PUVA apoptotic response in activated and resting human lymphocytes.

In extracorporeal photopheresis (ECP) collected cells are treated by 8 methoxypsoralen and UVA (PUVA) which induced apoptosis. The mechanism of action of reinfused cell is unclear. A vaccination model postulates an efficient presentation of apoptotic alloreactive cells to the patient immune system. The efficiency may depend upon a predominance of apoptotic alloreactive cells after PUVA. Such selectivity could result from their activation. We studied apoptosis in resting and PHA-activated lymphocytes. Both were equally susceptible. Changes in early apoptosis were possibly missed. We evaluated the effect of preincubation before PUVA. During preincubation monocyte could affect lymphocytes susceptibility to apoptosis as an increase of number of apoptotic cells was observed after 72 hours in stimulated and resting cells. Our findings do not preclude a selectivity of other PUVA effects since expression of membrane marker also targets to PUVA is modified by activation.

IL-1ra and IL-1 production in human oral mucosal epithelial cells in culture: differential modulation by TGF-beta1 and IL-4.

Regulatory cytokines mediate the participation of oral mucosal epithelial cells (OMEC) in local immune responses. The aim of this study was to characterize the isoforms of IL-1 receptor antagonist (IL-1ra) in cultured human primary OMECs and to compare its production with that of IL-1 alpha (IL-1alpha) and IL-1 beta (IL-1beta). Western blot analysis showed that IL-1ra was 22 kDa in size hence slightly smaller than monocyte IL-1ra (25 kDa). A minor form of 20 kDa was also found in unstimulated cell culture lysates. In culture supernatants, IL-1 bioactivity increased after IL-1ra neutralization, indicating that the baseline production of IL-1ra is biologically relevant. Immunohistochemistry showed a relation between IL-1ra and involucrin expressions, suggesting that intracytoplasmic IL-1ra may be involved in cell terminal differentiation. In unstimulated culture lysates, there was far more IL-1ra than IL-1alpha and IL-1beta. TGF-beta1 markedly increased the IL-1ra/IL-1beta ratio from 93.6 : 1 to 300 : 1. IL-4, which is generally described as an anti-inflammatory cytokine, increased IL-1 but not IL-1ra production. TNF-alpha increased intracellular production of the three IL-1 members. IL-1ra levels were lower in supernatants than in lysates of cultured cells. Our results show that human OMECs constitutively produce significant amounts of a biologically active form of IL-1ra. TGF-beta1 mu(p)-regulation points to a positive amplification loop and IL-4 to a down-regulation loop, both including Th2 cells and OMECs. They may be important in oral tolerance and IgA production, respectively.

No changes in the distribution of organisms responsible for septic arthritis over a 20 year period.

OBJECTIVE: To assess changes in the distribution and resistance of the pathogens responsible for septic arthritis over a 20 year period in patients admitted to the same hospital unit. PATIENTS AND METHODS: Retrospective study of the hospital records of patients admitted between 1979 and 1998 for septic arthritis with positive microbiological diagnosis after blood or joint cultures, or both. RESULTS: 303 cases of septic arthritis were studied, 141 in the period 1979-88 and 162 in the period 1989-98. The incidence between the first and second period did not vary significantly for the staphylococci (67% v. 63%), streptococci (16% v. 20%), and Gram negative bacilli (7% v. 10%). Tuberculous infections decreased from 9% to 4% (p<0.04). No gonococci were isolated in the second 10 year period. Among the staphylococcal species, there was an increase in the number of coagulase negative staphylococci (10 cases v. 21, p<0.05) between the two periods. There was no significant difference in the frequency of occurrence of methicillin resistant pathogens (12.6% v. 16.6%). The number of streptococcal B infections increased (2 v. 10 cases), and beta-lactamine resistant pneumococci emerged. In the second 10 year period, patients were older and were more likely to have co-existing disease, particularly tumoral growth, and less commonly were receiving dialysis. Localisation of joint infection was comparable except for an increase in prosthetic knee infections. CONCLUSION: The distribution and sensitivity of pathogens causing septic arthritis changed little over a 20 year period.

Pamidronate in the treatment of diffuse sclerosing osteomyelitis of the mandible.

