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ID PMID Title PublicationDate abstract
20176259 Immunologic rheumatic disorders. 2010 Feb We provide the basics for clinicians who might be called on to consider the diagnosis of diseases such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) in their practice. We will emphasize clinical recognition and first-line laboratory testing. Only characteristics of the classic rheumatic inflammatory diseases (ie, RA, seronegative spondyloarthropathy, SLE, antiphospholipid syndrome, Sjögren syndrome, scleroderma, and polymyositis/dermatomyositis) will be covered. In the past decade, treatment for RA and seronegative spondyloarthropathy has substantially improved. Their treatment has been revolutionized by the use of methotrexate and, more recently, TNF inhibitors, T-cell costimulation modulators, and B-cell depletion. The goal of RA treatment today is to induce a complete remission as early as possible in the disease process, with the mantra being "elimination of synovitis equals elimination of joint destruction." The hope is that if the major mediators of Sjögren syndrome, SLE, or scleroderma can be identified and then blocked, as in the example of TNF inhibitors in patients with RA, more specific treatments will become available. Thus RA has become an excellent model of this evolving paradigm. Through the identification of major mediators in its pathogenesis, novel and highly efficacious therapeutic agents have been developed.
19513730 [Translational aspects on the role of B-cells in autoimmune diseases. "From bench to bedsi 2009 Jul In recent years, new findings in immunology have been successfully converted to therapeutic principles, in particular for rheumatoid arthritis (RA) and spondylarthritides. The introduction of cytokine blockers in RA using tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 inhibitors presented the first original therapy modalities in rheumatology, after proliferation-inhibiting drugs, such as methotrexate and cyclophosphamide, had been accepted in oncology. This advance was and is still being extended with the co-stimulation blockade using abatacept and IL-6 receptor inhibition. Anti-CD20 therapies are of particular importance, initially approved for the treatment of non-Hodgkin's lymphoma (NHL), this therapy modality has been approved in recent years for the treatment of RA following the failure of TNF-blockade. However, questions remain regarding the role of B cells in a number of autoimmune diseases, as well as the working principles of B-cell targeted therapy. In this context, close clinical observation of patients has yielded answers to and confirmation of basic scientific concepts.
20022196 Lewis lead enhances atrial activity detection in wide QRS tachycardia. 2012 Aug BACKGROUND: The differential diagnosis of wide QRS tachycardia is a challenge for the emergency physician. The major tool is the electrocardiogram (ECG), even though the sensitivity and specificity may be variable, depending on presentation. Additional leads could be used to improve the diagnostic accuracy of the ECG. OBJECTIVE: To document the use of the Lewis lead in improving the diagnostic accuracy of the ECG in wide QRS tachycardia. CASE REPORT: A 52-year-old woman with rheumatoid arthritis, in treatment with methotrexate, was admitted with progressive dyspnea that evolved to acute respiratory distress and shock at arrival. Pneumonia was diagnosed as the infection and she received antibiotics, and respiratory and inotropic support. She was also using amiodarone for more than 10 years, but she couldn't state the reason. On cardiac monitoring, wide QRS tachycardia was detected and ventricular tachycardia was considered on the differential diagnosis. The standard 12-lead ECG was complemented with the Lewis lead, obtained with higher speed and amplitude, demonstrating atrioventricular concordance and excluding ventricular tachycardia. The patient was treated for septic shock, and she died 2 days later. CONCLUSION: The Lewis lead is a simple and easy strategy to enhance atrial activity detection in wide QRS tachycardia.
21125513 [Secondary aorto-enteral fistula as a cause of acute recurrent gastrointestinal bleeding, 2010 Dec Aorto-enteral fistulas (AEF) are a rare but life-threatening cause of acute gastrointestinal bleeding. Clinically, they can appear through massive haematochezia and haematemesis or as intermittent occult intestinal bleeding. The diagnostic procedure using endoscopy is often difficult but can contribute to making the correct diagnosis. We report on a patient who developed a secondary aorto-enteral fistula twenty years after a living kidney donation. The vascular surgery in combination with a chronic inflammatory reaction had resulted in the formation of a fistula between the renal artery stump and the duodenum. The inflammatory response was maintained by continuous treatment with methotrexate because of rheumatoid arthritis. Despite several total enteroscopies and diagnostic laparotomies, the fistula was seen on several occasions but was overlooked and misinterpreted in the absence of bleeding at first. The suspected fistula was finally marked with two endoclips and confirmed subsequently by radiological imaging by means of an abdominal CT scan.
