Pulse cyclophosphamide for severe neuropsychiatric lupus.

We studied the effect of parenteral pulse cyclophosphamide therapy in nine patients with active systemic lupus erythematosus and severe central nervous system involvement. Seven patients had focal neurological deficits and/or seizures associated with abnormalities on cerebrospinal fluid analysis and/or magnetic resonance imaging. Two patients had organic brain syndrome with psychosis and normal cerebrospinal fluid and/or magnetic resonance imaging analysis. Six patients were unresponsive to treatment with high dose corticosteroid. Cyclophosphamide, 0.75-1.0 g/m2 body surface area, was administered intravenously every month for at least 2 months. Eight patients had a complete recovery or recovered with minor residuals. Cyclophosphamide was well tolerated with few side effects. We conclude that parenteral pulse cyclophosphamide is an effective adjunctive therapy for the management of patients with active systemic lupus erythematosus and central nervous system symptoms.     

NIH conference. Membranous nephropathy.

Membranous nephropathy is a worldwide problem that accounts for about 20% of the cases of the adult-onset nephrotic syndrome. This disease places many patients at risk for both end-stage renal failure and the complications of hyperlipidemia. Immune-mediated injury to the glomerular capillary wall in patients with membranous nephropathy is characterized by subepithelial immune complex formation and generation of the membrane attack complex of complement. Glomerular capillary hypertension, hyperlipidemia, and possibly cytokines could contribute to the glomerular sclerosis seen in the advanced stages of the disorder. In some cases, production of pathogenic antibody can be suppressed by treating the underlying condition. The mechanisms of action of immunosuppressive agents are being investigated and treatments are being tested in clinical trials to optimize the balance of efficacy and toxicity. Alternate-day treatment with corticosteroids is often recommended for nephrotic patients with idiopathic membranous nephropathy, but this approach has not been proved beneficial. Ongoing studies are evaluating whether cytotoxic drugs or cyclosporin A combined with prednisone is more effective than treatment with corticosteroids alone. Lipid-lowering drug therapy is warranted in cases of the persistent nephrotic syndrome to avert the cardiovascular sequelae of hyperlipidemia.     

乳腺管状小叶癌

乳腺管状小叶癌（Tubulolobular carcinoma，TLC）最初是被作为小叶癌的管状变型。作者总结了27例TLC的组织学、免疫表型和临床特征，并与纯小管癌和经典型小叶癌进行了比较。此组患者年龄43-79岁（中位年龄60岁）。1例双侧乳腺受累，5例病变为多灶性。肿瘤直径0．5-2．5cm，色灰褐，质硬。组织学观察：TLC的肿瘤细胞形成管状和条索状两种结构模式并相互混杂，且两者比例相当（统称为管状小叶模式）。     

Germline mutations of the CDKN2 gene in UK melanoma families

Germline mutations in CDKN2 on chromosome 9p21, which codes for the cyclin D kinase inhibitor p16, and more rarely, mutations in the gene coding for CDK4, the protein to which p16 binds, underlie susceptibility in some melanoma families. We have sequenced all exons of CDKN2 and analysed the CDK4 gene for mutations in 27 UK families showing evidence of predisposition to melanoma. Five different germline mutations in CDKN2 were found in six families. Three of the mutations (Met53Ile, Arg24Pro and 23ins24) have been reported previously. We have identified two novel CDKN2 mutations (88delG and Ala118Thr) which are likely to be associated with the development of melanoma, because of their co-segregation with the disease and their likely functional effect on the CDKN2 protein. In binding assays the protein expressed from the previously described mutation, Met53Ile, did not bind to CDK4/CDK6, confirming its role as a causal mutation in the development of melanoma. Ala118Thr appeared to be functional in this assay. Arg24Pro appeared to bind to CDK6, but not to CDK4. No mutations were detected in exon 2 of CDK4, suggesting that causal mutations in this gene are uncommon. The penetrance of these mutant CDKN2 genes is not yet established, nor is the risk of non-melanoma cancer to gene carriers.      

Multigenic control of skin tumor susceptibility in SENCARA/Pt mice

Skin tumors induced in mice by initiation-promotion (2 microg DMBA-2 microg TPA) protocols were found to be under multigenic control. Eighty- one N2 mice from the cross (BALB/cAnPt x SENCARA/Pt)F1 x SENCARA/Pt that were either solidly resistant (no papillomas) or highly susceptible (> or = 7 papillomas/mouse) were subjected to a 'genome scan' using 89 microsatellite markers to check for associations with susceptible and resistant phenotypes. A locus on Chr 5 (Skts4) was found to control the susceptibility of SENCARA/Pt mice and the resistance of BALB/cAnPt mice to papilloma formation. In addition, higher than expected linkage scores were seen for the markers D9Mit271, D11Mit268 and D12Mit56. Further work is required to establish whether genes determining papilloma formation are located in these regions of the genome. In general, no evidence was seen for loss of heterozygosity in microsatellite markers on Chrs 5, 9 and 11 in 17 microdissected papillomas from (BALB/c x SENCARA)F1 hybrid mice.      

