In situ hybridization analysis of synovial and systemic cytokine messenger RNA expression in superantigen-mediated Staphylococcus aureus arthritis

Objective. To investigate patterns of synovial and systemic cytokine messenger RNA (mRNA) expression in mice with superantigen-mediated Staphylococcus aureus arthritis. Methods. Mice were inoculated intravenously with 1 × 10⁷ colony-forming units of toxic shock syndrome toxin–1–producing S aureus LS-1. Synovial tissues and spleens were obtained at varying time intervals after bacterial inoculation, and examined for mRNA expression of interleukin-1β (IL-1β), IL-4, IL-10, IL-12, tumor necrosis factor α (TNFα), TNFβ, interferon-γ (IFNγ), transforming growth factor β, and perforin, by an in situ hybridization technique. Results. In situ hybridization revealed early synovial up-regulation of TNFα and IL-1β mRNA expression. Peak frequencies of these proinflammatory cytokines were observed at the second and third week of the infection. Expression of T cell-derived cytokine mRNAs was detected later, and in a relatively low frequency. Notably, induction and peak numbers of Th2 cytokine (IL-4 and IL-10) mRNA expression preceded Th1 cytokine (IFNγ and TNFβ) mRNAs. In comparison with synovial tissues, peak spleen cytokine mRNA expression of IL-1β, TNFα, TNFβ, IL-12, and IFNγ occurred earlier, but displayed a clearly lower magnitude of expression. Conclusion. These findings demonstrate synovial and systemic up-regulation of cytokine mRNA expression during S aureus arthritis, indicating that both monocyte/macrophage and T cell–derived products are involved in the pathogenesis of this disease.     

Helicobacter pylori antibiotic eradication coupled with a chemically defined diet in INS-GAS mice triggers dysbiosis and vitamin K deficiency resulting in gastric hemorrhage

ABSTRACT

Infection with Helicobacter pylori causes chronic inflammation and is a risk factor for gastric cancer. Antibiotic treatment or increased dietary folate prevents gastric carcinogenesis in male INS-GAS mice. To determine potential synergistic effects, H. pylori-infected male INS-GAS mice were fed an amino acid defined (AAD) diet with increased folate and were treated with antibiotics after 18 weeks of H. pylori infection. Antibiotic therapy decreased gastric pathology, but dietary folate had no effect. However, the combination of antibiotics and the AAD diet induced anemia, gastric hemorrhage, and mortality. Clinical presentation suggested hypovitaminosis K potentially caused by dietary deficiency and dysbiosis. Based on current dietary guidelines, the AAD diet was deficient in vitamin K. Phylloquinone administered subcutaneously and via a reformulated diet led to clinical improvement with no subsequent mortalities and increased hepatic vitamin K levels. We characterized the microbiome and menaquinone profiles of antibiotic-treated and antibiotic-free mice. Antibiotic treatment decreased the abundance of menaquinone producers within orders Bacteroidales and Verrucomicrobiales. PICRUSt predicted decreases in canonical menaquinone biosynthesis genes, menA and menD. Reduction of menA from Akkermansia muciniphila, Bacteroides uniformis, and Muribaculum intestinale were confirmed in antibiotic-treated mice. The fecal menaquinone profile of antibiotic-treated mice had reduced MK5 and MK6 and increased MK7 and MK11 compared to antibiotic-free mice. Loss of menaquinone-producing microbes due to antibiotics altered the enteric production of vitamin K. This study highlights the role of diet and the microbiome in maintaining vitamin K homeostasis.     

Dependence on interferon‐γ for the spontaneous occurrence of arthritis in DBA/1 mice

Objective

Male DBA/1 mice are known to spontaneously develop arthritis in the hind legs. The present study was undertaken to investigate the role of endogenous interferon‐γ (IFNγ) in the pathogenesis of this ankylosing enthesopathy.

