[From "primitive spleen epithelioma" to Gaucher's disease. Story of a forerunner]. / De "l'epithélioma primitif de la rate" à la maladie de Gaucher, une thèse visionnaire?

This report is devoted to Philippe Gaucher's life and career. His MD thesis, presented while he was just an intern, is a quite unfrequent example of the description of a new disease, based on the anatomoclinical study of a single case. Since more than 100 years, its eponym is still used in the international literature.

Cardiopulmonary bypass impairs left ventricular function determined by conductance catheter measurement.

OBJECTIVE: Postoperative cardiac depression is attributed to ischemia and the effects of cardiopulmonary bypass (CPB). To evaluate the effect of CPB alone on postoperative left ventricular (LV) dysfunction, we used a conductance catheter to determine the LV performance by pressure-volume relation before and after CPB. METHODS: Twenty-two 3-week-old piglets underwent sternotomy and normothermic CPB for one hour. A conductance catheter was placed in the LV cavity. End-systolic pressure-volume relationships (ESPVR), left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance (SVR) were measured under steady-state conditions before and 15 min after weaning from CPB in group A (n = 11). Group B included 11 piglets without CPB and served as control. RESULTS: There was no difference between groups before initiating CPB. As an indication of depressed LV function, the ESPVR slope (mmHg/ml) was significantly lower in group A after weaning from CPB than in group B (1.69 +/- 0.5 vs. 1.86 +/- 0.55; p = 0.008). In group A, peak dP/dt (max index) (mmHg/s/m (2)) decreased markedly (1596 +/- 339 vs. 2045 +/- 206; p = 0.03), while LVEDP (mmHg) was significantly increased (11.7 +/- 2.6 vs. 5.4 +/- 0.9; p < 0.0001). In addition, SVR (index) (dyn x s x cm (-5)/m (2)) in group A was significantly lower (1407 +/- 176 vs. 1677 +/- 313; p < 0.0001) than in group B. CONCLUSION: Using the very sensitive conductance catheter technique in a pig model, we could show that CPB leads to a significant depression of LV contractility and elastance even without ischemic arrest.

Oculomotor palsy in six patients with systemic lupus erythematosus. A possible role of antiphospholipid syndrome.

The objective of this study was to describe clinical, laboratory, and radiological features in systemic lupus erythematosus (SLE) patients with oculomotor palsy (OMP). Among a cohort of 750 SLE patients receiving follow-up at our unit between 1985 and 2000, all patients with OMP were studied. Clinical and laboratory data were recorded, as well as cerebral magnetic resonance imaging (MRI) findings where available. Immunological tests included tests for presence and specificity of antinuclear and antiphospholipid antibodies. Six patients had OMP, which occurred within the first 3 years in two patients and after more than 20 years in two patients. Four patients had focal neuropsychiatric SLE (NPSLE) manifestations and two had diffuse neurological involvement. The four patients with focal NPSLE were either anticardiolipin- or lupus anticoagulant-positive. Cerebral fluid was abnormal in two of four patients who had this test. In four of the six patients, cerebral MRI showed evidence of vasculopathy. The therapeutic regimens varied, although all six patients initially received high-dose corticosteroids. OMP resolved or improved significantly in all six patients. OMP in SLE occurs in a broad spectrum of clinical situations but is an infrequent manifestation of NPSLE. This case series, together with literature review data, suggests various pathophysiological mechanisms in patients with focal or diffuse neurological symptoms. In patients with focal NPSLE, a possible cause of OMP is microthrombosis associated with presence of antiphospholipid antibodies.

Iron saturation of serum ferritin in patients with adult onset Still's disease.

OBJECTIVE: Patients with Still's disease show a prominent acute phase reaction. Our hypothesis is that under these circumstances the iron uptake of ferritin will not keep pace with its synthesis, and is therefore not a valid reflection of the iron status in these patients. METHODS: Previously we developed a method to measure the iron content of ferritin; we investigated the usefulness of this method to establish the iron status of patients with anemia of inflammation. RESULTS: In 9 patients with adult onset Still's disease (AOSD) we observed high ferritin concentrations and measured the iron saturation of ferritin. The mean value of saturation was 9.1%, while saturation in the healthy control group was 17.8%, a statistically significant difference (p < 0.005). Soluble transferrin receptor concentrations indicated a functional iron deficiency. CONCLUSION: We conclude that the acute phase ferritin in patients with AOSD contains less iron in comparison to ferritin in healthy controls. We suggest that soluble transferrin receptor is the method of choice in estimating the iron status of patients with an acute phase reaction.

