Assessment of long-term safety and efficacy of etanercept in a 5-year extension study in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate long-term safety and efficacy of etanercept (ETN) in patients with rheumatoid arthritis (RA) without concomitant disease-modifying antirheumatic drug therapy. METHODS: A total of 549 patients enrolled in this 5-year, open-label extension after completing 1 of 2 randomised controlled studies; all patients received ETN 25 mg twice weekly during the extension. Safety assessments included physical exams, adverse events (AEs), vital signs, laboratory tests, and autoantibody evaluations. Key efficacy endpoints included numbers of responders achieving the American College of Rheumatology (ACR) criteria, low disease activity scores, and disease remission. RESULTS: Three hundred and eight (56%) patients completed the 5-year extension study. Total ETN exposure, including that received during the double-blind studies was 2212 patient-years. Withdrawals for efficacy- and safety-related reasons were 12% and 19%, respectively. The most common AE was upper respiratory infection (44%). Rates of serious infections decreased over the 5-year period; one case of suspected tuberculosis was reported. Rates of malignancies remained generally consistent during the 5-year period. There were no reports of demyelinating disease, serious blood dyscrasias, or opportunistic infections. The relationship between autoantibody titres and clinical events was not statistically significant. Less than 5% of patients tested positive for anti-etanercept antibodies and all antibodies were non-neutralising. After 5 years, ACR 20, 50, and 70 response rates were 78%, 51%, and 32%, respectively; the mean percentage of patients achieving low disease activity score (DAS ≤ 2.4) and remission (DAS ≤ 1.6) were 44% and 20%, respectively. CONCLUSIONS: ETN maintained a favourable safety profile and consistent efficacy throughout the 5-year study duration.

The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial.

OBJECTIVE: To assess the safety, tolerability and efficacy of abatacept in patients with rheumatoid arthritis (RA) who had failed anti-tumour necrosis factor (TNF) therapy and were switched to abatacept directly or after completing washout. METHODS: In this international, 6-month, open-label trial, patients had active RA, an inadequate response to anti-TNF therapy for 3 months or longer and a disease activity score in 28 joints (DAS28 (C-reactive protein; CRP) of 5.1 or greater. "Washout" patients discontinued anti-TNF therapy 2 months or longer pre-screening; "direct-switch" patients began abatacept ( approximately 10 mg/kg) at their next scheduled anti-TNF therapy dose. RESULTS: 1046 patients were treated (449 washout, 597 direct-switch; baseline characteristics were similar between groups). At 6 months, adverse events (AE; 78.0% vs 79.2%), serious AE (11.1% vs 9.9%) and discontinuations due to AE (3.8% vs 4.0%) and serious AE (2.0% vs 1.3%) were comparable in washout versus direct-switch patients. There were no opportunistic infections. At 6 months, in washout versus direct-switch patients, similar clinically meaningful improvements were seen in DAS28 (CRP) (> or =1.2 unit improvement, 59.5% vs 53.6%, respectively; low disease activity state, 22.5% vs 22.3%; DAS28-defined remission, 12.0% vs 13.7%), physical function (health assessment questionnaire disability index > or =0.22 improvement; 46.3% vs 47.1%) and health-related quality of life (mean change in short-form 36 scores: physical component summary, 5.5 vs 6.1; mental component summary, 4.8 vs 5.4). CONCLUSION: Abatacept demonstrated acceptable safety and tolerability and clinically meaningful efficacy over 6 months in patients with inadequate response to anti-TNF therapy. Results were comparable with or without a washout, supporting direct switching from anti-TNF therapy to abatacept as an option in clinical practice. TRIAL REGISTRATION NUMBER: NCT00124982.

Interleukin-12 gene polymorphisim in patients with giant cell arteritis, polymyalgia rheumatica and elderly-onset rheumatoid arthritis.

