies. Her youngest son had developed idiopathic thrombocytopenia at age 3 years. A paternal aunt had breast cancer and a nephew had cystinosis. She was unmarried, unemployed, and homeless. Three of her children were grown; the youngest two were in state custody. The patient had smoked 1 pack of cigarettes/day since age 15 years. She denied injection drug use and did not drink alcohol, but smoked cocaine and used intranasal heroin. The patient reported headache and fatigue secondary to poor pain control and disrupted sleep. She denied visual changes, sicca symptoms, jaw pain, oral ulcers, and dysphagia. She denied shortness of breath, cough, chest pain, palpitations, gastrointestinal symptoms, and abdominal pain. She had no genitourinary symptoms, arthritic pain, or musculoskeletal tenderness. She reported new upper extremity edema in her hands and arms bilaterally, more significant on the left than on the right, and equal bilateral lower extremity swelling. She had no sick contacts or recent travel. The patient was an obese woman in significant pain from her skin lesions. She was afebrile but had a pulse of 108/minute. Her blood pressure was 163/86 mm Hg, her respiratory rate was 22/minute, and her oxygen saturation was 97% on room air. She had a rash distributed in a symmetric pattern overlying fatty areas on the breasts, abdomen, upper arms, back, and flanks. The lesions consisted of stellate, purpuric plaques ranging in size from 5 cm to 15 cm (Figure 1A). The largest lesion was located on the left upper extremity (Figure 1B). The lesional borders were well demarcated and contained a reticular pattern surrounded by a 5-mm rim of erythema (Figure 1C). Small 1–2-cm lesions were also located on the earlobes bilaterally (Figure 1D). Many of the lesions were associated with flaccid bullae and exquisite tenderness to palpation. An additional dermatologic finding was a livedo pattern on her back and extremities. There was pitting edema in the upper and lower extremities bilaterally. Picture of the patient's necrotic rash. A, Multiple purpuric plagues were distributed symmetrically over the patient's back and flanks. Each lesion had reticulated borders consistent with a vasculopathic process. B, The largest lesion on the left arm had a necrotic appearance and contained central bullae. C, Borders were well demarcated and surrounded by a rim of erythema. D, Purpuric and necrotic lesions, 1–2 cm in diameter, were located on the earlobes. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2151-4658. Examination of the head and neck was unremarkable, and there was no lymphadenopathy. The cardiovascular examination demonstrated a regular rate and rhythm, normal heart sounds, and no murmurs. The lungs were clear to auscultation. The abdomen was soft, nondistended, nontender, and without palpable masses. A neurologic examination showed intact cranial nerves and normal sensation and strength. Cerebellar signs were absent, and the gait was normal. The complete blood cell count, coagulation times, electrolytes, bilirubin levels, liver enzymes, cardiac biomarkers, and urinalysis were within normal limits. The patient had a mild normochromic anemia with a hematocrit of 35% and a mean corpuscular volume of 82 femtoliters (normal range 80–100). The serum iron saturation level was 4.5% and the ferritin was mildly elevated at 217 ng/ml (normal range 10–200). The erythrocyte sedimentation rate was 33 mm/hour (normal range 0–17). The patient's D-dimers were significantly elevated at 5,541 ng/ml (normal value <500), but the fibrinogen concentration was normal. Blood and urine cultures showed no growth. Assays for syphilis, hepatitis B and C, and the human immunodeficiency virus were nonreactive. An antinuclear antibody assay was positive at a titer of 1:160 (speckled). Assays for antibodies to both double-stranded DNA and histones were positive at titers of 1:20 (normal titer <1:10) and 2.2 units (normal value <1.5), respectively. Assays for antibodies to the Ro, La, Sm, and RNP antigens were negative. The serum C3 and C4 levels were 137 mg/dl (normal range 86–184) and 10 mg/dl (normal range 20–58), respectively; cryoglobulins were not detected. An IgM anticardiolipin antibody (aCL) assay was strongly positive at 150 IgM phospholipid units (normal range 0–15), but the IgG aCL assay was negative at 4.2 IgG phospholipid units (normal range 0–15). Assays for a lupus anticoagulant and antibodies to β2-glycoprotein I were negative. The serum antithrombin IIIA level was 66% (range 