A new type of acquired C1 inhibitor deficiency associated with systemic lupus erythematosus.

Acquired C1 inhibitor (C1-INH) deficiency with consequent angioedema is a rare condition that may indicate an underlying lymphoproliferative disorder. The defect is caused by increased catabolism, which is often associated with the presence of serum autoantibodies to C1-INH. The present report describes 3 patients with systemic lupus erythematosus who developed typical symptoms of acquired angioedema, characterized by recurrent swelling of subcutaneous and mucous tissues. The 3 patients demonstrated a major classical pathway-mediated complement consumption, with very low levels of C3 antigen and decreased levels of C1-INH antigen. Neither antibodies to C1-INH nor associated lymphoproliferative disease was found. No patient had clinical and biologic signs of lupus activity at the time the angioedema occurred. All patients were treated with steroids and exhibited a good response, without relapse of angioedema and with normalization of plasma levels of C1-INH. In lupus patients who present with an angioedema syndrome, acquired or hereditary angioedema must be sought by examining parameters of the classical pathway and levels of C1-INH. Our observations suggest the existence of a new form of acquired C1-INH deficiency associated with a major classical pathway-mediated complement consumption and systemic autoimmunity.

Coexisting pseudo-xanthoma elasticum and rheumatoid arthritis. three cases and review of the literature.

Pseudo-xanthoma elasticum (PXE) is an inherited disorder of the connective tissue characterized by cutaneous, ocular and vascular lesions. Coexisting PXE and rheumatoid arthritis (RA) is rare because three cases have only been described. We report three new cases of this association. Analysis of these six cases failed to show any particular biological or clinical features of rheumatoid arthritis associated PXE. The possible association of PXE and RA is discussed.

The family history of patients with primary or secondary antiphospholipid syndrome (APS).

OBJECTIVE: To evaluate familial history for evidence of antiphospholipid syndrome (APS) and autoimmune disease in rheumatology department patients with primary or secondary APS. METHODS: We retrospectively studied patients with APS and systemic lupus erythematosus (SLE) managed at the Rheumatology Department of the Bichat University Hospital, Paris, between 1987 and 1996. Data were collected by chart review and by a 1997 standardized telephone interview. RESULTS: We identified 108 patients with APS managed during the ten-year study period. According to classical classification criteria, 39 patients had primary antiphospholipid syndrome (PAPS) and 69 secondary antiphospholipid syndrome (SAPS). Family history data were obtained for 29 (74%) and 55 (80%) PAPS and SAPS patients. respectively (78% of the 108 patients). Twelve PAPS (41% and 19 SAPS (35%) patients had one or more relatives with evidence of at least one clinical feature of APS such as thrombosis or recurrent fetal loss; of these patients, seven in the PAPS (24%) and 11 in the SAPS (20%) group had two or more relatives with evidence of a clinical feature of APS. Three PAPS (10%) and 14 SAPS (25%) patients had one or more family members with an autoimmune disease. CONCLUSION: A positive family history for autoimmune disease and/or antiphospholipid syndrome is common in patients with PAPS or SAPS. This finding supports a genetic contribution to APS. The percentage of a positive family history for autoimmune disease tend to be higher in patients with SAPS than in those with PAPS.

[Outcome of pregnancies in lupus: experience at one center]. / Devenir des grossesses lupiques: une expérience monocentrique.