OBJECTIVE: The cytokine profile suggests that giant cell arteritis (GCA) is a Th1-driven disease, in which local IFN-gamma plays a critical role in the development of a systemic arteritis. IL-12 is a potent inducer of IFN-gamma and is critically involved in biasing an immune response towards a Th1 pathway. The purpose of this study was to investigate whether there was an association between an IL-12 gene polymorphism (-1188 A/C 3UTR) and disease susceptibility for GCA and two other age-related inflammatory conditions, such as polymyalgia rheumatica (PMR) and elderly-onset rheumatoid arthritis (EORA). Furthermore, we attempted to correlate such polymorphism with in vitro IL-12 production. MATERIALS AND METHODS: We analyzed genotypes at -1188 in the 3UTR of the IL-12 promoter by PCR-RFLP in 68 GCA, 138 PMR, and 72 EORA patients as well as in 465 healthy controls (HC). IL-12p70 levels in culture supernatants after stimulation with PMA+Ionomycin was assessed by ELISA. RESULTS: All groups were in Hardy-Weinberg equilibrium. Allelic and gen-omic distribution was not significantly different among the study groups. None of the genetic variants was associated with disease severity. Although the differences were not statistically significant, HC genotypes were associated with distinct IL-12 p70 production. CONCLUSIONS: The IL-12 (-1188 A/C 3UTR) gene polymorphism is not associated with disease susceptibility or severity in three age-related chronic inflammatory syndromes. The production of IL-12 p70 is dependent on the genetic background in HC, although in patients such association may be biased by other unknown factors.

A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects.

OBJECTIVE: Open label studies have suggested that tumour necrosis factor (TNF) antagonists led to sustained improvement and corticosteroid sparing effect in patients with giant cell arteritis (GCA). To confirm these observations, we conducted a randomised, double-blind, placebo controlled trial with etanercept in patients with biopsy-proven GCA with side effects secondary to corticosteroids. METHODS: We randomly assigned patients with GCA to receive etanercept (n = 8) or placebo (n = 9) over 1 year together with corticosteroids that were reduced according to a predefined schedule. The primary outcome was the ability to withdraw the corticosteroid therapy and control the disease activity at 12 months. RESULTS: Baseline characteristics were similar in the two groups, although patients in the etanercept group showed higher levels of basal glycaemia (p = 0.02) and a higher erythrocyte sedimentation rate (ESR) (p = 0.01). After 12 months, 50% of the patients in the etanercept group and 22.2% in the placebo group were able to control the disease without corticosteroid therapy (p value not significant). Patients in the etanercept group had a significant lower dose of accumulated prednisone during the first year of treatment (p = 0.03). There were no differences in the number and type of adverse events. CONCLUSION: The limited number of patients included in this study does not allow us to draw definitive conclusions. Etanercept therapy was well tolerated in this aged population. The therapeutic role of etanercept in patients with GCA should be evaluated in studies with a larger number of patients.

Combination of Ca2+ -activated K+ channel blockers inhibits acetylcholine-evoked nitric oxide release in rat superior mesenteric artery.

BACKGROUND AND PURPOSE: The present study investigated whether calcium-activated K+ channels are involved in acetylcholine-evoked nitric oxide (NO) release and relaxation. EXPERIMENTAL APPROACH: Simultaneous measurements of NO concentration and relaxation were performed in rat superior mesenteric artery and endothelial cell membrane potential and intracellular calcium ([Ca2+]i) were measured. KEY RESULTS: A combination of apamin plus charybotoxin, which are, respectively, blockers of small-conductance and of intermediate- and large-conductance Ca2+ -activated K channels abolished acetylcholine (10 microM)-evoked hyperpolarization of endothelial cell membrane potential. Acetylcholine-evoked NO release was reduced by 68% in high K+ (80 mM) and by 85% in the presence of apamin plus charybdotoxin. In noradrenaline-contracted arteries, asymmetric dimethylarginine (ADMA), an inhibitor of NO synthase inhibited acetylcholine-evoked NO release and relaxation. However, only further addition of oxyhaemoglobin or apamin plus charybdotoxin eliminated the residual acetylcholine-evoked NO release and relaxation. Removal of extracellular calcium or an inhibitor of calcium influx channels, SKF96365, abolished acetylcholine-evoked increase in NO concentration and [Ca2+]i. Cyclopiazonic acid (CPA, 30 microM), an inhibitor of sarcoplasmic Ca2+ -ATPase, caused a sustained NO release in the presence, but only a transient increase in the absence, of extracellular calcium. Incubation with apamin and charybdotoxin did not change acetylcholine or CPA-induced increases in [Ca2+]i, but inhibited the sustained NO release induced by CPA. CONCLUSIONS AND IMPLICATIONS: Acetylcholine increases endothelial cell [Ca2+]i by release of stored calcium and calcium influx resulting in activation of apamin and charybdotoxin-sensitive K channels, hyperpolarization and release of NO in the rat superior mesenteric artery.