19016697 Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms. 2009 Feb BACKGROUND: The use of methotrexate is limited by interindividual variability in response. Previous studies in patients with either rheumatoid arthritis or psoriasis suggest that genetic variation across the methotrexate metabolic pathway might enable prediction of both efficacy and toxicity of the drug. OBJECTIVES: To assess if single nucleotide polymorphisms (SNPs) across four genes that are relevant to methotrexate metabolism [folypolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC)] are related to treatment outcomes in patients with psoriasis. METHODS: DNA was collected from 374 patients with psoriasis who had been treated with methotrexate. Data were available on individual outcomes to therapy, namely efficacy and toxicity. Haplotype-tagging SNPs (r(2) > 0.8) for the four genes with a minor allele frequency of > 5% were selected from the HAPMAP phase II data. Genotyping was undertaken using the MassARRAY spectrometric method (Sequenom). RESULTS: There were no significant associations detected between clinical outcomes in patients with psoriasis treated with methotrexate and SNPs in the four genes investigated. CONCLUSIONS: Genetic variation in four key genes relevant to the intracellular metabolism of methotrexate does not appear to predict response to methotrexate therapy in patients with psoriasis.
19786771 Drug monitoring in inflammatory bowel disease: helpful or dispensable? 2009 Thiopurines, methotrexate and the calcineurin inhibitors cyclosporin A and tacrolimus are classical immunosuppressive treatment modalities for inflammatory bowel disease (IBD). Since a high inter-patient variability exists in drug efficacy and toxicity, their application requires the knowledge of appropriate indications as well as strategies for individualization of dosage and monitoring for adverse events. Results of pharmacogenetic studies that examine the relationship between single-gene polymorphisms and associated effects on the pharmacokinetics and pharmacodynamics may be helpful for the optimization of individualized therapy. Although 85-95% of patients worldwide present with the homozygote thiopurine S-methyltransferase (TPMT) wild-type genotype and a normal enzyme activity, cost-benefit analyses suggest assessment of TPMT enzyme activity prior to thiopurine therapy for IBD to prevent life-threatening toxicity. Monitoring of 6-mercaptopurine metabolites is a helpful, but not an indispensable tool in thiopurine non-responders to discriminate poor adherence and under-dosing from pharmacogenetic thiopurine resistance and thiopurine refractory disease. Response to and adverse events of methotrexate therapy are hard to predict. Pharmacogenetic indices of methotrexate metabolization have been evaluated in rheumatoid arthritis (RA) but not in IBD yet. In contrast to RA, concentration of methotrexate polyglutamates correlates positively with non-response and adverse effects in IBD. Calcineurin inhibitor metabolism is mainly controlled by cytochrome P-450 isoenzymes 3A4/3A5 and P-glycoprotein that underlie a variety of gene polymorphisms and are susceptible to drug interactions. Independent from pharmacokinetic alterations a MDR1 polymorphism may predict cyclosporin failure in severe ulcerative colitis. Frequent monitoring of whole blood levels is required since efficacy and toxicity are dose-dependent.
19389524 Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. 2009 May BACKGROUND: Methotrexate remains a valuable option for the treatment of psoriasis. This report will summarize studies regarding the use of methotrexate since the last guidelines were published in 1998. OBJECTIVE: A task force of the National Psoriasis Foundation Medical Board was convened to evaluate treatment options. Our aim was to achieve a consensus on new updated guidelines for the use of methotrexate in the treatment of psoriasis. METHODS: Reports in the literature were reviewed regarding methotrexate therapy. RESULTS: A consensus was achieved on use of methotrexate in psoriasis including specific recommendations on dosing and monitoring. The consensus received unanimous approval from members of the Medical Board of the National Psoriasis Foundation. LIMITATIONS: There are few evidence-based studies on the treatment of psoriasis with methotrexate. Many of the reviewed reports are for the treatment of rheumatoid arthritis. CONCLUSIONS: Methotrexate is a safe and effective drug for the treatment of psoriasis. Appropriate patient selection and monitoring will significantly decrease the risks of side effects. In patients without risk factors for hepatic fibrosis, liver biopsies may not be indicated or the frequency of liver biopsies may be markedly reduced.