80–130%). Because of the resemblance of the skin lesions to warfarin necrosis, a serum warfarin level was assayed and found to be normal. An immunofluorescence assay for antineutrophil cytoplasmic antibodies (ANCAs) was positive in a perinuclear ANCA (pANCA) pattern of staining. Enzyme-linked immunosorbent assays (ELISAs) confirmed the presence of antibodies to myeloperoxidase (MPO ANCA). Antibody activity was measured at 1,050 units (normal value ≤2.8). An ELISA for antibodies to proteinase 3 (PR3) was negative. A serum parathyroid hormone (PTH) was normal, and assays for PTH-related peptide and plasma activated inhibitor 1 were negative. A serum protein electrophoresis with immunofixation studies was normal. Cocaine, oxycodone, and opiates were identified in a urine toxicology screen. A chest radiograph was normal, and ultrasound studies of the lower extremities and left arm showed no deep venous thromboses. A diagnostic test was performed. The patient is a 44-year-old woman with active cocaine and heroin use who presented with a painful, bullous, necrotic rash that developed after receiving a short course of antibiotics. The skin lesions have persisted despite conservative management for 5 weeks. The physical examination is otherwise remarkable for bilateral upper and lower extremity swelling. Laboratory studies are significant for an IgM aCL and MPO ANCA. Here we discuss the differential diagnosis of the patient's necrotic rash in the context of her laboratory abnormalities. A primary concern on admission was a hypercoagulable state. Heritable disorders of coagulation typically are considered in patients with a history of venous or arterial thrombi or pregnancy loss, or a family history of such events. Our patient had no such history. Laboratory testing confirmed the absence of mutations in the prothrombin, antithrombin III, and factor V Leiden genes. Protein C and S activities and the homocysteine level were normal. Acquired hypercoagulable states were considered early in the management of this patient. The patient had no history of recent surgery, immobilization, cancer, pregnancy, or hormonal therapy. All of these risk factors are associated more strongly with venous thrombi than with arterial clots, and ultrasonography excluded evidence of venous thrombosis. In any event, the distribution and necrotic appearance of the rash were more consistent with an arterial process. One common hypercoagulable state that leads to arterial or venous thrombi (or both) is the antiphospholipid syndrome (APS). The APS can develop at any age, is more common among women, and has a diverse range of clinical manifestations (1). The APS is characterized by the detection within serum of antiphospholipid antibodies (aPL); specifically, aCL, antibodies to β2-glycoprotein I, or a lupus anticoagulant. By the Sapporo criteria, the diagnosis of APS is entertained in the setting of a typical rash (e.g., livedo racemosa) and the presence of aPL within the serum (2, 3). To fulfill the laboratory criteria, aPL must be detected on at least two occasions separated by more than 12 weeks. Overall, we had a high suspicion of APS, given the clinical manifestations and laboratory findings of IgM aCL. Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis of medium-sized arteries that can affect any organ system. Skin involvement is common. The characteristic skin findings include livedo reticularis (racemosa), tender erythematous nodules, bullae or vesicular eruptions, and ulcers (4). Palpable purpura can be present to a minor degree and when found, represents concomitant small-vessel involvement. Skin lesions can result in infarction and gangrene of the distal extremities or deep ulcerations that extend into the subcutaneous tissue. In PAN, the cutaneous involvement is often accompanied by renal disease (e.g., renin-mediated hypertension, kidney infarctions), an axonal sensorimotor mononeuritis multiplex, and mesenteric vasculitis. None of these other features was present in our patient. A form of PAN limited to the skin exists, but that condition is more subacute in its presentation and seldom leads to such dramatic bulla formation (5). PAN is a “seronegative” condition, i.e., one that is not associated with known autoantibodies. This fact poses a significant challenge in diagnosis compared with, for example, systemic lupus erythematosus and the ANCA-associated vasculitides (AAVs). A minority of PAN patients have been infected recently by the hepatitis B virus and have serologies consistent with