Plasma adrenomedullin levels in patients with polymyalgia rheumatica and giant cell arteritis.

OBJECTIVE: Plasma adrenomedullin (AM) levels are elevated in several inflammatory rheumatic diseases. The aims of the present study were: a) to assess whether plasma AM levels are abnormal in patients with polymyalgia rheumatica and giant cell arteritis (PMR and GCA) and b) to investigate if this parameter is related to clinical and biochemical indicators of disease activity in these patients. MATERIALS AND METHODS: AM plasma levels were analyzed in 17 patients with PMR and GCA and in 14 healthy subjects. Twelve patients (9 PMR and 3 GCA) were studied when they had active disease before any steroid therapy and the remaining 5 patients (2 PMR and 3 GCA) were in complete clinical remission and no longer receiving steroid treatment. AM was measured by a specific radioimmunoassay. RESULTS: Plasma AM concentration was significantly higher in patients with active GCA compared to the control group (p < 0.05) and with patients with isolated PMR (p < 0.05). However, there were no significant differences between patients with active PMR and the control group. Within the PMR/GCA group with active disease, AM plasma levels were positively correlated with ESR (r = 0.6, p = 0.02), and negatively with hematocrit (r = -0.57, p = 0.03) and hemoglobin (r = -0.55, p = 0.04). No correlations were found between AM and CRP. CONCLUSION: Plasma levels of AM are elevated in patients with active GCA and correlate with parameters that reflect the acute phase response. The differences in the secretion of AM between patients with PMR and GCA might reflect the severity of the vascular endothelial cell damage in these conditions. The role of AM in the pathogenesis of PMR and GCA needs to be assessed in a larger series of patients.

Polymyalgia rheumatica without significantly increased erythrocyte sedimentation rate. A more benign syndrome.

BACKGROUND: An erythrocyte sedimentation rate (ESR) of at least 40 mm/h is considered an important requisite for the diagnosis of polymyalgia rheumatica (PMR). However, the relative frequency and clinical features of PMR in patients without a significantly increased ESR are unclear. METHODS: We performed a retrospective study of patients diagnosed as having PMR at the rheumatology divisions of 3 teaching hospitals. The diagnosis of PMR was established, regardless of the ESR, in 201 consecutive patients fulfilling the following criteria: (1) age 50 years or older, (2) severe proximal pain for more than 1 month in at least 2 of 3 areas: neck, shoulder, and/or pelvic girdles, and (3) rapid resolution of the syndrome while taking low-dose prednisone. Patients with giant cell arteritis were previously excluded from the study. The frequency and clinical features of patients with PMR and an ESR lower than 40 mm/h were analyzed. A comparative study between these patients and those with high ESRs was performed. RESULTS: An ESR lower than 40 mm/h was found in 41 patients (20.4%). These patients were younger (P = .02), were more frequently men (P = .006), and experienced a lower frequency of fever (P = .003) and weight loss (P = .07). Furthermore, these patients were characterized by an absence of anemia (P = .002) and a lower frequency of abnormal protein electrophoresis results (P < .001). Otherwise, their clinical syndrome, response to therapy, and frequency of relapses were similar to those of patients with classic PMR. In the entire population of 201 patients, the ESR was related to the length of treatment, number of areas involved, presence of fever, weight loss, and laboratory test result abnormalities, but it was unrelated to the duration of the illness prior to diagnosis. CONCLUSIONS: It is not uncommon to find a patient with PMR with an ESR lower than 40 mm/h. This syndrome is more frequent in men and it is clinically less severe than the classic form of PMR. Its recognition will allow these patients to benefit from an effective treatment with low-dose corticosteroids.

Cutaneous vasculitis in children and adults. Associated diseases and etiologic factors in 303 patients.