Diffuse sclerosing osteomyelitis of the mandible is characterized by bouts of intense pain, sometimes associated with trismus and paresthesia, and leads to progressive deformity. It is of unknown etiopathology, but it is suggested to be one manifestation of the synovitis, acne, pustulosis, hyperostosis, osteomyelitis syndrome, the other features of which may have been overlooked. Treatment results are disappointing, and decortication may be necessary to achieve an acceptable outcome. We report a case restricted to the mandible that responded favorably to treatment with pamidronate. Further trials of pamidronate in patients with diffuse sclerosing osteomyelitis of the mandible, even in those with the aforementioned syndrome, are needed to assess its effectiveness.

[Secondary Gougerot-Sjogren syndrome]. / Syndromes de Gougerot-Sjögren secondaires.

Secondary Sjögren's syndrome is due to another disease. When it develops in connective tissue diseases, their causative role is unchallenged. In AIDS or hepatitis C, exocrine involvement is virus related. Whether or not it qualifies for Sjögren's syndrome is debated. Amyloidosis and sarcoidosis do not produce direct, autoimmune lesions of the glands, hence their exocrine involvements are considered as differential diagnoses. The most common Sjögren's syndrome is found in rheumatoid arthritis. When it appears, the arthritis has been evolving for years, and has reached its typical, seropositive and erosive stage. Accordingly, dryness is not a major concern and should be sought for by proper questioning, specially on eye dryness. When a secondary Sjögren's syndrome is an early complication of rheumatoid arthritis, it could be confused with a primary syndrome with prominent joint involvement. In systemic lupus erythematosus, secondary Sjögren's syndrome develops rarely in the first years of evolution but later in life, when the patient becomes menopausal. In systemic sclerosis, especially in CREST, secondary syndrome can lead to the discovery of the unsuspected connective tissue disease thanks to mouth dryness. It can reveal primary biliary cirrhosis or auto-immune hepatitis. Often precede a true primary Sjögren dysfunctions of the thyroid.

Pyogenic arthritis in adults.

Septic arthritis has shown no change in incidence, and despite advances in antimicrobial therapy is often responsible for residual functional impairment and for a high mortality rate among debilitated patients. Risk factors include older age, diabetes mellitus, rheumatoid arthritis, immunodeficiency, and a preexisting joint disease (e.g., rheumatoid arthritis) to which the symptoms of septic arthritis are sometimes ascribed. Staphylococcus aureus contributes over two-thirds of identified organisms; a range of streptococci and gram-negative bacilli are next in frequency. The most common site is the knee, followed by the hip and shoulder. Over 10% of patients have polyarticular involvement reflecting bacteremia and diminished resistance to infection; (over 50% of polyarticular forms occur in rheumatoid arthritis patients). Prosthetic joint infection is becoming increasingly common; chronic forms due to intraoperative contamination and resulting in septic loosening should be distinguished from acute hematogenous infection in which emergency treatment can allow to salvage the prosthesis. Demonstration of the organism in the joint is the key to the diagnosis. Joint aspiration should be performed on an emergency basis, if needed after identification of radiographic landmarks or under ultrasonographic guidance. Seeding the fluid on blood culture flasks immediately after aspiration increases the yield. Antibiotics should be started as soon as the microbiological specimens have been collected. When aspiration is difficult (hip) or inadequate, arthroscopic drainage usually makes arthrotomy unnecessary. Early antiinflammatory therapy (nonsteroidal antiinflammatory drugs, systemic or local glucocorticoids, anticytokines, and antiinflammatory cytokines) are being considered as tools for limiting joint damage; their efficacy and safety will first have to be established in animal studies.

Increased serum levels of interleukin 10 in Sjögren's syndrome; correlation with increased IgG1.