that condition. Our patient had no history of hepatitis B exposure, and the titers of aCL and MPO ANCAs suggested alternative diagnoses. Cryoglobulinemia was considered in the differential diagnosis because the patient had palpable purpura and bilateral earlobe lesions. Both of these physical findings suggest small vessel involvement. Nonetheless, the absence of lymphadenopathy, hepatosplenomegaly, peripheral neuropathy, and renal insufficiency made cryoglobulinemia less likely. Secondary causes of type I cryoglobulinemia were considered. Electrophoresis studies of the serum and urine were negative, appearing to exclude a paraproteinemia. Mixed cryoglobulinemia (types II and III) can occur secondary to hepatitis C or human immunodeficiency virus infections, but testing for our patient was negative. Most importantly, careful attempts to isolate cryoglobulins from the serum were unsuccessful. The necrotic rash and positive ANCA assay are consistent with an AAV. There are two major ANCA immunofluorescence patterns: cytoplasmic ANCA (cANCA) describes diffuse staining throughout the cytoplasm and pANCA refers to perinuclear staining. In patients with systemic vasculitis, the preponderance of cANCA staining is caused by antibodies directed against serine PR3. In contrast, in a patient who has a primary vasculitic syndrome, the pANCA pattern is generally caused by antibodies to MPO. In our patient, the high-titer MPO ANCA suggested several possibilities: Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), and drug-induced AAV. The clinical presentations of WG and MPA are difficult to distinguish in some cases. In WG, skin lesions can range from mild erythematous purpura to severe ulcerations (6). Skin manifestations are reported in 40% of patients with WG and generally correspond to the presence of generalized disease (7). However, vasculitic involvement of the skin in WG is unlikely to involve the trunk and upper extremities in the absence of lower extremity disease. In addition, our patient had no sign of the classic extracutaneous disease manifestations that typify WG: specifically, upper respiratory tract dysfunction, pulmonary disease, and glomerulonephritis. The MPO ANCA detected in our patient is more typical of either MPA or CSS than of WG. In MPA, skin findings usually consist of purpura or livedo racemosa rather than bullae and extensive necrosis (8). Approximately 50% of CSS patients are ANCA positive, and in such cases, the antibody specificity is directed against MPO. However, the diagnosis of CSS is unlikely in the absence of renal or pulmonary involvement and eosinophilia. In summary, the diagnosis of an idiopathic form of AAV is tenuous without some sign of extracutaneous disease. The constitutional symptoms, necrotic rash, and high MPO ANCA titer are consistent with both drug-induced AAV and drug-induced lupus. The two entities, which have been described both together and separately in the literature, may represent a spectrum of the same disease process. Both syndromes are associated with arthralgia, myalgia, and rash at disease onset (9). Dramatically elevated MPO ANCA titers are more strongly associated with drug-induced AAV than with idiopathic AAV (10). In addition, antihistone and aPL antibodies (both present in this case) are observed more commonly in drug-induced processes than in idiopathic AAV (11, 12). In both drug-induced ANCA vasculitis and lupus, the syndromes occur after exposure to a drug over a prolonged period of time. This contrasts with the short exposures to medications usually linked to hypersensitivity vasculitis syndromes, of which antibiotics are the most common offenders (13). Numerous medications have been implicated in both drug-induced AAV and drug-induced lupus (Table 1). However, the strongest correlations are with medications used to treat hyperthyroidism (particularly propylthiouracil) and with hydralazine, D-penicillamine, and minocycline (10, 14, 15). Our patient had no exposure to any of these agents. She had been treated previously with a short course of doxycycline, but tetracyclines other than minocycline have not been associated with drug-induced AAV (15). Ciprofloxacin has been implicated in vasculitis case reports (16, 17). In the 5 most recent reports, ciprofloxacin exposure ranged from 3–14 days, similar to our patient's 7-day course. However, the skin findings in ciprofloxacin-induced cutaneous vasculitis are generally mild in comparison to our patient's lesions, and those patients do not develop ANCAs