Cutaneous vasculitis (CV), a condition characterized by palpable purpura and nonspecific histopathologic findings, presents a diagnostic and therapeutic challenge because it may be a primary disorder or it may be a cutaneous manifestation of another entity, such as systemic necrotizing vasculitis, connective tissue disease, systemic bacterial infection, or malignancy. We studied 303 unselected patients (172 adults and 131 children) with CV to assess the disease associations and etiologic factors, to identify the frequency of primary and secondary CV in different age-groups, and to characterize features that help to distinguish between primary and secondary CV. Of the 131 children, 130 had primary CV: Henoch-Schönlein purpura (HSP) in 116 and hypersensitivity vasculitis (HV) in 14. In contrast, of the 172 adults, only 120 had primary CV: HSP in 39, HV in 70, and essential mixed cryoglobulinemia in 11. CV was a manifestation of systemic necrotizing vasculitis in 23 adults (polyarteritis nodosa in 17, Wegener granulomatosis in 4, and Churg-Strauss syndrome in 2). CV was secondary to other processes in 29 adults: in 20 patients CV was associated with connective tissue disease or another autoimmune or rheumatic disease, in 5 patients CV was a manifestation of severe bacterial infection, especially bacterial endocarditis (4 cases), and in the other 4 patients CV was the presenting symptom of an underlying malignancy. The patients for whom CV was a manifestation of systemic necrotizing vasculitis or secondary to a connective tissue disease, severe bacterial infection, or malignancy had clinical and laboratory data suggestive of the associated disorder. The clinical picture and outcome of primary CV in both children and adults were benign. By contrast, the prognosis of patients with CV in the context of systemic necrotizing vasculitis or secondary to other entities depended on the primary process. Given the different disease association in children and adults, we propose a simple diagnostic workup in children with CV. By contrast the diagnostic approach in adults with CV should be more cautious and the workup more extensive. The early differentiation between primary CV, secondary CV, and CV presenting as a symptom of systemic necrotizing vasculitis, especially in adults, is of paramount importance for an adequate diagnosis and appropriate treatment.

Hereditary articular chondrocalcinosis. Clinical and genetic features in 13 pedigrees.

Thirteen pedigrees with familial articular chondrocalcinosis were identified through a systematic radiologic survey of the first-degree blood relatives of 76 patients with chondrocalcinosis. Forty-one persons, 30 women and 11 men, distributed in 25 sibships were affected. Their mean age at the time of study was 65.09 +/- 11.36 years. The disease was of early onset only in four pedigrees. The clinical manifestations in these four pedigrees were similar to those found in the kindred with a late onset. In 15 persons, the process was asymptomatic. In the 26 symptomatic patients, the arthropathy was mild, with clinical and radiologic features similar to those observed in sporadic chondrocalcinosis. There was no linkage of chondrocalcinosis to the HLA-A and HLA-B antigens in the 11 pedigrees in which tissue typing was performed. The pattern of involvement in these 13 pedigrees supports an autosomal dominant mode of inheritance. These data suggest that hereditary chondrocalcinosis is not infrequent and very often is clinically indistinguishable from the sporadic form of the disease.

Clinical features and outcome of 95 patients with hypersensitivity vasculitis.

PURPOSE: To evaluate the clinical features and outcome of patients with isolated hypersensitivity vasculitis (HV). PATIENTS AND METHODS: Retrospective study of patients with cutaneous vasculitis followed up at a University Hospital from 1975 to 1994. Patients with vasculitis secondary to collagen vascular diseases, neoplasia, or major infections were excluded. Patients were classified as HV according to the differential criteria proposed by Michel et al (J Rheumatol. 1992;19:721-728). RESULTS: Ninety-five patients were classified as HV. The mean age was 42.7 +/- 21.7 years, with similar disease frequency in both sexes. In 43 patients, the precipitating event was drug therapy, either alone or as a treatment for a coexistent infection, usually an upper respiratory tract infection. The most frequent clinical manifestation was palpable purpura followed by joint symptoms. Systemic involvement was infrequent: 7 patients had nephropathy, manifested almost exclusively by microhematuria, and 5 patients had gastrointestinal symptoms. In 54 subjects the vasculitis did not require treatment; 26 patients were treated with NSAIDs, and 14 required corticosteroids (associated to immunosuppressive agents in 2 of them). After a mean follow-up of 15.5 +/- 28.9 months (median 6), only 2 patients had slight renal impairment, whereas the remaining had a complete recovery. CONCLUSION: Hypersensitivity vasculitis is usually a benign syndrome, often secondary to drugs or infections, or both. Its main clinical manifestations are skin and joint symptoms. The systemic involvement is scarce and its prognosis is excellent.

Risk factors and predictive models of giant cell arteritis in polymyalgia rheumatica.