Evidence-based recommendations for the management of ankylosing spondylitis: systematic literature search of the 3E Initiative in Rheumatology involving a broad panel of experts and practising rheumatologists

Objective. Recommendations and/or guidelines represent a popularway of integrating evidence-based medicine into clinical practice.The 3E Initiatives is a multi-national effort to develop recommendationsfor the management of rheumatic diseases, which involves a largenumber of experts combined with practising rheumatologists addressingspecific questions relevant to clinical practice. Methods. Ten countries participated in three rounds of discussionsand votes concerning the management of AS. A set of nine questionswas formulated in the domains of diagnosis, monitoring and treatment,after a Delphi procedure. A literature search in MedLine wasconducted. Predefined outcome parameters for the domains ofdiagnosis, monitoring and treatment were assessed. The evidenceto support each proposition was evaluated and scored. Afterdiscussion and votes, the final recommendations were presentedusing brief statements by each national group, following whichthe final international recommendations were formulated. Results. A total of 2699 papers were found and 467 were selectedfor analysis. Twelve key recommendations were developed: threein the domain of diagnosis addressing general diagnostic considerations,early AS diagnosis and general practitioners’ referralrecommendations; three concerning monitoring of AS disease activity,severity and prognosis; six concerning pharmacological treatment(except biologics): non-steroidal anti-inflammatory drugs/COX-IIinhibitors, bisphosphonates and treatment of enthesitis. Thecompiled agreement among experts ranged from 72% to 93%. Conclusion. Recommendations for the management of AS were developedusing an evidence-based approach followed by expert/physicianconsensus with high level of agreement. Involvement of a largerand more representative group of rheumatologists may improvetheir dissemination and implementation in daily clinical practice. KEY WORDS: Ankylosing spondylitis, Systemic literature search, Recommendations, Non-steroidal anti-inflammatory drugs, COX-II inhibitors, Monitoring, Diagnosis, Treatment     

Comparative effectiveness and survival of infliximab,adalimumab, and etanercept for rheumatoid arthritis patients in the Hellenic Registry of Biologics: Low rates of remission and 5-year drug survival

Objective

To compare effectiveness, drug survival, and safety between infliximab, adalimumab, and etanercept, in a nationwide cohort of rheumatoid arthritis (RA) patients.

Methods

This study is a prospective cohort study of 1208 active RA patients. Effectiveness, drug survival, and serious adverse events during entire follow-up (median 2.9 years) were monitored.

Results

EULAR and CDAI responses were comparable between the three agents (EULAR good/moderate responses at 12 months ranged 76–79%). At 12 months, 15–23% achieved remission. For adalimumab and etanercept, adjusted hazard rate (HR) for EULAR/ACR remission (reference: infliximab) was 2.7 and 2.1 (95% confidence interval was 1.7–4.1 and 1.3–3.4, respectively); males (HR 1.6; 1.1–2.4), use of glucocorticoids (HR 2.0; 1.3–3.0), and swollen joint count >7 (HR 0.36; 0.24–0.55) were independent predictors. Five-year drug survival was 31%, 43%, and 49% for infliximab, adalimumab, and etanercept, respectively (p = 0.010). Infliximab was associated with significantly more withdrawals due to adverse events. Disease activity, CRP, and use of glucocorticoids predicted efficacy-related drug survival; age, use of methotrexate, and prior DMARDs failures predicted safety-related survival. Risk for serious infections was lower with adalimumab (odds ratio [OR] 0.62; 0.38–1.00) or etanercept (OR 0.39; 0.21–0.72) than infliximab, independent of the effects of age (OR 1.65; 1.37–2.00 per 10 years), tender joint count >10 (OR 1.86; 1.21–2.86), and glucocorticoids >35 mg/week (OR 1.83; 1.12–2.99).

Conclusions

Response rates were comparable among anti-TNF agents. Overall, 5-year drug survival was below 50%, with infliximab demonstrating increased safety-related discontinuations. Remission rates are low in clinical practice. Strategies to increase effectiveness and long-term survival of anti-TNF agents in RA are needed.