or antinuclear antibodies (17). In both drug-induced AAV and drug-induced lupus, early withdrawal of the offending agent usually leads to resolution of the clinical syndrome (9). Prolonged cases of AAV can occur if exposure to the medication has been lengthy, as in some cases of propylthiouracil-associated disease. In our patient's case, her doxycycline and ciprofloxacin had been stopped even before the onset of the rash. In summary, the likelihood that the antibiotics to which she had been exposed had caused her severe skin rash appeared low. Case reports correlating cocaine use with skin lesions emerged first in the 1980s (18, 19). Since that time, palpable purpura; violaceous papules, bullae, and blisters; livedo racemosa with cutaneous necrosis; and multifocal necrotic lesions of the skin and muscle have been associated with cocaine use (4, 20-22). Skin biopsy samples in such patients often demonstrated vasculopathic patterns rather than frank vasculitis (21, 22). Cocaine use is well known to trigger a disorder known as midline destructive lesion that mimics limited WG closely, even including the finding of cANCA positivity on immunofluorescence testing (21-23). In such cases, ELISA testing demonstrates ANCA directed against PR3 and/or human neutrophil elastase (HNE). It is not clear if ANCA contributes to the pathogenesis of these lesions. HNE and PR3 are both serine proteinases that share gene localization as well as structural and functional characteristics. It has been speculated that the true antigen in cases of cocaine-induced midline destructive lesion is HNE, and that the PR3 ANCA results from cross-reactivity with HNE (21, 24). However, investigators recently demonstrated the coexistence of distinct antigen-specific antibodies that recognize unique epitopes (25). Cocaine use is also associated with the APS. One prospective study showed a higher percentage of aCL positivity in cocaine users compared with controls (26). Whether this was an incidental finding or has broader clinical implications for the occurrence of APS in the setting of cocaine use remains unknown. Some cocaine users who have experienced acute strokes or myocardial infarctions have been reported to have aPL, suggesting the possibility of a synergistic effect between cocaine and aPL that propagates thromboembolic phenomena (27, 28). Based on the patient's clinic findings and serologic abnormalities, the two most likely causes of the patient's presentation appeared to be either drug-induced AAV or drug-induced APS, either of which might have been induced by cocaine. Skin biopsy was essential to distinguish between these two conditions, which require different approaches to treatment (in addition to cocaine cessation). Skin biopsy samples were obtained from the right proximal and distal forearm. Histologic examination revealed fibrin thrombi within small and medium-sized blood vessels in the superficial and deep dermis and the subcutaneous tissue (Figures 2A and B). There was no evidence of endothelial swelling, leukocytoclasis, or fibrinoid necrosis within blood vessel walls. The histopathology was thought to be highly consistent with APS. Skin pathology. A, Small and medium-sized vessels (arrows) occluded by fibrin thrombi in the superficial dermis, deep dermis, and subcutaneous tissue (original magnification × 40). Inset: medium-sized artery with the lumen almost completely occluded by an organizing fibrin thrombus (original magnification × 200). B, Multiple small arteries (arrows) with luminal fibrin thrombi (original magnification × 200). The most striking features of this case were the rapid appearance of the patient's bullous, necrotic rash and the high titers of both aPL and MPO ANCA in her blood. Although we believe that both autoantibodies were induced by her cocaine use, the histopathology of her skin lesions suggests that aPL were responsible for her skin rash. This conclusion is consistent with the current knowledge regarding drug-induced ANCA positivity. In several cross-sectional and prospective studies of propylthiouracil, between 20% and 60% of patients treated with this medication on a long-term basis developed ANCA, usually in high titers (29, 30). However, only a minority of patients who developed ANCA demonstrate clinical manifestations of drug-induced AAV. In one study (31), 8 (26.7%) of 30 patients receiving long-term antithyroid medication became ANCA positive. Among those, none developed frank AAV but 3 experienced myalgia and arthralgias after the appearance