OBJECTIVE: To identify in polymyalgia rheumatica the best set of predictors for a positive temporal artery biopsy and to define predictive models with either a high or low probability of giant cell arteritis (GCA). PATIENTS AND METHODS: Retrospective study of 227 patients, 137 with polymyalgia rheumatica unassociated with arteritis (group A) and 90 with polymyalgia associated with biopsy-proven giant cell arteritis (group B or training set). Data on demographic features, clinical and laboratory abnormalities were collected. Risk factors for arteritis were estimated by nonlinear logistic regressions. Simple predictive models were constructed with those predictors more related to arteritis by multivariable analysis. These models were then tested in group B and in 89 cases of arteritis without polymyalgia rheumatica (group C or test set). RESULTS: The best predictors of arteritis were a new headache odds ratio (OR) 13.6 (95% confidence interval [CI] 4.7 to 39.3); age at onset < 70 years OR 0.11 (CI 0.04 to 0.35); abnormal temporal arteries OR 4.2 (CI 1.3 to 13.7); raised liver enzymes OR 2.9 (CI 1.1 to 7.8), and jaw claudication OR 4.8 (CI 1.0 to 22.7). Amaurosis was only observed in patients with arteritis. Three subsets had a very high risk of arteritis: (1) Patients with recent headache, abnormal arteries, and > or = 70 years at disease onset: sensitivity 44%, positive predictive value (PPV) 93%, likelihood ratio (LR) 20.3; (2) patients with a new headache, jaw claudication, and abnormal arteries: sensitivity 34.4%, PPV 96.9%, LR 47.2; and (3) those, that in addition to the last 3 features, were > or = 70 years of age at disease onset: sensitivity 26.7%, PPV 100%. We could also identify a subset with a very low risk of arteritis constituted by patients < 70 years, without headache, and with clinically normal temporal arteries: sensitivity 1.1%, PPV 1.7%, LR 0.03. In group C or the test set, these four predictive models correctly identified 57.3%, 29.2%, 23.6, and 3.4% of patients, respectively. CONCLUSIONS: In polymyalgia rheumatica it is feasible to identify subsets with a very high likelihood of GCA. Although in some of these subsets the diagnosis of arteritis is almost certain, we suggest that even then it should be confirmed by temporal artery biopsy. By contrast, in those patients with polymyalgia < 70 years and without cranial features of giant cell arteritis, the risk of vasculitis is so low that the biopsy could be initially avoided and the patient treated with low-dose corticosteroids.

Insufficiency fractures of the tibia and fibula.

OBJECTIVE: Insufficiency fractures (IF) occur when normal or physiological muscular activity stresses a bone that is deficient in mineral or elastic resistance. IF of the tibia and fibula are probably less common than IF of the ribs, vertebrae, hip, pelvis, and distal ulna, and therefore they are frequently underrecognized and mistaken for other conditions. Our aim was to analyze the main features and outcome of IF of the tibia and fibula in patients attending our Rheumatology Service. METHODS: IF was considered when occurring spontaneously or with minimal trauma. Between January 1984 and July 1997, 25 patients were diagnosed as having IF of the tibia and fibula. The main predisposing factors, clinical features, therapy, and outcome were retrospectively reviewed. RESULTS: All the patients except four were women (mean age, 66+/-12 years). Three cases were diagnosed between 1984 and 1990 (0.42 cases/year) and 22 between 1991 and 1997 (three cases/year). Eighteen patients had an underlying condition: rheumatoid arthritis (RA, 13 cases), psoriatic arthritis (2), systemic lupus erythematosus (SLE) (1), kidney transplant (1), and Crohn's disease (1). Eleven patients had osteoporotic fractures in other locations. Risk factors for osteoporosis were corticosteroids (13 cases), prolonged immobilization (10), early menopause (2), and methotrexate therapy (10). All patients had pain on weight bearing and marked functional impairment, 16 had local inflammatory signs, and 10 had deformity. In only five patients the diagnosis of IF was considered at the first examination. The diagnostic delay was 76+/-117 days (median, 21). The initial radiograph was diagnostic in 20 patients, and in the remaining the diagnosis was made by computed tomography (CT) scan (three cases), magnetic resonance imaging (MRI) (1), and bone scan (1). IF were located as follows: tibia (10 cases), fibula (seven), tibia and fibula (eight). Nineteen patients were treated with conservative management, four received no specific treatment, and two required surgery. Sixteen patients were hospitalized for a mean period of 12+/-8 days. Most patients had complete recovery. The high frequency of IF seen in RA patients is probably due to the severe disease in patients treated by our Service and that such patients have a higher risk for osteoporosis and its complications. CONCLUSIONS: IF of the tibia and fibula are probably more common than previously thought. They usually occur in patients with underlying rheumatic diseases, mainly RA, and are frequently mistaken for other joint and bone conditions. Despite a frequent delay in diagnosis, they have a good prognosis with conservative management. Nonetheless, a higher index of suspicion may avoid unnecessary investigations and treatments.