Methods

The role of IFNγ was studied by examining the development of arthritis in IFNγ receptor–knockout (IFNγR‐KO) DBA/1 mice as compared with wild‐type mice, and by treatment of wild‐type mice with monoclonal anti‐IFNγ antibody. IFNγ‐disrupted and wild‐type mice were mixed and housed in the same cage, and clinical symptoms of arthritis were assessed weekly for at least 9 weeks. Histologic examination was performed at the end of the experiment.

Results

In DBA/1 wild‐type mice, 70% of the animals developed clinical symptoms of spontaneous arthritis, such as redness and swelling of the proximal interphalangeal joints, toe stiffness, and ankylosis. As evident from microscopic evaluation, the arthritis was mainly characterized by formation of new cartilage and bone, originating at the entheses and leading to ankylosis. The incidence and severity of arthritis, both clinically and histologically, were significantly reduced in IFNγR‐KO mice. In wild‐type mice, neutralizing anti‐IFNγ antibody inhibited the occurrence of the disease for the duration of treatment.

Conclusion

The results suggest that endogenous IFNγ plays an important role in the initial stages of spontaneous arthritis, and that the inflammatory components in its pathogenesis are more prominent than has been believed. In view of the similarity between this disease and spondylarthropathies in humans, the data suggest that endogenous IFNγ may also play a disease‐promoting role in the human condition and thus may serve as a target for therapy.

     

High levels of inflammatory chemokines and cytokines in joint fluid and synovial tissue throughout the course of antibiotic‐refractory lyme arthritis

Objective

To investigate the possible role of chemokines and cytokines in the pathogenesis of Lyme arthritis.

Methods

Using cytometric bead array and flow cytometry techniques, chemokine and cytokine levels were determined in 65 synovial fluid (SF) samples and 7 synovial tissue (ST) samples from 17 patients with antibiotic‐responsive Lyme arthritis and 35 patients with antibiotic‐refractory Lyme arthritis seen during the past 18 years. In the ST samples, expression of chemokine receptors was measured using immunohistochemistry.

Results

Before or during antibiotic therapy, when the majority of patients had positive polymerase chain reaction (PCR) results for Borrelia burgdorferi DNA, SF from patients with antibiotic‐refractory arthritis contained exceptionally high levels of Th1 chemoattractants and cytokines, particularly CXCL9 and interferon‐γ (IFNγ). Compared with the patients whose arthritis was responsive to antibiotic treatment, those with antibiotic‐refractory arthritis had significantly higher levels of CXCL9 and CXCL10 (both P ≤ 0.001) and CCL3, CCL4, CXCL8, IFNγ, tumor necrosis factor α, interleukin‐1β (IL‐1β), and IL‐6 (all P ≤ 0.01). During the post‐antibiotic period, when the results of PCR for B burgdorferi DNA in SF and ST were uniformly negative, patients with antibiotic‐refractory arthritis continued to exhibit high SF and ST levels of these chemokines and cytokines. In addition, synovial samples showed marked expression of the receptors for T cell or macrophage chemokines, CXCR3 and CCR5.

Conclusion

Patients with antibiotic‐refractory Lyme arthritis have high synovial fluid levels of proinflammatory chemokines and cytokines, especially CXCL9 and IFNγ, throughout the illness. Thus, even when antibiotic treatment reduces or completely clears the infection in these patients, the inflammatory response in synovium persists.

     

Antibody responses to Borrelia burgdorferi in patients with antibiotic‐refractory,antibiotic‐responsive,or non–antibiotic‐treated lyme arthritis

Objective

To compare the pattern of antibody responses to Borrelia burgdorferi in patients with antibiotic‐refractory, antibiotic‐responsive, or non–antibiotic‐treated Lyme arthritis as an indirect measure of spirochetal persistence or eradication.

Methods

At least 3 serial serum samples from 41 patients with antibiotic‐refractory arthritis and 23 patients with antibiotic‐responsive arthritis, and samples from 10 non–antibiotic‐treated, historical control patients were tested for IgG reactivity with B burgdorferi sonicate and 4 differentially expressed outer surface lipoproteins of the spirochete, by enzyme‐linked immunosorbent assay.