of ANCAs. Patients with idiopathic AAV are known to have a predisposition to venous thrombotic events (32, 33). Variable degrees of thrombosis can also be observed on lesional biopsy samples from patients with AAV, but such findings are accompanied by more classic patterns of injury to the blood vessel wall: endothelial swelling, leukocytoclasis, and fibrinoid necrosis. Although it is impossible to exclude an interaction between the patient's aPL and MPO ANCA that heightened the intensity of her cutaneous reaction, the major histopathologic findings implicate aPL as the primary etiology of the patient's skin disease. One theory of APS pathogenesis proposes that aPL develop in genetically susceptible individuals after exposure to an unknown infectious agent. Clinical manifestations subsequently occur after a “second hit” such as smoking, prolonged immobilization, pregnancy, hormone use, or cancer. Various medications are suspected triggers of APS (Table 1). IgM aCL in particular have been linked to drug-induced APS cases. Cocaine has also been implicated in the pathogenesis of APS. Although our patient was a chronic cocaine user, it is of interest that prior to the onset of her rash she had found a new cocaine supplier, perhaps leading to exposure to new contaminants in the cocaine. One commonly recognized contaminant in cocaine is levamisole. Levamisole, an alkaline phosphatase inhibitor, appears to potentiate the action of cocaine on dopaminergic pathways. Levamisole is widely available because it is used in agriculture worldwide as an antihelminthic drug. In humans, levamisole has been studied in various clinical settings for the treatment of autoimmune and malignant diseases (34). The compound has established efficacy in relapsing nephrotic syndrome in children. Most recently, levamisole has been reported to cause agranulocytosis in cocaine users (35, 36). Approximately 70% of seized cocaine entering the US contains levamisole (35). We conducted a literature search on levamisole-induced vasculitis and vasculopathies. Levamisole-induced vasculitis has only been reported in 4 adult cases (37-39). The histopathology reported in these describes vasculitis, but the results of ANCA or aPL testing were not In the literature, there are case reports of cutaneous vasculitis secondary to levamisole Five cases were characterized by earlobe purpura and necrosis, as in our case In 4 of the skin biopsy samples demonstrated a thrombotic ANCA serologies were reported in 4 pANCA patterns in 3 cases and a cANCA pattern in 1 aPL antibodies were detected in 3 We that levamisole is the active compound in cases of cocaine-induced vasculitis or cocaine-induced This further associated with antiphospholipid her was with a and was to warfarin prior to discharge. was for the diagnosis of APS. the high ANCA there was among the the patient from her acute presentation and the of the skin lesions, the patient was on and this her skin lesions and her was after 3 after her she had from cocaine and had no of her rash. She has developed of her necrotic skin rash. All were in the or it for and the to be for had to of the in the study and for the of the and the of the and of and of

POS-138 SEVERE INFECTIONS IN ANTINEUTROPHIL CYTOPLASMIC ANTIBODY-ASSOCIATED VASCULITIS: CLINICO-BACTERIOLOGICAL PROFILE AND RISK FACTORS

Are Gastrointestinal Symptoms Specific for Coronavirus 2019 Infection? A Prospective Case-Control Study From the United States

Cocaine-induced midline destructive lesions: clinical, radiographic, histopathologic, and serologic features and their differentiation from Wegener granulomatosis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a disorder with poor prognosis. This study aimed to improve the diagnosis and treatment of ANCA associated vasculitis of children, to analyze the clinical features, pathological characteristics and the prognosis of children with ANCA-associated vasculitis. Fifteen children with ANCA associated vasculitis who were hospitalized from 2003 to 2012 in our hospital were included. Their data of pre-diagnosis status, clinical manifestations, renal pathology, treatment and prognosis were reviewed retrospectively. Of the 15 children, 11 were girls and 4 boys with a mean age of 10.7 years. Fourteen children were categorized as microscopic polyangitis. The time to diagnosis varied from 0.5 month to 40 months. Hematuria and proteinuria were revealed by urine analysis in all of them, only 6 children complained with gross hematuria or edema of oliguria. Decreased