Circulating CD8+ T cells in polymyalgia rheumatica and giant cell arteritis: a review.

BACKGROUND AND OBJECTIVE: During the last few years, there have been several studies on T cell subsets in polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), with conflicting results. Whereas some authors have found normal values of circulating CD8+ T cells, others have found a decreased number. Furthermore, in some studies, the level of CD8+ cells was found to be related to disease activity, and it has been proposed that a decrease of CD8+ T cells be used as a diagnostic criterion for PMR. The purpose of our study was to determine the value of assessing T cell subsets in PMR and GCA. METHODS: T lymphocyte subsets were determined by flow cytometry using a whole blood lysis technique in the following groups: 28 PMR and 6 GCA patients before corticosteroid treatment, 20 PMR and 12 GCA patients in clinical remission with steroid treatment, 55 PMR patients in remission without steroid treatment, 17 rheumatoid arthritis (RA) patients before treatment, and 18 age-matched controls with noninflammatory conditions. Total white cell, lymphocyte, and platelet counts, hemoglobin, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were measured by routine techniques. Comparisons were made by the Student's t-test and the Mann-Whitney test. A MEDLINE database search for studies published between 1983 and 1997 was performed. RESULTS: Compared with noninflammatory controls, CD8+ T cells were not reduced before steroid treatment in patients with active PMR/GCA in proportion (P =.7) or absolute numbers (P =.1). Patients with active disease had significantly lower hemoglobin levels and higher platelet counts, CRP, and ESR than noninflammatory controls (P <.05). When compared with active RA, CD8+ T cells were not reduced in patients with active PMR in proportion (P =.5) or absolute numbers (P =.2). Between these two groups, RA patients were significantly younger (P =.003) and had lower ESR values (P =.003). We did not find significant differences between patients with active PMR/GCA and those in remission with steroid therapy, except for the lower hemoglobin levels and higher platelet count, CRP, and ESR in the active disease group (P <.05). The same results were found when patients with active disease were compared with PMR in remission and no longer on steroid therapy, the only significant differences were those parameters reflecting the acute phase response (hemoglobin levels, platelet count, CRP and ESR). CONCLUSIONS: This study does not confirm the previous findings that the proportion or number of circulating CD8+ T cells are reduced in patients with active PMR/GCA. The utility of the determination of CD8+ T cells for diagnostic and prognostic purpose should be evaluated in a large multicenter study.

Increase in prostaglandin bioavailability precedes the onset of human parturition.

The traditional paradigm that prostaglandins (PGS) are of central importance in the initiation of labor has been challenged. A group of investigators has recently reported that the amniotic fluid concentrations of PGE(2) and PGF(2 alpha) increase only late in the course of labor implying that "the accumulation of prostaglandins in amniotic fluid is an after-effect of labor and not indicative of a role of these compounds in the initiation of human parturition." The present study was conducted to determine whether amniotic fluid prostaglandin concentrations increase prior to the onset of human labor, the central question in this controversy. Three amniocenteses were performed in 17 women with intrahepatic cholestasis of pregnancy -- the first two prior to the onset of labor and the third during early spontaneous labor. PGE(2) and PGF(2 alpha) were measured with sensitive and specific radioimmunoassays. Amniotic fluid concentrations of PGE(2) and PGF(2 alpha) increased prior to the onset of spontaneous labor. An additional increase in the concentrations of PGE(2) and PGF(2 alpha) was found in samples obtained in early labor. We conclude that an increase in prostaglandin bioavailability precedes the onset of spontaneous human parturition.

Polymyalgia rheumatica with normal erythrocyte sedimentation rate: clinical aspects.

