Recognition and management of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an inflammatory systemic disease that causes organ damage by the deposition of autoantibodies and complement activating immune complexes or by vascular occlusion due to procoagulant states associated with antiphospholipid antibodies. The vast majority of cases occur in women of childbearing age. SLE is diagnosed on the basis of its clinical manifestations and the demonstration of characteristic immunological phenomena, especially anti-nuclear antibodies. The prognosis in SLE has shown a distinct improvement over recent decades, the 5-year survival rate now approaching or exceeding 90%. The 15-year survival rate of 63 to 79%, on the other hand, underscores the need for further advances in diagnosis and treatment of the disease. Management of the disease includes regular monitoring of disease activity, avoidance of predisposing factors and close supervision of therapy. Drug therapy is guided by the activity and severity of the leading organ manifestations and ranges from nonsteroidal antirheumatic drugs to intensive treatment with cytotoxic agents. Corticosteroids remain irreplaceable for the control of acute flares. Antimalarials and azathioprine are important long term drugs for treating mild or moderate disease activity. Intravenous pulse cyclophosphamide is safer than other regimens and at least as effective as oral cyclophosphamide for severe lupus nephritis. It is also effective in the treatment of central nervous disease and of other organ-threatening manifestations. Recently, an intensified protocol which included cyclophosphamide induced long term treatment-free remission in 60% of patients. The toxicity of cyclophosphamide is considerable, but can be ameliorated by various measures. The value of several new immunosuppressants and other compounds remains to be determined.     

Hepatobiliary complications of idiopathic intestinal inflammations

Extraintestinal manifestations and metabolic complications are very frequent in patients with idiopathic inflammations of the gut and are encountered in at least 35% of these patients. In Crohn's disease extraintestinal manifestations are more frequent than in ulcerative colitis, in particular when the large bowel is affected. Metabolic complications are the result of inflammatory changes of the small intestine or develop as a result of the reduced reabsorption surface of the gut. As to the relationship to the activity of the idiopathic inflammation of the gut, extraintestinal manifestations can be differentiated into those which depend on the activity of the basic disease and those which lack this dependence. From the aspect of a long-term prognosis extraintestinal manifestation independent on the activity of the inflammation of the gut are much more serious, because as a rule they have a long-term and usually progressive trend. The most serious extraintestinal complication is primary sclerotizing cholangitis which in the majority of patients leads to destruction of the biliary pathways and the development of biliary cirrhosis. Depending on the predominantly affected site of the biliary system, primary sclerotizing cholangitis is divided into three types. It is encountered much more frequently in ulcerative colitis than in Crohn's disease. Treatment of primary sclerotizing cholangitis is not very effective. At present it appears that the only drug with an effect on the course of the disease is long-term administration of urodesoxycholic acid. For patients with manifestations of hepatic insufficiency the only solution is transplantation of the liver. In all patients where the diagnosis of primary sclerotizing cholangitis was established, at the same time the possibility of inclusion in a transplantation programme should be considered. The relationship between sclerotizing cholangitis and pericholangitis has not been resolved conclusively. At present the majority of authors is inclined to believe that pericholangitis is part of changes associated with sclerotizing cholangitis. Other hepatobiliary complications of idiopathic inflammations of the gut such as cholelithiasis and parenchymatous liver damage, steatosis of the liver and chronic autoimmune hepatitis are not such a serious problem as sclerotizing cholangitis.     

Gaucher disease: assessment of skeletal involvement and therapeutic responses to enzyme replacement

The clinical, pathological and radiological manifestations of type 1 Gaucher disease and the role of imaging techniques such as CT, MRI and sulfur-colloid scintigraphy in the management of these patients is discussed. MRI appears to be the most valuable imaging technique for evaluating bone marrow involvement and detecting disease activity. MRI is also useful in assessing therapeutic responses to enzyme replacement therapy.     