OBJECTIVE: To determine levels of interleukin 10 (IL-10) and IgG subclasses in serum from 53 patients with primary Sjögren's syndrome (SS). METHODS: Serum levels of IL-10 were measured using specific sandwich ELISA in 25 patients with "definite" SS, 28 with "possible" SS, and 32 healthy controls. Interferon-gamma (IFN-gamma) and transforming growth factor-beta1 (TGF-beta1) were also measured by immunoassays. Immunoglobulin classes, IgG subclasses, and C-reactive protein were measured by nephelometry. RESULTS: Circulating IL-10 was elevated in 25 patients. The increase reached significance in the group with possible SS (p = 0.03) versus controls. In the group with definite SS, IL-10 level was correlated with IgG1 level (p = 0.01, r = 0.67) and with focus score (p = 0.01). IFN-gamma was undetectable in most patients. TGF-beta1 was higher (not significantly) in possible SS than in definite SS. CONCLUSION: IL-10 is increased in SS and may account for the overproduction of IgG1 in the syndrome. High IL-10 in the absence of increased IgG1 in possible SS suggests that IL-10 may be necessary but not sufficient for IgG1 overproduction and that other factors are involved. Whereas the correlation of IL-10 level with focus score was expected, it is intriguing that IL-10 was more frequently increased in the incomplete (possible) form of SS than the complete (definite) form. Elevated IL-10 may characterize the lower stage of eccrine dysfunction and perhaps contributes to limiting its severity.

Isolation of Pantoea agglomerans in two cases of septic monoarthritis after plant thorn and wood sliver injuries.

Arthritis after plant injury is often apparently aseptic. We report two cases due to Pantoea agglomerans. In one case, the bacterium was isolated only from the pediatric blood culture media, BACTEC Peds Plus, monitored in BACTEC 9240, and not from the other media inoculated with the joint fluid. This procedure could help improve the diagnosis of septic arthritis.

HLA and self-limiting, unclassified rheumatism. A role for HLA-B35?

OBJECTIVE: To test the hypothesis of increased frequency of HLA-B35 in self-limiting, unclassified rheumatism (SUR). METHODS: Patients (n = 50) were included if they had swelling of one or more joints for more than 24 h and/or pain without trauma of 2 or more joints for one month or longer, and at least one of (1) history of joint swelling, (2) morning stiffness, (3) elevated erythrocyte sedimentation rate and/or C-reactive protein. Patients fulfilling diagnostic criteria sets of any rheumatic disease and patients with other identified diseases were excluded. Controls were 50 patients with rheumatoid arthritis (RA) and 199 healthy blood donors. RESULTS: HLA-B35 frequency (0.32) was significantly greater in SUR than in RA (0.14) and controls (0.17). HLA-DR4 frequency was significantly increased in HLA-B35 positive SUR, while that of HLA-DR1 was decreased (NS). Clinical characteristics of SUR were: history of atopy; transient, mono or oligoarticular synovitis and widespread, longlasting pain. HLA-B35 positive patients with SUR more often had hip, knee, or back pain than HLA-B35 negative patients. CONCLUSION: HLA-B35 frequency is increased in SUR, while HLA-DR1 frequency is not. A likely hypothesis of attenuated immune inflammation in SUR is further supported by results in juvenile RA, adult Still's disease, and a series of mild inflammatory arthritides, and by indirect evidence of decreased Th1 response and increased Th2 response in HLA-B35 positive patients with various conditions.

A new case of NSAID-induced infertility.

A 38-year-old woman on piroxicam for hip osteoarthritis secondary to hip dysplasia developed secondary sterility. Ova collected for in vitro fertilization were immature and failed to fertilize. A further attempt done after piroxicam discontinuation produced seven mature ova that fertilized, allowing embryo implantation. Nonsteroidal antiinflammatory drugs may induce infertility by reducing the production of prostaglandins, most notably via inhibition of the enzyme cyclooxygenase 2. The impact of nonsteroidal antiinflammatory drug therapy on reproductive function needs to be evaluated.

[Treatment of rheumatoid polyarthritis: evolution of concepts and strategies]. / Le traitement de la polyarthrite rhumatoïde. Evolution des idées et des stratégies.