Polymyalgia rheumatica is a relatively common syndrome of the elderly characterized by severe pain and stiffness in the neck shoulder and pelvic girdles, along with increased acute phase reactants. The current diagnostic criteria include as a requirement an erythrocyte sedimentation rate (ESR) higher than 30 or 40 mm/1 hr. Nevertheless, in several reports, a sizable proportion of patients with PMR, from 7% up to 22%, had an ESR that was either normal or slightly increased at the time of diagnosis, supporting the notion that an increased ESR should not be an absolute requirement for its diagnosis. This subset is characterized by a younger age, a less marked predominance of females, a longer diagnostic delay and a lower frequency of constitutional symptoms such as fever or weight loss. When determined, a majority of these patients had increased levels of C reactive protein. The recognition of this subset of patients with PMR and a low ESR can be very useful to the clinician, avoiding unnecessary suffering of the patients and the risks of ineffective therapy with nonsteroidal antiinflammatory drugs. To avoid the over-diagnosis of PMR in patients with a low ESR, we propose a set of criteria that can be easily applied in daily practice to patients with a clinical picture consistent with PMR but with a normal or slightly increased ESR.

Familial aggregation of polymyalgia rheumatica and giant cell arteritis: genetic and T cell repertoire analysis.

OBJECTIVE: Several reports of familial aggregation of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) have been described although detailed genetic and immunological studies are scarce. Our aims were to investigate the influence of HLA-DRB1 alleles and to analyze the phenotype and T cell receptor (TCR) usage of circulating T lymphocytes in a familial case of GCA and PMR. METHODS: HLA-DRB1 typing was carried out using polymerase chain reaction amplification with specific primers. The study of the circulating T cell repertoire was performed by staining with specific monoclonal antibodies and flow cytometry analysis. RESULTS: Patient 1 developed GCA at the age of 71, four years prior to the diagnosis of PMR in her older brother. The HLA-DRB1 typing of Patient 1 was DRB1*04 (DRB1*0401)/DRB1*12 and in Patient 2 was DRB1*07/DRB1*12. In our patient population, GCA was associated with an increased frequency of HLA-DRB1*04 compared with PMR patients. Regarding T cell phenotype, the brother with active PMR had a higher expression of surface markers indicating activation in both T cell subsets (CD25 and HLA-DR). The sister with GCA showed a pronounced decrease of CD4+/CD45RA+ T cells with respect to her brother with PMR. Both patients carried a significant depletion of CD28 in both subsets, specially within the CD8+ T cell compartment. The BV gene usage differed from one patient to the other. T cell expansions were identified in both patients but the specificities were different. CONCLUSION: We describe an association of GCA and PMR between two first degree relatives with significant genetic and immunologic differences. Our results suggest that the pathogenic mechanisms leading to the development of GCA and PMR are probably multifactorial, and both genetic and environmental factors may contribute to the development of these diseases.

Mycotic (infected) aneurysm of the popliteal artery and arthritis following Salmonella bacteriemia.

We report a case of a mycotic (infected) aneurysm of the popliteal artery due to Salmonella enteritidis. The clinical presentation may be confused with other more common causes of diffuse swollen leg, causing a delay in the diagnosis and proper therapy. Prompt surgical resection of the infected aneurysm together with medical therapy is required for successful treatment.

Radiographic features of hereditary articular chondrocalcinosis. A comparative study with the sporadic type.

To assess the radiological features of hereditary articular chondrocalcinosis, we performed a blind comparative study between 21 randomly selected patients with hereditary disease and 21 cases of sporadic pseudogout matched for age and sex. Each individual had AP projections of the hands, pelvis and knees. The films were evaluated for the presence of articular chondrocalcinosis and for the severity of the associated degenerative arthropathy. A grade of 0 to 3+ was assigned to each of the 4 variables of osteoarthritis: joint space narrowing, sclerosis, osteophytosis and subchondral cysts. The mean number of joints with chondrocalcinosis and its distribution was similar in both groups. In addition, no differences were found in the overall severity of the associated degenerative arthropathy. In both groups the disease was characterized by oligoarticular calcification and a mild degenerative arthropathy. These data along with data from other reported pedigrees, show that the radiological appearance in the hereditary type is frequently indistinguishable from that commonly observed in sporadic articular chondrocalcinosis.

Vertebral osteomyelitis in northern Spain. Report of 62 cases.