We determined the outcome of all pregnancies in SLE patients in our lupus cohort between 1991 and 1997. The women were advised that pregnancy was acceptable if the disease had been inactive for 6 months (SLEDAI < or = (4 at 2 serial examinations) and daily prednisone dose was below 10 mg. Patients were advised against pregnancy in case of active nephritis or neurolupus. In case of antiphospholipid antibodies, patients were treated with aspirin or heparin if previous fetal losses were documented. In case of anti-SSA ab, patients were monitored with ultrasound and given dexamethasone in case of atrioventricular block. Fifty-nine pregnancies were registered among 31 women: mean age at diagnosis of SLE was 25.3 +/- 3.7 years (range: 17-31); mean disease duration before pregnancy 4.4 +/- 3 years (0-14); mean ACR score 5.4 +/- 1.5 (4-9). Seven patients had ACL ab, 8 had anti-SSA ab. Pregnancies ended in: 13 early spontaneous abortions (9 not related to disease flare up, 4 related to SAPL); 7 elective abortions (patient decision in 5 cases, severe lupus flare up in 2); one in utero death; 19 full term births (> 38 weeks); and 19 preterm births. Cesarean section was performed in 11 cases (6 for fetal distress, dystocia and previous ceasarian; 5 for active lupus). Severe sepsis occurred in one premature infant who died at the age of 1 week. Intrauterine growth retardation was observed in 11 cases, mean APGAR score was 8.9 +/- 1.43. Child development was normal in all cases except one child with mild mental retardation. Severe lupus flare ups occurred in 6 cases, of which 4 were pregnancies in unadvised situations. Six mild flare ups were documented in the post partum. One fatal case of neonatal lupus with AVB was observed. In conclusion, in our experience, the live birth rate is similar to the general population and the risk of lupus flare up is low when the above mentioned criteria are applied. Systematic increase of steroid dose at pregnancy onset does not seem to be necessary. The high rate of prematurity remains a problem to be solved.

IgG anti-beta2-glycoprotein I antibodies in adult patients with systemic lupus erythematosus: prevalence and diagnostic value for the antiphospholipid syndrome.

OBJECTIVE: To investigate the prevalence of serum anti-beta2-glycoprotein I (anti-beta2-GPI) antibodies and other antiphospholipid antibodies (aPL) in patients with systemic lupus erythematosus (SLE). To study their diagnostic value for the antiphospholipid syndrome (APS). METHODS: Anti-beta2-GPI and IgG anticardiolipin (aCL) were determined in sera from 102 consecutive patients with SLE using ELISA. Serum and plasma tests were also done for lupus anticoagulant (LAC), syphilis, and antibodies to dsDNA. Clinical and laboratory features of APS were observed. RESULTS: Prevalences were 23.5% for aCL and 18.6% for anti-beta2-GPI. Correlations between the presence of aCL and anti-beta2-GPI and between their titers were statistically significant (p<0.0001). No associations were found between anti-beta2-GPI and disease activity criteria (SLEDAI, ECLAM, dsDNA). Anti-beta2-GPI were significantly associated with LAC (p = 0.005), APS (p = 0.005), and a high aCL titer (aCL > 5 SD; p< or =0.001). LAC was the best diagnostic criterion for APS. CONCLUSION: These data suggest that determination of anti-beta2-GPI in addition to aCL and LAC is unlikely to improve the diagnosis of APS in patients with SLE.

Classification of an intermediate group of patients with antiphospholipid syndrome and lupus-like disease: primary or secondary antiphospholipid syndrome?

OBJECTIVE: (1) To classify an intermediate group of patients (IntAPS) with antiphospholipid syndrome (APS) and lupus-like disease either as primary (PAPS) or secondary APS (SAPS) and to discuss 2 different classifications. (2) To compare patients of a division of rheumatology with either PAPS or SAPS. METHODS: Patients with APS and patients with systemic lupus erythematosus (SLE) followed at the Department of Rheumatology, University Hospital Bichat, Paris, from 1987 to 1996 were analyzed. A chart review and a standardized telephone interview in 1997 completed the data of this study. RESULTS: (1) We found a total of 108 patients with APS: 22 with PAPS, 69 with SAPS, and 17 with IntAPS. The group of IntAPS did not differ from PAPS in any clinical or laboratory signs with the exception of antibodies to dsDNA and to extractable nuclear antigen (ENA). Between IntAPS and SAPS, there were several significant differences in clinical signs of SLE (malar rash, discoid rash, arthralgia) and in laboratory values (leukocytopenia). (2) Comparison of PAPS and SAPS showed statistically significant differences for positive Coombs' test, leukocytopenia, lymphocytopenia, antinuclear antibodies, antibodies to dsDNA and to ENA, and hypocomplementemia. CONCLUSION: The mainstay of the diagnosis of APS is the clinical event of thrombosis or miscarriage in the presence of antiphospholipid antibodies. Less important are laboratory values, which may help to differentiate PAPS from SAPS in order to initiate adequate therapy (e.g., anticoagulation in the first and additional corticosteroids in the second). Patients with IntAPS are more likely to be integrated into the group of PAPS than in the group of SAPS; therefore, special exclusion criteria for PAPS are not appropriate.