Results

Among non–antibiotic‐treated patients, antibody titers to B burgdorferi antigens remained high throughout a 2–5‐year period of arthritis. In contrast, in patients with antibiotic‐responsive arthritis, in whom joint swelling usually resolved during a 1‐month course of oral antibiotic therapy, the median antibody titers to most of the spirochetal antigens remained steady or decreased during the first 1–3 months after starting antibiotic therapy. In patients with antibiotic‐refractory arthritis, who had persistent joint swelling for a median duration of 10 months despite 2–3 months of oral or intravenous antibiotics, the median titers to most antigens increased slightly during the first 1–3 months. However, by 4–6 months after starting antibiotic therapy, reactivity with all antigens declined similarly in both antibiotic‐treated groups.

Conclusion

Whereas the antibody titers to B burgdorferi remained high in non–antibiotic‐treated patients, the titers declined similarly 4–6 months after starting therapy in patients with antibiotic‐responsive or antibiotic‐refractory arthritis, suggesting that synovial inflammation persisted in patients with antibiotic‐refractory arthritis after the period of infection.

     

A randomized,double-blind study comparing twenty-four-week treatment with recombinant interferon-γ versus placebo in the treatment of rheumatoid arthritis

Objective. To evaluate the safety and efficacy of recombinant interferon-γ (rIFNγ) in patients with active rheumatoid arthritis (RA), using an induction and maintenance regimen. Methods. A multicenter, randomized, double-blind trial of 197 patients with RA was conducted to compare the effects in a group receiving 50 μg of rIFNγ, given subcutaneously in a decreasing regimen over 24 weeks, with those in a placebo group receiving injections of placebo at the same time frequency. Standard clinical assessments were performed. Results. Both rIFNγ and placebo produced a significant improvement from baseline to end point visit for most measurements (except erythrocyte sedimentation rate, duration of morning stiffness, and grip strength), but no significant intergroup differences were seen. Regarding adverse effects, mild local skin reactions at the site of injection were observed, and among the cardiovascular events, mild edema and vasodilatation were reported. Conclusion. IFNγ proved no more effective than placebo in this group of patients with RA. IFNγ was well tolerated in this group of patients, without increased toxicity compared with placebo.     

Interferon‐γ regulates susceptibility to collagen‐induced arthritis through suppression of interleukin‐17

Objective

The enhanced expression of experimental arthritis in the absence of interferon‐γ (IFNγ) suggests that IFNγ suppresses arthritis. Interleukin‐17 (IL‐17) is a pivotal T cell cytokine in arthritis, and in vitro studies have indicated that IFNγ suppresses IL‐17 production. We undertook this study to test the hypothesis that resistance to collagen‐induced arthritis (CIA) in C57BL/6 (B6) mice is regulated by IFNγ‐mediated suppression of IL‐17.

Methods

Wild‐type (WT) B6 mice, IFNγ‐knockout (KO) B6 mice, and DBA/1 mice were immunized with type II collagen (CII) in Freund's complete adjuvant (CFA). Lymphocytes from immunized mice were analyzed for cytokine production ex vivo by intracellular staining or restimulation with CII and enzyme‐linked immunosorbent assays. In vivo blockade of IL‐17 was achieved with an anti–IL‐17 monoclonal antibody (mAb).

Results

CII restimulation of T cells from CII/CFA‐immunized mice resulted in an ∼5‐fold increase in IL‐17 production in IFNγ‐KO B6 mice compared with WT B6 mice. Neutralization of IFNγ increased IL‐17 production in WT B6 mice, and neutralization of IL‐4 had a synergistic effect. Interestingly, the prototypical CIA‐susceptible strain DBA/1 also demonstrated a high IL‐17 and a low IFNγ cytokine profile compared with WT B6 mice. Administration of the anti–IL‐17 mAb attenuated arthritis in DBA/1 mice and almost completely prevented expression of arthritis in IFNγ‐KO B6 mice.

Conclusion

These results indicate that sensitivity of IFNγ‐deficient B6 mice to CIA is associated with high IL‐17 production and that this cytokine is required for expression of arthritis in this strain.