Anti-neutrophil cytoplasmic antibodies in 566 European patients with systemic lupus erythematosus: prevalence, clinical associations and correlation with other autoantibodies. European Concerted Action on the Immunogenetics of SLE

OBJECTIVES: To evaluate, in a cohort of 566 patients with systemic lupus erythematosus (SLE) drawn from 11 European centres: (i) the prevalence of ANCAs and their subspecificities in a large series of European SLE patients; (ii) the possible associations of ANCA with the most common clinical manifestations of the disease; and (iii) whether ANCAs correlate with some of the autoantibodies commonly found in SLE. METHODS: ANCA detection was performed by indirect immunofluorescence (IIF), and by ELISA for lactoferrin (LF), myeloperoxydase (MPO), proteinase3 (PR3) and lysozyme (LZ) subspecificities. RESULTS: The prevalence of ANCA was 16.4% (IIF). The prevalence of LF was 14.3%, LZ 4.6%, MPO 9.3%, and PR3 1.7%. Our results show that ANCA is associated with certain clinical manifestations of SLE. In particular, positive correlations were found between IIF ANCA and serositis (p = 0.026), livedo reticularis (p = 0.01), venous thrombosis (p = 0.03) and arthritis (p = 0.04), while anti-LF antibodies were associated with serositis (p = 0.05) and livedo reticularis (p < 10(-3). Nevertheless, multivariate analysis demonstrated that other autoantibodies, such as aCL and SSA/Ro, are more closely correlated than ANCA with some of the aforementioned clinical features. CONCLUSION: Our results demonstrate that ANCA are detectable in SLE sera and that some of them are associated with particular clinical manifestations. Whether ANCA plays a direct pathogenetic role in the vascular damage of SLE or only represents an epiphenomenon or a marker of disease activity remains to be elucidated.     

Pitted keratolysis: clinical manifestations in 53 cases

Pitted keratolysis (PK) has been reported to be more common among bare-footed people living in tropical regions. It is now known that the disease is not limited to the tropics but has a world-wide distribution. However, no study has previously been performed analysing the clinical manifestations of the disease in temperate countries. A survey of 53 patients revealed several distinctive clinical features. Hyperhidrosis is the most frequently observed symptom of this condition. Malodour and sliminess of the skin are also distinctive features, evident in 88.7% and 69.8% of the cases, respectively. The most common sites of onset of PK are the pressure-bearing areas, such as the ventral aspect of the toe, the ball of the foot and the heel. The next most common site is a friction area, the interface of the toes. Lesions are rarely seen on the non-pressure-bearing locations. Some of the primary lesions originate as a small defect along the plantar furrow, which gradually grows into the characteristics crateriform pit. Several clinical features are helpful in diagnosing PK.     

Measures of disease activity and damage in SLE

Criteria for the classification of systemic lupus erythematosus (SLE) are not sufficient to describe the degree of disease activity. Several instruments to assess disease activity have been developed. This chapter reviews the derivation, validation, and clinical application of current disease activity measures in SLE, as well as comparison among them. As patients with lupus survive longer, the sequelae of the disease activity and its therapy are becoming more common. The derivation and validation of the single, generally accepted SLICC/ACR damage index is also discussed.     

Analysis of histopathological manifestations of chronic hepatitis C virus infection with respect to virus genotype

Hepatitis C virus (HCV) causes acute and often chronic hepatitis. On the basis of variations in nucleotide sequence, at least six genotypes and several subtypes have been identified. Histopathologically, chronic HCV infection is characterized by relatively mild hepatic inflammatory activity and a low degree of fibrosis, but hepatic lesions might be accompanied by bile duct damage, intraportal lymphoid aggregates, steatosis, or a combination of these manifestations. The histopathological lesions thus appear quite heterogeneous. To address the question of whether distinct histopathological manifestations are related to particular genotypes of HCV, 90 patients with chronic HCV infection were analyzed regarding histopathological features, biochemical liver parameters, demographic data, and virus genotype. The results revealed a significantly higher prevalence of both steatosis and bile duct lesions among patients infected by HCV type 3a compared to patients infected by types 1a or 1b. Furthermore, the data suggest interrelationships between virus genotype, patient's age, and a history of intravenous drug abuse. However, none of the histopathological manifestations were found to be related to a history of drug abuse. The data further corroborate the relationship of HCV type 1b infection to age, duration of disease, and the degree of fibrosis, respectively. Irrespective of HCV genotype, elevated serum ALT activity was shown to be associated with pronounced inflammatory activity or pronounced steatosis as well. Thus, the current data support the hypothesis that distinct genotypes of HCV appear to be associated with distinct manifestations of disease.     