glomerular filtration rate was revealed in 13 children, 8 of whom had a creatinine clearance rate of less than 15 ml/(min·1.73 m(2)). Twelve children underwent renal biopsy, crescent formation was found in 11 children. Most of the crescents were cellular fibrous crescents or fibrous crescents. Six children were diagnosed as crescentic nephritis; the process of rapidly progressive nephritis was only observed in 2 children. Segmental glomerulosclerosis or global glomerulosclerosis were found in 10 children, 3 of them were diagnosed as sclerotic glomerulonephritis. Anemia and pulmonary injury were the most common extra renal manifestations. Other extra renal manifestations included rash, pain joint, gastrointestinal symptoms, abnormal findings of cardiac ultrasonography and headache. Eight children were treated with steroid combined with cyclophosphamide, 4 were treated with steroid and mycophenolate mofetil, 2 were treated with steroid, cyclophosphamide and mycophenolate mofetil, 3 children were treated with plasma exchange. Fourteen children were followed up for 0.5 month to 4 years. The renal function did not recover in children with creatinine clearance rate of less than 30 ml/(min·1.73 m(2)), who showed crescentic glomerulonephritis or sclerotic glomerulonephritis. The children who had creatinine clearance rate of more than 30 ml/(min·1.73 m(2))had better prognosis. More attention should be paid to ANCA-associated vasculitis among school age girls with anemia or pulmonary diseases. The renal damage was serious in children; however, the clinical manifestations were not obvious. Children with a creatinine clearance rate of less than 30 ml/(min·1.73 m(2)) had poor prognosis. Early accurate diagnosis is very important.

Background: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmic antibody (ANCA)-associated necrotizing vasculitis primarily affecting small and medium-sized vessels. The typical presentation commonly includes upper and/or lower respiratory tract and renal involvement. GPA has a particularly strong association with proteinase-3 (PR3) ANCA. Though well defined, GPA may be clinically difficult to recognize, particularly in early disease. Initial presentations may include nonspecific symptoms, including but not limited to fatigue, fever, and sinus congestion or sinusitis, which may be mistaken for infection. Though initial ANCA testing is useful, it is not definitive as early stages of disease may be negative, thus delaying diagnosis; Clinical Significance: This case highlights the importance of including GPA in the differential diagnosis of patients with unremitting upper or lower respiratory and constitutional symptoms despite negative ANCA testing. Though atypical, GPA cases may lack renal involvement and even have negative ANCA serologies, leading to a delay in diagnosis and increased morbidity. ANCA positivity can be as low as 60% in limited GPA cases, and less than 20% of individuals have renal involvement at presentation. If GPA suspicion is high, repeat testing and biopsy are warranted; Case Presentation: A woman in her 50s initially presented to the emergency department with recurrent/persistent fever with nonspecific sinus symptoms that remained unresolved despite multiple outpatient treatments and tests. Infectious work-up was negative. She was found to have multiple pulmonary nodules on various scans. Initial testing on admission was unremarkable or nondiagnostic, including anti-neutrophil cytoplasmic antibody (ANCA) serologies. The patient's hospital course was complicated by acute hypoxic respiratory failure with distributive shock during bronchoscopy. Repeat serological testing was positive for PR3-ANCA, and lung biopsy demonstrated necrotizing granulomatous vasculitis consistent with a diagnosis of granulomatosis with polyangiitis (GPA). The patient demonstrated clinical improvement with avacopan, glucocorticoids, and rituximab; Conclusions: The diagnosis of GPA should be suspected in all patients with nonspecific constitutional symptoms along with clinical evidence of upper/lower respiratory tract involvement, regardless of renal function. Physicians with a strong suspicion of an autoimmune disease, such as GPA, should utilize a thorough clinical history, physical exam, and other labs in the setting of a negative autoimmune marker and/or negative imaging. Clinical judgment is required to not rule out GPA despite a negative workup when other more serious causes have been excluded, as the diagnosis may be life-threatening.