18762934 Limits of add-on trials: antirheumatic drugs. 2009 Jan PURPOSE: This paper assesses the design of clinical studies used in the process of regulatory approval, focusing on how add-on studies affect regulatory decisions. METHODS: The sample case taken is that of the new agents for rheumatoid arthritis (RA) authorised by the European Medicine Agency (EMEA). The European Public Assessment Reports (EPARs) accompanying the marketing authorisations were the source of information on the studies presented in the registration dossiers. RESULTS: The recently approved anti-RA agents are all indicated in combination with methotrexate (MTX) for treating adults with active RA who have responded inadequately to disease-modifier drugs (DMARDs). The add-on design was frequently used in registration studies. For infliximab, etanercept, adalimumab and rituximab, add-on trials contributed, together with parallel-group trials, to gaining the approval as combination therapy. Anakinra and abatacept were authorised on the basis of add-on trial results only. CONCLUSIONS: Add-on trials do not allow assessment of the intrinsic efficacy and safety of new agents and their value as alternatives to available treatments. The indications granted for the new anti-RA agents do not specify whether newer drugs can replace standard treatments in nonresponders, can do better in the overall patient population or can be used as first-line treatment.
20703490 [Tocilizumab. What comes after TNF-blockers in clinical routine?]. 2010 Sep Tocilizumab, a monoclonal humanized antibody against IL-6, was licensed in January 2009 in combination with Methotrexate for the treatment of adult patients with moderately to severely active rheumatoid arthritis and inadequate response to one or more DMARDs or TNF antagonists. Tocilizumab is given once every 4 weeks as a 60-min single intravenous infusion at a dosage of 8 mg/kg body weight and may be used as a monotherapy in the case of MTX or DMARD incompatibility. Clinical response is rapid and lasting according to clinical measurements such as ACR response rates or DAS28, irrespective of previous therapy. Within 2 weeks of the first infusion, inflammatory parameters such as CRP and ESR decline and the haemoglobin concentration increases. Adverse events often include mild respiratory infections, transient elevation in liver enzymes, decrease in neutrophile counts and increase in serum lipids. In 8% of patients a lipid lowering therapy needs to be initiated. Diverticulitis with perforation has been observed. Serious infections occur in the range known with other biological therapies. The radiological data show a reduced rate of joint destruction after 1 year of therapy. Long-term follow-up shows good clinical efficacy with an increasing percentage of patients with good clinical response and good safety profile.
19486063 Methotrexate-induced primary cutaneous diffuse large B-cell lymphoma with an 'angiocentric 2010 Jan A patient with a 25-year history of rheumatoid arthritis and a 3-year history of methotrexate treatment developed a generalized papular rash. The papules rapidly became necrotic and then resolved, leaving a depressed scar. The rapid course of lesion development and regression was reminiscent of pityriasis lichenoides. Histology revealed a nodular infiltrate composed of a mixture of pleomorphic large B cells positive for CD20, CD30 and CD79a, and of small T cells positive for CD3 and CD4. The T cells had a striking angiocentric distribution, with some of the vessels exhibiting fibrinoid necrosis of the vessel wall reminiscent of lymphomatoid granulomatosis. However, B cells were consistently negative for Epstein-Barr virus (EBV) antigen expression. A thorough examination excluded involvement of organs other than the skin. Thus, this patient was classified as having a rare form of an EBV-negative primary cutaneous T-cell-rich B-cell lymphoma in association with methotrexate treatment.
20834190 Dihydrofolate reductase gene intronic 19-bp deletion polymorphisms in a Japanese populatio 2010 Dihydrofolate reductase gene (DHFR) 19-bp deletion polymorphisms result in varied DHFR enzymatic activity affecting the risk for preterm delivery, spina bifida, and the efficacy of methotrexate (MTX). Ethnic differences in DHFR 19-bp polymorphisms may be responsible for the divergent findings in previous genetic studies. We compared genotype and allele frequency of DHFR intronic 19-bp deletion polymorphisms in ethnically homogenous East Asians (from Japan) and others by polymerase chain reaction assay conducted on 277 healthy Japanese individuals. The genotype distribution was as follows: wild/wild, 11.9% (n=33); wild/deletion, 40.1% (n=111); deletion/deletion, 48.0% (n=133). The frequencies of wild type and deletion alleles were 0.32 and 0.68, respectively. The obtained genotype distribution was consistent with those calculated by Hardy-Weinberg equilibrium. The genotype distribution and allele frequencies in the Japanese population were significantly different from those previously reported for other ethnic populations. Determination of intronic 19-bp deletion polymorphisms of DHFR may be useful for monitoring the efficacy and side effects of MTX for the treatment of diseases such as rheumatoid arthritis and childhood acute leukemia in the Japanese population because the frequency of the deletion allele is higher.