Quantitative patterns in the clinical manifestations of radiation sickness in large laboratory animals exposed to radiation at superlethal doses. The quantitative patterns in the manifestations of radiation sickness in dogs

Radiation sickness manifestations have been studied in dogs exposed to electrons (electron energy 25 MeV) and gamma-neutron radiation (neutron energies of 0.37 and 1.2 MeV) in a wide dose range. Dose-response relationships have been calculated for mortality and some clinical manifestations of the intestinal and cerebral forms of radiation sickness. With regard to mortality, the highest effect has been observed for gamma-neutron radiation with a neutron energy of 1.2 MeV. For equal physical doses and for those equally effective in relation to mortality, clinical manifestations of damage are more prominent following exposure to electrons.     

The undetermined form of Chagas' heart disease: concept and forensic implications

The undetermined form of Chagas' disease is diagnosed in asymptomatic subjects with a positive blood test for Chagas' disease, normal resting electrocardiogram, chest X-ray, barium esophageal and large bowel radiological studies. Other investigation methods are not recommended for identification of other organs damage lesions in this phase of the disease. When other methods of investigation were employed, cardiac and digestive abnormalities of small magnitude were detected without prognostic implications. These findings do not warrant frequent examinations of patients with undetermined form of the disease except for the electrocardiogram or if the patients report other clinical manifestations. The benign course of the disease does not preclude ability to work and the subjects should be considered apt for work in any profession.     

Development of a clinical chart to compute different disease activity indices for systemic lupus erythematosus

Between 1990 and 1995 a European Consensus Group carried out a multicenter study to reach agreement of the definition of disease activity in systemic lupus erythematosus (SLE). A new index, the European Consensus Lupus Activity Measurement (ECLAM) index, was developed. In a second phase of the study, a prospective survey aimed at validating ECLAM and 4 other scales as steady-state and transition indices for disease activity in SLE was completed. We present the results of this survey. A standardized clinical chart was developed, together with a computer program that could automatically calculate the ECLAM score, as well as the scores for some of the disease activity scales most widely used at present, i.e., the British Isles Lupus Assessment Group, Systemic Lupus Activity Measure, SLE Disease Activity Index, and the SLE Index Score (SIS). With the participation of 28 centers in 15 different European countries, data from 121 prospectively selected new lupus patients were collected. The validity of the 5 activity scales was assessed by comparing the computed scores for each patient to a gold standard, i.e., the physician's subjective judgment on disease activity measured using a semiquantitative scale. All the indices were found to be valid instruments for measuring disease activity in SLE in both the steady-state and transition phases. The results for the various indices closely correlated with one another. Thus, the computerized chart developed by the European Consensus Group offers a simple and reliable instrument to assess disease activity and could be used to monitor lupus patients both in clinical practice and in clinical trials.     

Measuring health status in psoriatic arthritis: the Health Assessment Questionnaire and its modification