Objective : To summarize the experience of three years of positive ANCA (anti-neutrophil cytoplasmic antibodies) testing in a single university based hospital. We describe the clinical features according to ANCA phenotype of patients who did and did not have ANCA- associated vasculitis (AAV). Methods : We did a review of all samples tested for ANCA in a 3 year-period (2005-2007). Each sample was tested by indirect immunofluorescence (IIF) and enzyme-linked-immunosorbent assay (ELISA). Sera were considered as positive for ANCA testing if either IIF or ELISA for MPO or PR3 antigen specificity was positive. Patients were considered as having AAV on established diagnostic criteria and algorithms. Results : The positive ANCA population consisted in 209 patients, 54 were classified in the AAV group and 155 patients constituted the “Others” group. The typically most relevant ANCA phenotypes (C-ANCA/anti-PR3+ and P-ANCA/anti-MPO+) were detected in 90 % (49/54) of patients in the AAV group and only 10% (15/155) of the “Others” group (p < 0.001). Among the latter none developed AAV during follow-up. Positive IIF alone was found in 4% (2/54) of the AAV group and in 68% (105/155) of the “Others” group (p < 0.001). In patients without AAV, positive IIF alone or positive ELISA with negative IIF represented the main ANCA pattern. Conclusion : In routine clinical practice, most patients with positive ANCA testing do not have AAV. The typical ANCA pattern (C-ANCA/anti-PR3+ or P-ANCA/anti-MPO+) remains a strong predictor of AAV in patients with a high level of suspicion for systemic vasculitis. In other cases, ANCA positivity should be interpreted with extreme caution.

The relationship between anti-neutrophil cytoplasmic antibodies (ANCA) and inflammatory bowel disease has attracted significant attention due to shared immunopathological mechanisms and clinical associations. This case report describes a 20-year-old African woman with a history of ulcerative colitis who developed diffuse alveolar haemorrhage in the setting of elevated proteinase 3 (PR3)-ANCA. She was treated for ANCA-associated vasculitis with corticosteroids, plasma exchange, and rituximab, leading to a complete resolution. The case highlights the association between ulcerative colitis and ANCA-associated vasculitis, particularly with PR3-ANCA, and the importance of recognizing this overlap. Although ANCA are frequently present in inflammatory bowel disease, especially ulcerative colitis, their pathogenic role remains unclear. The incidence of ANCA-associated vasculitis is higher in inflammatory bowel disease patients, with ulcerative colitis often preceding ANCA-associated vasculitis. Despite the common presence of ANCA in inflammatory bowel disease, not all patients progress to ANCA-associated vasculitis. This case underscores the need for careful monitoring in ulcerative colitis patients with elevated PR3-ANCA and the role of ANCA in guiding diagnosis and treatment. High proteinase 3 (PR3)-anti-neutrophil cytoplasmic antibodies (ANCA) titre impacts the severity and management of ulcerative colitis patients.ANCA-associated vasculitis is more frequent in ulcerative colitis patients and occurs several years after ANCA positivity.Close monitoring of ulcerative colitis patients with PR3-ANCA is essential for early detection of progression to ANCA-associated vasculitis.

Background:Anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV), affects small and medium-sized vessels. The exact mechanisms leading to an excess production of ANCA are not clear. In healthy individuals, ANCA specific...

A syndrome comprising asthma, allergic rhinitis, pulmonary and systemic small-vessel vasculitis, and extravascular granulomas was described in 1951 by Churg & Strauss, mainly from autopsied cases (1). Clinical studies of patients with polyarteritis nodosa, associated asthma, pulmonary in®ltrates, and eosinophilia had been reported previously (2±5). Churg & Strauss described the pathologic lesions and distinguished this entity from polyarteritis nodosa. They described basic anatomic changes consisting of ``widespread vascular lesions of the type seen in polyarteritis nodosa, and of characteristic tissue alteration in the vessel wall and in the extravascular system. This tissue alteration . . . comprised necrosis of eosinophilic exudate, severe `®brinoid' collagen change, and granulomatous proliferation of epithelioid and giant cells.'' Churg & Strauss considered it to be a distinct histopathologic entity which they termed ``allergic granuloma''.

ANCA-associated renal vasculitis

Investigating the concomitance of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides and inflammatory bowel disease (IBD)