OBJECTIVE: The records of 62 patients with clinical and radiographic evidence of vertebral osteomyelitis and positive bacteriological diagnosis, seen between 1979 and 1996, were reviewed in order to gather data on the epidemiology and the clinical pattern displayed by patients with this condition in northern Spain. RESULTS: Staphylococcus aureus (15 cases), Mycobacterium tuberculosis (15 cases) and Brucella melitensis (13 cases) were the microorganisms most frequently found in our patient series. After improvement of the sanitary and hygienic control of food products, the role of Brucella melitensis is decreasing as a causative agent (only 3 cases in the last 6 years). Staphylococcus epidermidis, present in 4 cases (6.6%), should be suspected in elderly patients with previous intravenous cannulations (3 of 4 cases). The most frequent risk factors were alcoholism (7 cases), chronic hepatic disease (7 cases), diabetes (6 cases) and previous surgery (6 cases). Delay in diagnosis was high (the mean number of days between the onset of symptoms and diagnosis was 125). The lumbar region was the most commonly affected site. Neurologic involvement was present in 10 patients on admission (16%). ESR was > 50 mm/hr in a high number of cases. Blood cultures were found to be the most valuable routine test. Plain x-rays were normal in 10 patients (16%); in 6 of them Staphylococcus aureus was the responsible organism. Other imaging modalities showed a high sensitivity. Surgical drainage was necessary in 12 individuals (in 7 due to Mycobacterium tuberculosis). Outcome was good in the majority of cases: only 2 patients with associated endocarditis died. Neurologic sequelae were present in another 3 patients. CONCLUSION: Vertebral osteomyelitis can be caused by a variety of pathogens. Therefore, bacteriological studies are necessary to establish the etiologic diagnosis and determine the specific antimicrobial treatment required.

Relationship of maternal and infant nutrition to infant growth.

A cohort of all infants born between January 1, 1969 and February 28, 1977 in four rural villages in Eastern Guatemala which were participating in a longitudinal project of nutrition and mental development was studied. As part of the study, prospective information on anthropometric measurements, morbidity, dietary intake and socioeconomic and cultural characteristics was collected. In addition, two types of food supplements were distributed: calorie and protein-calorie. Attendance at the feeding centers in each village and the amount of supplements consumed by children and pregnant and lactating mothers were recorded daily. We studied the effect of the supplements consumed by the mother during pregnancy and lactation and by the infant on trimestral infant weight and length changes during the first year of life. The data indicate that infant calorie supplementation before three months of age is significantly and negatively associated with infant growth; after three months of age, supplemental calories consumed by the infant are significantly and positively associated with infant weight and length gains. In addition, a small positive association was found between maternal caloric supplementation during lactation and infant growth during the first two trimesters of life, after controlling for potentially confounding factors for which data are available in this study.

PIP: The interrelationships between maternal nutrition, breastfeeding, infant nutrition, and infant growth in the context of a quasi-experimental longitudinal investigation carried out in rural Guatemala was examined. This is the 1st publication from the Guatemalan study to focus on the relationship of maternal and infant nutrition to infant growth during lactation utilizing all data collected between 1969-1977. The subjects were inhabitants of 4 agricultural villages participating in a longitudinal study of the relationship between malnutrition, physical growth, and mental development, which was conducted between 1969 and 1977. The entire population of the 4 communities was 3359 in 1975. The sample for these analyses was all children born between January 1, 1969 and February 28, 1977 (n=1106) and who were followed up to 12 months of age. Data on a variety of anthropometric measurements were taken by trained and standardized anthropometrists at specific ages (15 days, 3, 6, 9, and 12 months for children and quarterly for mothers during pregnancy and lactation). The main independent variable is nutrient intake, which includes supplement consumed at the feeding center and home diet and supplement intake. In general, the results of the longitudinal study attest to an effect of maternal dietary supplementation on infant growth, particularly infant weight gain from birth to 3 months and from 3-6 months of age. The data indicate that infant supplementation prior to 3 months of age is significantly and negatively correlated with infant growth, after controlling for potentially confounding factors for which data are available in this study. After 3 months of age, supplemental calories consumed by the infant are significantly, positively correlated to infant weight and length gains. The small association between maternal food suppplementation and infant growth could be due, in part, to the fact that only a small fraction of the energy consumed by the infant is utilized for growth after the 1st trimester of age and infant adaptation to limited caloric intake could be achieved by a reduction of physical activities. The negative association between infant supplementation and infant growth is probably because mothers whose infants were not growing adequately began to give supplements to the infants earlier than those with more adequate growth. The results also reflect the previously reported relationship between such factors as anthropometric measurement of the parents, obstetrical characteristics, infant morbidity, lactation, and infant growth.