21186199 Right coronary artery fistula to the coronary sinus and right atrium associated with giant 2011 Mar We present the case of a 54-year-old female with a previous history of lung fibrosis secondary to methotrexate used for rheumatoid arthritis who was referred to cardiology evaluation due to precordial pain. Echocardiography showed biatrial enlargement with an enlarged coronary sinus and tubular image posterior to the heart. On the coronary angiogram, the right coronary artery was enlarged, and a distal fistula was identified. The patient underwent a contrast enhanced cardiac computed tomography which demonstrated an aneurysmatic right coronary artery with a distal fistula to the right atrium and coronary sinus. As the chest pain did not recur and there was a high risk of the intervention to correct coronary fistula, the patient remained on conservative treatment.
21122509 Methotrexate-induced pneumonitis in a patient with Crohn's disease. 2010 Jun Pulmonary toxicity is a well recognised but infrequent adverse event of treatment with methotrexate. The vast majority of cases have occurred in patients with rheumatoid arthritis; here we present the case of a 44-year old woman with ileo-colonic Crohn's disease who developed methotrexate pneumonitis. The patient had a 10 year history of Crohn's disease and, in the last 18 months, she was treated with oral methotrexate because of steroid-dependency and intolerance to thiopurines. She was admitted to the hospital because of acute dyspnoea, non-productive cough and fever. High-resolution CT scan showed diffuse bilateral areas of ground-glass opacity, and pulmonary function tests disclosed a mild obstructive pattern with a decrease in carbon monoxide diffusing capacity. Blood cultures for pathogenic bacteria or fungi were negative as well as serologic tests against major pneumotropic agents. Methotrexate-induced lung injury was considered: the drug was discontinued and the patient received a steroid course with rapid symptomatic improvement. After 4 weeks pulmonary function tests and high-resolution chest CT scan were normal. To our knowledge this is the second reported case of methotrexate-induced pneumonitis occurring in a patient with Crohn's disease. A definite diagnosis has been made not invasively according to clinical, laboratory and radiological criteria and excluding any infectious aetiology of the pulmonary findings.
19383496 Methotrexate induces apoptosis in CaSki and NRK cells and influences the organization of t 2009 Jun 24 Methotrexate is a widely used drug in treatments of various types of malignancies and in the therapy of rheumatoid arthritis. The goal of our study was to look at the effect of this dihydrofolate reductase inhibitor on the actin cytoskeleton, since actin plays an important role in cancer transformation and metastasis. For this reason we compared results obtained from experiments on CaSki (human uterine cervix cancer) and NRK (normal fibroblastic rat kidney) cells treated with methotrexate. It has been shown previously that methotrexate can induce apoptosis. Therefore we first examined whether methotrexate induces apoptosis in our model cells. For this aim we applied several assays like Caspase Glo 3/7, DNA fragmentation and binding of phosphatidylserine by annexin V-fluorescein. The data obtained indicated that methotrexate induces programmed cell death in CaSki and NRK cells. However, differences between CaSki and NRK cells were observed in the morphological alterations and dynamics of apoptosis induced by methotrexate. It seemed that cancer cells were more sensitive towards the cell death inducing activity at lower concentrations of methotrexate. Analysis by confocal microscopy of methotrexate-treated cells demonstrated that treatment with this folate antagonist affected the actin cytoskeleton, although the dis-organization of the actin cytoskeleton after treatment with methotrexate differed between cancer and normal cells.