INTRODUCTION: The treatment of rheumatoid arthritis includes non-steroid anti-inflammatory drugs (NSAID), low-dose steroids and drugs which modify the evolution of the disease (disease modifying anti-rheumatic drugs, [DMARD]). In the last few years, the long-term efficiency of the recommended treatment strategies in rheumatoid arthritis has been a matter of debate and their basic assumptions have been challenged. Numerous studies were undertaken to settle the question. They tried to delineate the rules for an optimal use of current drugs and other therapeutic means. CURRENT KNOWLEDGE AND KEY POINTS: Rheumatoid arthritis is a crippling disease. It decreases life expectancy and irreversible bone and joint damage may develop even in the first months of evolution. The sooner the prescription of DMARD, the higher the frequency and quality of rheumatoid arthritis improvement and, in the long-term, the lesser the functional impairment. Low dose steroids, when administered early, can slow down the development of radiologic lesions. Some of their effects are thus closer to those of DMARD than to those of symptomatic treatment. NSAID are at least as equally dangerous as DMARD and possibly more so in terms of the potential number of severe side effects. The combination of several DMARD does not increase their overall toxicity. An evaluation of the most efficient combinations and of the clinical situations in which combinations show promise of improved results is in progress. FUTURE PROSPECTS AND PROJECTS: At present, the tendency is to treat early and intensively, in order to obtain complete remission, improve evolution and reduce functional impairment. This strategy requires early diagnosis and early evaluation of prognosis of rheumatoid arthritis. Rheumatoid arthritis with benign evolution would not warrant intensive treatment. Studies are in progress to evaluate the prognostic factors in early rheumatoid arthritis that would enable us to adapt the strength of initial treatment to the disease's putative severity.

IL-1 receptor antagonist (IL-1RA) gene polymorphism in Sjögren's syndrome and rheumatoid arthritis.

The gene encoding interleukin-1 receptor antagonist (IL-1ra) has a variable allelic polymorphism. The IL1RN*2 allele was recently described as a factor of severity in several autoimmune diseases and was paradoxically associated with increased production of IL-1ra by monocytes in vitro. We studied this polymorphism in 36 patients with possible or definite primary Sjögren's syndrome and found that IL1RN*2 was significantly more frequent in the definite than in the possible form. In rheumatoid arthritis, the frequency of the allele was not different from that of controls. The serum levels of IL-1ra were markedly higher in Sjögren patients than in those of healthy subjects. By contrast, the salivary IL-1ra levels were decreased. Patients with the allele generally had lower salivary levels and higher serum levels than patients without the allele. In the group of patients with the definite syndrome, CRP and TGF-beta 1, two in vitro stimulators of IL-1ra production, were correlated with IL-1ra serum levels. Our results suggest that IL1RN*2 is a marker of more severe forms of Sjögren's syndrome. Its effect on salivary and serum IL-1ra may be distinct, suggesting separate regulatory mechanisms.

Modulation of Leydig cell testosterone production by secretory products of macrophages.

Unstimulated macrophages from testes inhibited the production of testosterone by Leydig cells from adult, but not immature, Sprague-Dawley rats (significant after 48 h). Similar results were observed with unstimulated macrophage-conditioned media, suggesting that the observed effect was mediated by one or more secretory products. None of these substances was interleukin-1, since macrophage supernatants tested negative in an interleukin-1 alpha and interleukin-1 beta sensitive, thymocyte assay. Interleukin-6 was detected by a B cell proliferation assay. After stimulation by LPS, testicular macrophages enhanced testosterone production by Leydig cells from adult and immature rats. This enhancement was dose-dependent and required low concentrations (but over 2.5%) of conditioned media. Interleukin-1 and interleukin-6 activities were detected in LPS-stimulated macrophage supernatants. Supernatants of LPS-stimulated, human monocytes had similar effects on Leydig cells. They were rich in interleukin-1, interleukin-1 receptor antagonist and interleukin-6. The present study suggests that, in adult rats, testicular macrophages modulate Leydig cell steroidogenesis by secretory products whose secretion depends on the physiological state of macrophages. The factor or factors responsible for stimulation are not species-specific. The effect cannot be accounted for by variations in the concentration of the above mentioned interleukins in macrophage supernatants.

Arterial obliteration in POEMS syndrome: possible role of vascular endothelial growth factor.

Acute arterial obliteration is a newly acknowledged manifestation of the POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes), in which overproduction of proinflammatory cytokines has been implicated. We describe a case in which serum levels of proinflammatory cytokines were normal or slightly raised. In contrast, vascular endothelial growth factor (VEGF) was greatly increased. This angiogenic and vascular permeability factor is involved in the development of atheromatous and thrombotic lesions and may be responsible for the arterial complications of the disorder.