Spinal tuberculosis in adults. A study of 103 cases in a developed country, 1980-1994.

Spinal tuberculosis (TB) accounts for about 2% of all cases of TB. New methods of diagnosis such as magnetic resonance imaging (MRI) or percutaneous needle biopsy have emerged. Two distinct patterns of spinal TB can be identified, the classic form, called spondylodiscitis (SPD) in this article, and an increasingly common atypical form characterized by spondylitis without disk involvement (SPwD). We conducted a retrospective study of patients with spinal TB managed in the area of Paris, France, between 1980 and 1994 with the goal of defining the characteristics of spinal TB and comparing SPD to SPwD. The 103 consecutive patients included in our study had TB confirmed by bacteriologic and/or histologic studies of specimens from spinal or paraspinal lesions (93 patients) or from extraspinal skeletal lesions (10 patients). Sixty-eight percent of patients were foreign-born subjects from developing countries. None of our patients was HIV-positive. SPD accounted for 48% of cases and SPwD for 52%. Patients with SPwD were younger and more likely to be foreign-born and to have multiple skeletal TB lesions. Neurologic manifestations were observed in 50% of patients, with no differences between the SPD and SPwD groups. Of the 44 patients investigated by MRI, 6 had normal plain radiographs; MRI was consistently positive and demonstrated epidural involvement in 77% of cases. Bacteriologic and histologic yields were similar for surgical biopsy (n = 16) and for percutaneous needle aspiration and/or biopsy (n = 77). Cultures for Mycobacterium tuberculosis were positive in 83% of patients, and no strains were resistant to rifampin. Median duration of antituberculous chemotherapy was 14 months. Surgical treatment was performed in 24% of patients. There were 2 TB-related deaths. Our data suggest that SPwD may now be the most common pattern of spinal TB in foreign-born subjects in industrialized countries. The reasons for this remain to be elucidated.

Anti-heat shock protein 70 kDa and 90 kDa antibodies in serum of patients with rheumatoid arthritis.

OBJECTIVES: Stress proteins (HSPs) are highly conserved immunodominant antigens found in various species. The purpose of this study was to assess the prevalence and prognostic significance of antibodies to HSC 70 kDa and HSP 90 kDa in three groups of patients with longstanding rheumatoid arthritis (RA) defined based on the severity of articular erosions. METHODS: 73 patients with longstanding (> 6 years) RA whose HLA-DR genotype was known were divided in three groups according to Larsen's score and compared with 47 recent onset (<1 year) RA patients and with control groups composed of patients with other inflammatory diseases (n=137) or of normal controls (n=48). IgGs and IgMs to HSC 70 kDa and HSP 90 kDa were determined using an ELISA with purified bovine HSC 70kDa or HSP 90 kDa. RESULTS: Concentrations of IgGs and IgMs to HSC 70 were significantly increased in 41.1% and 42.5% of longstanding RA patients, respectively. Corresponding figures for IgGs and IgMs to HSP 90 were 39.7% and 56%. IgMs to HSC 70 and HSP 90 were less frequent in recent onset RA (19% and 13% respectively). Among the groups with other inflammatory diseases, only the MCTD group exhibited high frequencies of IgGs to HSC 70 (80%) and HSP 90 (85%). DRB1*0401 positive RA patients (n=23) were not more likely to have increased concentrations of antibodies to HSC 70 kDa or HSP 90 kDa than other RA patients (DR4 positive but DRB1*0401 negative, or DR1 positive, n=31; or negative for both DR4 and DR1, n=14). IgGs to HSP 90 kDa were significantly more frequent (p<0.05) in longstanding RA patients whose Larsen's score was 4 or more (57%) than in those whose Larsen's score was 2 or 3 (39.4%) or less than 2 (16%). No associations were found between Larsen's score and IgGs or IgMs to HSC 70 kDa or IgMs to HSP 90 kDa. A significant correlation was demonstrated between IgGs to HSP 90 kDa and two other serological markers for RA, rheumatoid factor, and anti-Sa antibody; there were no correlations with antikeratin antibody, antiperinuclear factor, or anti-RA 33. CONCLUSION: IgGs to HSP 90 kDa are most common in longstanding RA patients with articular erosions, suggesting that they may be related to the articular prognosis in RA