     

Suppurative lymphadenitis

Suppurative lymphadenitis is an important and common form of soft tissue infection. Most acute cases of suppurative lymphadenitis are caused by Staphylococcus aureus or by Streptococcus pyogenes. Empiric antibiotic therapy is frequently successful in the early stages of the disease process, but increasing prevalence of methicillin-resistant S. aureus in particular has necessitated a shift in antibiotic choice that is dictated primarily by specific local resistance patterns. Several other organisms and noninfectious inflammatory processes may give rise to a clinical syndrome suggestive of suppurative lymphadenitis. Failure to respond to empiric antibiotics should trigger a diagnostic re-evaluation to determine the need for surgical intervention and/or the possibility of alternative microbiologic diagnoses.     

Ceftriaxone therapy of chronic inflammatory arthritis. A double-blind placebo controlled trial

To determine whether chronic inflammatory arthritis may respond to antibiotic therapy (implying a bacterial origin), we conducted a placebo-controlled, double-blind study. Sixty patients with inflammatory arthritis and antibody titers to Borrelia burgdorferi 1:64 or more were randomized to receive placebo (n = 20) or 2 g/d of ceftriaxone intravenously (n = 40) for 2 weeks. Two of 20 placebo- and 19 of 40 antibiotic-treated patients improved. At 1 month, the placebo-treated patients could elect to receive ceftriaxone. Altogether, 58 patients were treated with ceftriaxone and followed up for 13 to 24 months. Improvement was noted in 27 of the 58 antibiotic-treated patients. Patients with a wide diversity of inflammatory arthritis were studied. Response to ceftriaxone was seen in all groups, including 5 of 12 with rheumatoid arthritis, 5 of 8 with psoriatic arthritis, 3 of 5 with vasculitis, and 14 of 33 with less well-differentiated chronic inflammatory arthritis. In 16 of the 27 who responded to the antibiotic, the arthritis worsened 6 to 18 months after the initial response to ceftriaxone. Previous improvement of arthritis after oral antibiotic was a better predictor of response to ceftriaxone than either duration of disease or Lyme antibody titer. Side effects to ceftriaxone were frequent and included diarrhea (29/60) and acute allergic reactions (9/58). We conclude that some patients may have an occult bacterial infection underlying their chronic inflammatory arthritis, and may respond to antibiotic therapy. The response to ceftriaxone in patients with even weakly reactive Lyme titers encourages further prospective placebo-controlled studies of antibiotics in various subsets of chronic arthritis.     

Joint inflammation and chondrocyte death become independent of Fcγ receptor type III by local overexpression of interferon‐γ during immune complex–mediated arthritis

Objective

It has previously been shown that the onset and the degree of joint inflammation during immune complex (IC)–mediated arthritis depend on Fcγ receptor type III (FcγRIII). Local adenoviral overexpression of interferon‐γ (IFNγ) in the knee joint prior to onset of IC‐mediated arthritis aggravated severe cartilage destruction. In FcγRI^−/− mice, however, chondrocyte death was not enhanced by IFNγ, whereas matrix metalloproteinase (MMP)–mediated aggrecan breakdown was markedly elevated, suggesting a role for the activating FcγRIII in the latter process. We undertook this study to determine the role of FcγRIII in joint inflammation and severe cartilage destruction in IFNγ‐stimulated IC‐mediated arthritis, using FcγRIII^−/− mice.

Methods

FcγRIII^−/− and wild‐type (WT) mice were injected in the knee joint with recombinant adenovirus encoding murine IFNγ (AdIFNγ) or with adenovirus encoding enhanced green fluorescent protein 1 day prior to induction of IC‐mediated arthritis. Histologic sections were obtained 3 days after arthritis onset to study inflammation and cartilage damage. MMP‐mediated expression of the VDIPEN neoepitope was detected by immunolocalization. Chemokine and FcγR expression levels were determined in synovial washouts and synovium, respectively.