OBJECTIVE: The Health Assessment Questionnaire (HAQ) has proven to be a reliable and valid measure of outcome for a variety of arthritides. A recent modification of HAQ for spondyloarthropathy (HAQ-S) has also been reported. Our purpose was to evaluate the HAQ and HAQ-S as outcome measures in the assessment of patients with psoriatic arthritis (PsA). METHODS: The HAQ, including HAQ-S was administered to all patients attending our Psoriatic Arthritis Clinic between June and December, 1993. Clinical and radiological assessments were performed according to a standard protocol that measures disease activity, fibrositic tender points (TP), disease severity and damage. Analysis was performed using SAS for the PC. RESULTS: The patient population included 114 patients, 70 men and 44 women with a mean age of 49.3 years and a mean arthritis duration of 15.1 years. The mean HAQ score was 0.50, while the mean HAQ-S score was 0.53 (scores range 0 to 3 for this instrument). The overall HAQ and HAQ-S disability scores were highly correlated with several clinical measures of function, including grip strength (r = -0.63 and -0.59, respectively). American College of Rheumatology functional class (r = 0.59 and 0.60, respectively), as well as the number of fibrositic TP (r = 0.54 and 0.57, respectively). These disability scores also correlated highly with the overall number of actively inflamed joints (r = 0.49 and 0.50, respectively); however, they correlated only moderately or poorly with other measures of disease activity such as morning stiffness, total number of joint effusions, erythrocyte sedimentation rate (ESR) and the PASI score for psoriasis and with all measures of disease severity. A similar pattern of correlations was found between the individual subscales of the HAQ and HAQ-S and the clinical measures of function, activity, and severity, as well as between the pain scale and the various clinical measures. However, the correlations are generally lower. CONCLUSION: Our data suggest that HAQ and HAQ-S capture clinical measures of function and pain in PsA but do not correlate with disease severity. The HAQ and its modification for spondyloarthropathy may reflect fibromyaglia as a measure of pain and tenderness in these patients. Thus, the clinical assessment of disease activity and both clinical and radiological assessments of joint damage remain important outcome measures in PsA.     

Heterogeneity of cognitive profiles in dementias of the Alzheimer type: theoretical aspects and clinical consequences

Presently, Alzheimer's disease can only be diagnosed with the coexistence of clinical symptoms and the presence of neuropathological alterations. Thus, in the absence of pre mortem biological markers, cognitive deficits form the starting point and the basis of inclusion criteria on which the clinician relies in order to make a putative diagnose of dementia of the Alzheimer type (DTA). Cognitive deficits should thus be accurately described through neuropsychological testing since it is essential to identify the cognitive deterioration patterns of the patients--in terms of selective impairment of cognitive functions--as well as the evolution of these patterns. Regarding this issue, the classical teaching of the Geneva school has proposed a homogeneous deterioration of the aphasic-apraxicagnosic syndrome into four stages. However, recent work does not support this hypothesis. On the contrary, these studies tend to show the presence of heterogeneity in neuropsychological manifestations of the disease. The aim of the present paper is to provide a critical review of this topic through a brief survey of the classical work and research that have recently been conducted. An analysis of the possible candidates responsible for the existence of this heterogeneity of cognitive profiles is presented. Finally, theoretical implications and clinical repercussions are discussed.     

Chronic venous insufficiency: mechanisms and management

CVI is a common disease with significant morbidity that results from venous hypertension of the extremities. Increased perfusion pressure probably traps excessive numbers of white blood cells in the capillaries. Activated leukocytes subsequently damage capillary endothelium, increase capillary permeability, and cause ischemia of the overlying skin as a result of leakage of fibrinogen and formation of a fibrin cuff. Diagnosis of CVI is not difficult because its clinical manifestations are usually evident. Vascular compression therapy remains the foundation of medical management for CVI. Refractory cases may require a combined medical and operative approach.     

Partial purification and properties of enzymes involved in the processing of a chloroplast import protein from Chlamydomonas reinhardii

Two stromal peptidases (SPP-1 and SPP-2) were partially purified from chloroplasts of Chlamydomonas reinhardii. They specifically processed in vitro the precursor of the small subunit of ribulose-1,5-bisphosphate carboxylase (pSS), which had been synthesized by using the cloned rbcS-2 gene of Chlamydomonas. SPP-1 shortened pSS to an intermediate-sized form (iSS), while SPP-2 cut pSS and iSS to the mature small subunit SS. N-terminal amino acid sequencing demonstrated that the reaction product obtained with SPP-2 had an N-terminus identical to natural SS, and that iSS derived from pSS by hydrolysis at the amino side of the methionine located within the transit sequence. By gel filtration, apparent molecular masses of 340 kDa and 90 kDa were determined for SPP-1 and SPP-2, respectively. The comparison of these molecular masses with the protein patterns obtained by SDS/PAGE of the partially purified enzymes suggested that at least SPP-1 was a multimeric protein. The enzymes differed also in their pH optima of about 8 (SPP-1) and 9 (SPP-2) and in their sensitivity to different inhibitors. However, both enzymes seem to be serine proteases as they were completely blocked by N-alpha-tosyl-L-lysinechloromethane or tosylphenylalaninechloromethane, respectively. Competition experiments, using either mature SS or a synthetic hexadecapeptide with 15 amino acids similar to the C-terminal end of the transit sequence of pSS, indicated that SPP-2 had some affinities not only to the transit sequence of pSS, but especially to sequences in the mature protein part. We conclude that SPP-2 in Chlamydomonas is the enzyme involved in import of pSS into chloroplasts and responsible for its processing by a one-step mechanism.     