Systemic lupus erythematosus-associated catastrophic antiphospholipid syndrome occurring after typhoid fever: a possible role of Salmonella lipopolysaccharide in the occurrence of diffuse vasculopathy-coagulopathy.

We report a case of well-documented typhoid fever in a 30-year-old woman with inactive systemic lupus erythematosus with asymptomatic lupus anticoagulant and high-titer anticardiolipin antibody (aCL). Despite prompt eradication of the Salmonella typhi obtained with appropriate antibiotic therapy, multiple organ system dysfunction occurred. The central nervous system was involved, with ischemic infarcts in the occipital lobes. High-dose corticosteroid therapy failed to improve the neurologic manifestations, which responded to repeated plasmapheresis. A sharp fall in aCL and anti-beta2-glycoprotein I antibody titers was recorded before the start of plasmapheresis. At the same time, IgM and IgG antibodies to Salmonella group O:9 lipopolysaccharide became detectable; the IgM antibodies disappeared within 4 months, whereas the IgG antibodies remained detectable during the next 13 months. Despite treatment with high-dose corticosteroids and cyclophosphamide, rapidly progressive glomerulonephritis developed, leading to chronic renal failure. There is convincing evidence of a link between the S. typhi infection and the ensuing catastrophic syndrome in this patient, probably precipitated by bacterial antigens.

Systemic lupus erythematosus with optical neuromyelitis (Devic's syndrome). A case with a 35-year follow-up.

Optical neuromyelitis or Devic's syndrome is a very uncommon neurological manifestation of systemic lupus erythematosus. It is also associated with antiphospholipid antibodies, limited responsiveness to glucocorticoid treatment and a poor prognosis. We report the case of a female systemic lupus erythematosus patient who developed recurrent flares of optical neuritis and transverse myelitis. These flares consistently responded to glucocorticoid therapy. Despite the absence of overt anticardiolipin antibodies in the course of the disease, long-term anticoagulant therapy has been introduced with positive results. Treatments are usually of limited efficacy in Devic's syndrome. In our patient, however, aggressive glucocorticoid treatment resulted in prolonged survival.

Corticosteroid sparing effect of low dose methotrexate treatment in adult Still's disease.

OBJECTIVE: Adult Still's disease (ASD) is a rare chronic polyarthritis, usually treated with corticosteroid therapy. Because some patients become dependent on high dose prednisone or are refractory to that treatment, and because adverse events are frequent with corticosteroid, we evaluated the efficacy of low dose methotrexate (MTX) as a second-line drug. METHODS: We retrospectively studied 26 patients with ASD treated with low dose MTX because their disease was either resistant to or dependent on corticosteroids. RESULTS: The group included 13 women and 13 men, with a mean age of 32.6 years at onset of ASD. Mean disease duration at the beginning of MTX treatment was 59.9 mo (range 7 to 444). Evaluation took place at the maximum followup, which averaged 48.9 mo (range 8 to 136). The mean dose of MTX was 11.5+/-3.6 mg/week (range 7.5 to 17.5). Twenty-three patients responded to MTX; 18 had complete remission. No difference was seen between patients with or without extraarticular manifestations. Leukocyte and neutrophil counts and erythrocyte sedimentation rate were significantly reduced (p = 0.0001). Daily prednisone intake decreased by 69% (21.5 mg) (p = 0.0001). Eleven patients were able to stop taking corticosteroids. One patient with AA amyloidosis renal failure died of neutropenia: this was the only serious adverse event. CONCLUSION: MTX is an effective second-line treatment of ASD that does not respond to prednisone. It allows significant reduction of corticosteroid doses, which is beneficial to these patients, who have frequent and numerous corticosteroid related adverse events.