Results

Injection of AdIFNγ in naive knee joints markedly increased levels of messenger RNA for FcγRI, FcγRII, and FcγRIII. Upon IFNγ overexpression prior to induction of IC‐mediated arthritis, joint inflammation was similar in FcγRIII^−/− and WT mice. The percentage of macrophages in the knee joint was increased, which correlated with high concentrations of the macrophage attractant macrophage inflammatory protein 1α. Furthermore, IFNγ induced 2‐fold and 3‐fold increases in chondrocyte death in WT controls and FcγRIII^−/− mice, respectively. Notably, VDIPEN expression also remained high in FcγRIII^−/− mice.

Conclusion

IFNγ bypasses the dependence on FcγRIII in the development of IC‐mediated arthritis. Furthermore, both FcγRI and FcγRIII can mediate MMP‐dependent cartilage matrix destruction.

     

Early reduction of infected hepatocytes by activated immunity at the time of interferon withdrawal hepatitis followed by lamivudine administration resulted in higher seroconversion in hepatitis Be antigen-positive patients with chronic hepatitis B

Background It has been found that the efficacy of lamivudine (LAM) therapy can be improved by preceding administration with a short course of corticosteroid that induces a flare of the disease upon its withdrawal. Because of the side effects of corticosteroid, we tested the effect of a short course of interferon (IFN) as the primer instead of prednisolone, which was followed by LAM when the hepatitis flare occurred. The incidence of LAM resistance mutations and the effect of core promoter and precore mutations on the durability of the responses were also studied. Methods Patients treated with interferon (IFN)-LAM therapy (n = 73) were compared to those treated with IFN alone (n = 117). The IFN-LAM group received IFN-α MU/day, t.i.w. for a 3-month period. LAM (10mg/day during 1 year) was started when IFN withdrawal hepatitis occurred during 2–10 months after stopping IFN. The LAM-resistant, core promoter, and precore mutations were examined by sequencing. Results (1) The IFN-LAM group developed exacerbated hepatitis following IFN withdrawal in 63 patients before starting LAM therapy. The seroconversion (SC) rate was significantly higher in the IFN-LAM group than in the IFN-alone group (61% vs 26%, P = 0.0001). (2) The LAM resistance mutation rate was 31% at 1 year after initiating LAM therapy. (3) In a stepwise discriminant-function analysis, decreased level of HBeAg determined at 4 weeks after LAM administration and increased level of HBeAb before the start of LAM administration contributed significantly on seroconversion to anti-HBe (P = 0.0073 and 0.004, respectively). (4) The reappearance rate of HBeAg within 6 months after the therapy (relapse) was 33% in the IFN-LAM group and 10% in the IFN-alone group. The prevalence of core promoter and precore mutations did not change before and after the therapy, nor did these mutations correlate with the relapse after stopping IFN-LAM therapy. Conclusions (1) Our findings suggest that early reduction of infected hepatocytes expressed by HBeAg by LAM may contribute to a high SC rate of IFN-LAM therapy. (2) The emergence of LAM-resistant mutations was similar to the previously reported rate, and neither core promoter nor precore mutations correlated with relapse of seroconverters after IFN-LAM withdrawal.     

Risk factors for serious infection during treatment with cyclophosphamide and high-dose corticosteroids for systemic lupus erythematosus

Objective. To determine risk factors for serious infection during treatment with cyclophosphamide (CYC) and high-dose corticosteroids in systemic lupus erythematosus (SLE). Methods. Records of 100 SLE patients who had received CYC were examined for documentation of serious infections that occurred during CYC therapy and the subsequent 3 months. Results. Infection occurred in 45 of 100 patients during CYC therapy. Patients with infection were more likely to have multiple organ disease (49% versus 29%; P = 0.04), a lower nadir in the white blood cell (WBC) count (2,818 versus 3,558 cells/μl; P = 0.02), and a higher maximum corticosteroid dose (195 versus 73 mg; P ≤ 0.01) than patients without infection. Infection occurred with equal prevalence in those who received intravenous (IV) (39%) or oral (40%) CYC, but was more common with use of sequential IV and oral therapy (68%). By multivariate analysis, the strongest association with infection was a WBC nadir ≤3,000 cells/μl (odds ratio [OR] 2.8, 95% confidence interval [95% CI] 1.4–5.5) and use of sequential IV and oral CYC (OR 2.3, 95% CI 1.2–4.3). Infection occurred in more CYC-treated patients taking concomitant steroids than in those treated with high-dose steroids alone (45% versus 12%; P = 0.001). Fatal and opportunistic infections during CYC therapy were associated with a low WBC nadir and a high maximum corticosteroid dose. Conclusion. The risk of serious infection in patients with SLE is influenced by the inclusion of CYC in the treatment regimen. The likelihood of infection in this setting is enhanced by CYC-induced reductions in the total WBC count <3,000 cells/μl and by sequential IV and oral therapy. Both of these factors may be indicators of aggressive cytotoxic treatment, underscoring the need for close observation during treatment to minimize the risk of serious infection.     