18823045 Molecular and functional characteristics of proton-coupled folate transporter. 2009 May Proton-coupled folate transporter (PCFT) has recently been identified as the molecular entity of the carrier-mediated intestinal folate transport system. PCFT has been demonstrated to be most abundantly expressed in the upper small intestine, localizing at the brush border membrane of epithelial cells, transport folate and its analogs more efficiently at lower (acidic) pH by a H(+)-coupled cotransport mechanism, and have a high affinity for folate with a Michaelis constant (K(m)) of a few microM at pH 5.5 and somewhat lower affinities for reduced folates and methotrexate (MTX). A loss of PCFT function due to a homozygous mutation in its gene has been indicated to be responsible for hereditary folate malabsorption. Thus, PCFT has all the characteristics of the brush border H(+)-coupled cotransporter for folate and analogs, which has long been suggested to be present in the intestine. Furthermore, sulfasalazine was found to be a potent inhibitor of PCFT, suggesting that it is a risk factor that would cause malabsorption of folate and also MTX, when coadministered in the treatment of rheumatoid arthritis. Understanding the molecular and functional characteristics of PCFT should be important and helpful in exploring therapeutic strategies for folate malabsorption and in optimizing therapies using antifolate drugs.
19684849 Drugs Used in the Treatment of Rheumatoid Arthritis: Relationship between Current Use and 2009 Jun OBJECTIVES: Drugs used for the treatment of rheumatoid arthritis (RA) have the potential to affect cardiovascular risk factors. There is concern that corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors could affect cardiovascular risk adversely, while drugs such as the antimalarial, hydroxychloroquine, may have beneficial effects. However, there is limited information about cardiovascular risk factors in patients with RA receiving different drugs. METHODS: We measured cardiovascular risk factors including systolic and diastolic blood pressure, serum HDL and LDL cholesterol, glucose and homocysteine concentrations and urinary F(2)-isoprostane excretion in 169 patients with RA. Risk factors were compared according to current use of corticosteroids, methotrexate, antimalarials, NSAIDs, COX-2 inhibitors, leflunomide and TNF-alpha blockers. Comparisons were adjusted for age, sex, race, disease activity (DAS28 score), current hypertension, diabetes, smoking status and statin use. RESULTS: No cardiovascular risk factor differed significantly among current users and non-users of NSAIDs, COX-2 inhibitors, methotrexate and TNF-alpha blockers. Serum HDL cholesterol concentrations were significantly higher in patients currently receiving corticosteroids (42.2 +/- 10.5 vs. 50.2 +/- 15.3 mg/dL, adjusted P < 0.001). Diastolic blood pressure (75.9 +/- 11.2 vs. 72.0 +/- 9.1 mm Hg, adjusted P = 0.02), serum LDL cholesterol (115.6 +/- 34.7 vs. 103.7 +/- 27.8 mg/dL, adjusted P = 0.03) and triglyceride concentrations (157.7 +/- 202.6 vs. 105.5 +/- 50.5 mg/dL, adjusted P = 0.03) were significantly lower in patients taking antimalarial drugs. Plasma glucose was significantly lower in current lefunomide users (93.0 +/- 19.2 vs. 83.6 +/- 13.4 mg/dL, adjusted P = 0.006). CONCLUSIONS: In a cross-sectional setting drugs used to treat RA did not have major adverse effects on cardiovascular risk factors and use of antimalarials was associated with beneficial lipid profiles.
19170412 Adalimumab: in plaque psoriasis. 2009 Adalimumab is a recombinant, human, IgG1 monoclonal antibody specific for tumor necrosis factor. The clinical efficacy and safety of adalimumab (40 mg administered subcutaneously every other week) in patients with moderate-to-severe chronic plaque psoriasis have been demonstrated in several randomized, double-blind clinical trials, including the pivotal trials REVEAL (n = 1212) and CHAMPION (n = 271). Based on these trials, adalimumab was significantly more effective than placebo and methotrexate at relieving the signs and symptoms of psoriasis after 16 weeks of treatment, as assessed by the percentage of patients achieving a 75% improvement from baseline in Psoriasis Area and Severity Index. Based on open-label extension studies of up to 2 years' duration, the efficacy of adalimumab was sustained over the long term. Of patients who had responded to 33 weeks of treatment with adalimumab in REVEAL, patients randomized to remain on adalimumab for an additional 19 weeks of treatment were significantly less likely to experience loss of an adequate response than patients who were transferred to placebo. Compared with placebo or methotrexate, adalimumab was associated with significantly greater improvements in dermatology-specific and general measures of health-related quality of life in patients with plaque psoriasis. Adalimumab was generally well tolerated in trials in patients with plaque psoriasis, and the adverse-event profile was similar to that associated with its use in rheumatoid arthritis.