A new diarrhea pathogen: entero-adherent-invasive-toxigenic Escherichia coli

The number of Americans with diabetes mellitus has increased 50% since 1983 to 16 million. An interesting and startling factor is that only half of these diabetics are aware they have the disease. Diabetes mellitus can lead to blindness, heart disease, stroke, nerve damage, kidney failure, and periodontal disease. It is the fourth leading cause of death in the United States. A metabolic disorder affecting insulin metabolism and associated blood glucose intolerance regulation, diabetes may be classified by the following categories: type I-insulin dependent diabetes mellitus which is commonly found in children and adolescents and type II-non-insulin-dependent or adult-onset diabetes which occurs in patients over forty and is associated with obesity. The dental hygienist's role in education, prevention, and therapeutics has expanded to detection and recognition of oral manifestations of diabetes. The dental hygienist may be the first to recognize the presence of the disease. This article aims to acquaint the dental hygienist with the clinical picture of a dental patient with diabetes mellitus.     

Association of an insertion polymorphism of angiotensin-converting enzyme gene with the activity of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) shows various clinical manifestations, which are characterized by inflammation in many different organ systems. The cause of SLE is still unclear; however, the immunological abnormalities are considered to be responsible for the pathogenesis of SLE. As angiotensin I-converting enzyme (ACE) has been reported to be associated with various immunological phenomena, we investigated the correlation between insertion (I)/deletion (D) polymorphism of the ACE gene and the disease activity of SLE. Ninety-three patients with newly diagnosed SLE were enrolled in this study. ACE genotype was determined by the polymerase chain reaction (PCR). We measured serum levels of anti-double-stranded (ds) DNA antibody (Ab) and serum levels of total complements (CH50) as the parameter for lupus activity. Moreover, we evaluated the clinical disease activity by calculating SLE disease activity index (SLEDAI). Individuals with II genotype showed a significant increase in SLE activity. Patients with the ACE II genotype showed a higher serum level of anti-dsDNA Ab (14.3 IU/ml (5.475, 74.6, median (25th centile, 75th centile)) than those with the DD genotype (4.65IU/ml (4.05, 6.8)) (P<0.01). Moreover, patients with the 11 genotype also showed lower levels of serum CH50 than those with the DD genotype (P < 0.01). Patients with the II1 or DI genotype had significantly higher SLEDAI score than those with the DD genotype (P < 0.01). These results suggest that the ACE genotype could be associated with the disease activity of SLE. ACE insertion polymorphism might be used as one of predictive factors for the activity of lupus.     

Traumatic cerebrospinal fluid leakage: risk factors and the use of prophylactic antibiotics

Dysregulation of IL-6 production has been proposed as a pathogenic mechanism in SLE. We asked if serum or urine IL-6 levels could serve as indicators of systemic lupus erythematosus (SLE) disease activity. Using a sensitive enzyme-linked immunosorbent assay (ELISA), we measured serum and urine IL-6 in 56 SLE patients. Disease activity was assessed using a standard clinical index, the Systemic Lupus Activity Measure (SLAM). Only seven of 56 SLE patients had elevated serum IL-6 levels, compared with 1 of 32 controls (NS). SLE disease activity did not correlate with serum IL-6 levels. Sixteen of 50 SLE patients in whom urine IL-6 was measured exhibited elevated urine IL-6 levels, compared with 1 of 17 controls (p = < 0.05). Urine IL-6 levels correlated with overall disease activity and with the presence of active urinary sediment. Our results indicate that serum IL-6 is not a predictor of disease activity in SLE, but that urine IL-6 may be a marker of active nephritis.     