Treatment of staphylococcal septic arthritis in rabbits by systemic antibiotics and intra-articular corticosteroids

OBJECTIVE—To assess the effect of intra-articular corticosteroids added to systemic antibiotics in experimental septic arthritis.
METHODS—Rabbits were injected intra-articularely by Staphylococcus epidermidis. Rabbits received no additional treatment and served as control (group 1), were treated with systemic antibiotics (group 2), or treated with systemic antibiotics and intra-articular corticosteroids (group 3). After 15 days animals were killed and joint histopathological-histochemical parameters were assessed.
RESULTS—All rabbits survived the experiment. The treated groups (2-3) had lower histological-histochemical scores in comparison with the untreated group (1). Group 3 had significantly lower scores in joint sections in comparison with group 2: (mean (SD) 6.5 (1.4) v 4.0 (1.0), p=0.001 and 7.4 (2.6) v 4.2 (2.2), p= 0.01), because of lower damage expressed in clustering of chondrocytes, pannus formation, proteoglycan depletion, and synovitis.
CONCLUSION—Addition of local corticosteroids to systemic antibiotics in septic arthritis seems to be harmless, and improves joint histological-histochemical parameters in this experimental setting.

Keywords: infectious arthritis; corticosteroids; rabbits     

Interferon‐γ protects against the development of structural damage in experimental arthritis by regulating polymorphonuclear neutrophil influx into diseased joints

Objective

Local interaction between soluble mediators within the inflamed synovium is a key factor that governs the pathologic outcome of inflammatory arthritides. Our aim was to investigate the interplay between the Th1 lymphokine interferon‐γ (IFNγ) and pivotal cytokines that drive rheumatoid arthritis (RA) pathology (interleukin‐1β [IL‐1β] and tumor necrosis factor α [TNFα]) in modulating inflammation and arthritis in vitro and in vivo.

Methods

Monarticular antigen‐induced arthritis (AIA) was initiated in IFNγ‐deficient (IFNγ^−/−) mice and age‐matched wild‐type (IFNγ^+/+) mice. Joint swelling was measured and histologic analysis was performed in order to assess changes in both inflammatory and degenerative parameters in vivo. In vitro, the influence of IFNγ in regulating IL‐1β– and TNFα‐driven CXCL8 and CCL2 production was quantified by enzyme‐linked immunosorbent assay.

Results

In murine AIA, both inflammatory and degenerative arthritis parameters were significantly exacerbated in the absence of IFNγ. IFNγ appeared to be a crucial factor in regulating CXCR2+ neutrophil influx in the joint. In in vitro studies using RA fibroblast‐like synoviocytes, IFNγ modulated both IL‐1β– and TNFα‐driven chemokine synthesis, resulting in the down‐regulation of CXCL8 production.

Conclusion

IFNγ exerts antiinflammatory, chondroprotective, and antiosteoclastogenic effects in murine AIA through a mechanism that involves the regulation of chemokine synthesis and local neutrophil recruitment. These studies suggest a potential therapeutic role of modulating IFNγ signaling in the treatment of inflammatory arthritides.