19287931 [Vaccination against yellow fever among patients on immunosuppressors with diagnoses of rh 2009 Jan Yellow fever is endemic in some countries. The anti-yellow fever vaccine is the only effective means of protection but is contraindicated for immunocompromised patients. The aim of this paper was to report on a case series of rheumatological patients who were using immunosuppressors and were vaccinated against this disease. This was a retrospective study by means of a questionnaire applied to these patients, who were vaccinated 60 days before the investigation. Seventy patients of mean age 46 years were evaluated. Most of them were female (90%). There were cases of rheumatoid arthritis (54), systemic lupus erythematosus (11), spondyloarthropathy (5) and systemic sclerosis (2). The therapeutic schemes included methotrexate (42), corticosteroids (22), sulfasalazine (26), leflunomide (18), cyclophosphamide (3) and immunobiological agents (9). Sixteen patients (22.5%) reported some minor adverse effect. Among the eight patients using immunobiological agents, only one presented a mild adverse effect. Among these patients using immunosuppressors, adverse reactions were no more frequent than among immunocompetent individuals. This is the first study on this topic.
19309046 Idiopathic chondrolysis treated with etanercept. 2009 Mar Idiopathic chondrolysis of the hip in children has been well documented in the literature. The insidious nature of the symptoms and lack of early radiographic findings and diagnostic testing often delay diagnosis. Children often report a stiff, painful hip and have an associated limp in the absence of trauma or constitutional symptoms. Despite these symptoms it remains a poorly understood diagnosis with no identifiable cause. Some have speculated an inflammatory cause, as this disease exhibits joint space narrowing, presumably due to enzymatic activity similar to juvenile rheumatoid arthritis. Despite case reports attempting traction, physical therapy, nonsteroidal anti-inflammatories, steroids, and even operative intervention, no current treatment regimen exists that offers proven appreciable benefit. We hypothesized the powerful anti-inflammatory properties of etanercept would provide symptomatic and radiographic improvement of idiopathic chondrolysis of the hip. This article presents a case of an adolescent boy with a stiff, painful left hip that failed treatment with traction, physical therapy, naproxen, and methotrexate, prior to initiating etanercept. After 1 year of daily etanercept therapy, the patient's hip motion improved in all directions and his pain completely resolved. This novel therapeutic approach offered symptomatic relief and radiographic improvement, and may provide an effective treatment strategy for this difficult disease.
21123969 Atypical lymphoplasmacytic and immunoblastic proliferation of autoimmune disease : clinico 2010 Atypical lymphoplasmacytic immunoblastic proliferation (ALPIB) is a rare lymphoproliferative disorder (LPD) associated with autoimmune disease (AID). To further clarify the clinicopathologic, immunohistological, and genotypic findings of ALPIB in lymph nodes associated with well-documented AIDs, 9 cases are presented. These 9 patients consisted of 4 patients with systemic lupus erythematosus, 3 patients with rheumatoid arthritis, and one case each with Sjögren's syndrome and dermatomyositis. All 9 patients were females aged from 25 to 71 years with a median age of 49 years. Four cases presented with lymphadenopathy as the initial manifestation. In 4 patients, immunosuppressive drugs were administered before the onset of lymph node lesion. However, none of the 9 patients received methotrexate therapy. The present 9 cases were characterized by : (i) prominent lymphoplasmacytic and B-immunoblastic infiltration ; (ii) absence of pronounced arborizing vascular proliferation ; (iii) absence of CD10(+) "clear cells" ; (iv) presence of hyperplastic germinal center in 7 cases ; (v) immunohistochemistry, flow cytometry, and polymerase chain reaction demonstrated a reactive nature of the T- and B-lymphocytes ; and (vi) on in situ hybridization, there were no Epstein-Barr virus -infected lymphoid cells in any of the 9 cases. Overall 5-year survival of our patients was 83%. The combination of clinical, immunophenotypic, and genotypic findings indicated that the present 9 cases can be regarded as having an essentially benign reactive process. Finally, we emphasized that ALPIB should be added to the differential diagnostic problems of atypical LPDs, particularly lymph node lesions of IgG4-related diseases.