Murine MPS I: insights into the pathogenesis of Hurler syndrome

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease resulting from deficiency of the lysosomal enzyme alpha-L-iduronidase. A murine model which shows complete deficiency in alpha-L-iduronidase activity has been developed and shows phenotypic features similar to severe MPS I in humans. Here we report on the long-term clinical, biochemical, and pathological course of MPS I in mice with emphasis on the skeletal and central nervous system (CNS) manifestations. Affected mice show a progressive clinical course with the development of coarse features, altered growth characteristics and a shortened life span. Progressive lysosomal accumulation is seen in all tissues. Skeletal manifestations represent the earliest clinical finding in MPS I mice with histologic analysis of growth plate and cortical bone revealing evidence that significant early pathology is present. Analysis of the CNS has revealed the novel finding of progressive neuronal loss within the cerebellum. In addition, brain tissue from MPS I mice shows increased levels of GM2 and GM3 gangliosides. This murine model clearly shows phenotypic and pathologic features which mimic those seen in severe human MPS I and should be an invaluable tool for the study of the pathogenesis of generalized storage disorders.     

The identification of neurologically relevant items in the MMPI-2

The assessment of personality and (mal) adjustment after brain damage is regarded as an important aspect of rehabilitation. However, the administration of widely used self-report questionnaires, such as the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), is restricted because of the danger of overscoring psychopathology and personality disorders. This is due to the inclusion of items reflecting manifestations of neurological dysfunction. Earlier investigations revealed variable neurologically relevant items (NRIs), within and between discrete cerebral aetiologies for the MMPI as well as the first part of the MMPI-2. In this study, 10 neuropsychologists, 10 neurologists, 10 psychiatrists, and 10 physiatrists identified NRIs in the complete MMPI-2. An item was considered to be an NRI based on professional expertise as well as type of brain damage. Based on a substantial inter-rater agreement index, four sets of clinical relevant NRIs were selected: one for brain damage in general and three partially overlapping sets for stroke, traumatic brain damage, and whiplash. Thus, the findings of this study unveil items which may indicate bona fide symptoms or manifestations related to neurological damage or dysfunction, rather than just reflecting psychopathology or personality disorders. It is advocated to develop an interpretative approach to correct for the impact of these NRIs on MMPI-2 scores.     

A new view of pulmonary edema and acute respiratory distress syndrome

The old division of lung edema into two categories--cardiogenic (hydrostatic) and noncardiogenic (increased permeability)--is no longer adequate. For instance, it fails to distinguish between the capillary leak caused by acute respiratory distress syndrome from that caused by interleukin-2 treatment. Further, it fails to account for the capillary leak ('stress-failure') that may accompany edema. A modern view of edema must recognize the natural barriers to the formation and spread of edema. These barriers are the capillary endothelium and the alveolar epithelium. Varying degrees of damage to them can account for the varying radiographic and clinical manifestations of lung edema. Thus, interleukin-2 administration causes increased endothelial permeability without causing alveolar epithelial damage. The result is lung edema that is largely confined to the interstitium, causing little hypoxia and clearing rapidly. However, acute respiratory distress syndrome, which is characterized by extensive alveolar damage, causes air-space consolidation, severe hypoxia, and slow resolution. Thus, a reasonable classification of lung edema requires at least four categories: 1) hydrostatic edema; 2) acute respiratory distress syndrome (permeability edema caused by diffuse alveolar damage); 3) permeability edema without alveolar damage; and (4) mixed hydrostatic and permeability edema. The authors emphasize the importance of the barriers provided by the capillary endothelium and the alveolar epithelium in determining the clinical and radiographic manifestations of edema. In general, when the alveolar epithelium is intact, the radiographic manifestations are those of interstitial (not air-space) edema; this radiographic pattern predicts a mild clinical course and prompt resolution.