     

Comparison between oral and systemic antibiotics and their combined use for the prevention of complications in colorectal surgery

Ninety patients were included in this prospective randomized trial. Each required elective colorectal surgery and was prepared for operation with oral preoperative antibiotic therapy, systemic peroperative therapy, or by a combination of both. The number of each type of septic postoperative complication and their total did not differ between the group treated by oral antibiotics prior to operation and the group treated peroperatively with systemic antibiotic therapy. The total number of septic complications (wall abscesses, fistulas, subdiaphragmatic abscesses, septicemia, peritonitis), however, was significantly less (P<0.05) in the group treated by both preoperative oral antibiotics and peroperative systemic antibiotic therapy (3.3 per cent) than in either groups treated only orally preoperatively (30 per cent) or by systemic antibiotic therapy during the operation (23 per cent). The combination of oral antibiotic therapy prior to operation and of systemic peroperative antibiotic therapy, therefore, presents the most effective prophylactic effectiveness.     

Intraarticular corticosteroids in refractory childhood Lyme arthritis

Lyme arthritis caused by infection with Borrelia burgdorferi is a common late manifestation of Lyme borreliosis. Current treatment recommendations include at least one oral or intravenous antibiotic course, followed by antirheumatic therapy in case of refractory arthritis. We reviewed the course of 31 children with Lyme arthritis who had received antibiotic treatment and assessed outcome and requirement of antirheumatic therapy. Of a total of 31 patients, 23 (74 %) showed complete resolution of arthritis after one or two courses of antibiotics, whereas in 8 patients (28 %), steroid injections had been performed due to relapsing or remaining symptoms. All of these 8 patients showed immediate resolution of symptoms after intraarticular steroid injections. Four of them (50 %) remained asymptomatic so far with a follow-up period between five up to 40 months. In two cases, multiple intraarticular corticosteroid injections were required; three patients received additional or consecutive treatment with systemic antirheumatic treatment. Patients with antibiotic refractory arthritis showed a higher rate of positivity of the IgG p58 and OspC immunoblot bands (p = 0.05) at presentation. Antibodies against OspA, an indicator of later stage infection, occurred more frequently in the refractory group without reaching significant level. No clinical marker as indicator for severe or prolonged course of Lyme arthritis was identifiable. A quarter of childhood Lyme arthritis patients were refractory to antibiotics and required antirheumatic treatment. Intraarticular steroid injections in childhood Lyme arthritis refractory to antibiotics can lead to marked clinical improvement.     

Status of Borrelia burgdorferi infection after antibiotic treatment and the effects of corticosteroids: An experimental study

Sixteen specific-pathogen-free beagles were infected with Borrelia burgdorferi. Three groups of 4 dogs were treated with antibiotics for 30 consecutive days starting 120 days after tick exposure; 4 dogs were untreated controls. At day 420 after tick exposure and again before euthanasia, 2 dogs of each group were treated with prednisone for 14 days. All dogs contracted infection and 11 developed acute arthritis 50-120 days after exposure. After day 120, one of 12 antibiotic-treated dogs and 2 of 4 untreated dogs became lame. Antibiotic therapy reduced the frequency of Borrelia-positivity in subsequent skin biopsy samples. After prednisone treatment, both control dogs developed severe polyarthritis. At euthanasia, single tissues of the antibiotic-treated dogs and multiple tissues of all control dogs were Borrelia-positive by polymerase chain reaction. Viable spirochetes were not recovered from antibiotic-treated dogs. Two antibiotic-treated dogs showed histologic evidence of minimal lesions, whereas all control dogs had mild polyarthritis with periarteritis.     

Suppression of renal disease and arthritis,and prolongation of survival in MRL-lpr mice treated with an extract of tripterygium wilfordii hook F

Objective. Treatment of MRL-lpr/lpr mice with Tripterygium wilfordii Hook f (TWHf) to evaluate its effects on mortality, renal disease, and arthritis. Methods. Mice were fed water (group A, control), TWHf (group B), or first water and then TWHf (group C) from age 7 weeks until age 21 weeks. Results. Arthritis and glomerulonephritis were decreased in groups B and C mice, and survival was increased in group B mice. Conclusion. TWHf decreases the mortality rate, and severity of glomerulonephritis and arthritis in MRL-Ipr/lpr mice.