Exacerbation Of Arthritis Research Articles

Modulation of inflammation and response to dexamethasone by Annexin 1 in antigen-induced arthritis.

Annexin 1 (Anx-1) is a putative mediator of the antiinflammatory actions of glucocorticoids (GCs). This study investigated the role of Anx-1 in experimental arthritis and in GC-mediated inhibition of inflammation, using antigen-induced arthritis (AIA) in Anx-1 knockout (Anx-1(-/-)) mice. Arthritis was induced by intraarticular injection of methylated BSA (mBSA) in mice preimmunized with mBSA. Disease was assessed after 7 days by histologic examination of the knee joints. Serum levels of anti-mBSA IgG were determined by enzyme-linked immunosorbent assay. Cytokine messenger RNA (mRNA) expression was detected by real-time polymerase chain reaction. A significant exacerbation of arthritis was observed in the Anx-1(-/-) mice compared with wild-type (WT) mice. This was associated with increased mRNA expression of synovial interleukin-1 beta, tumor necrosis factor alpha, interleukin-6, and macrophage migration inhibitory factor. Dexamethasone significantly reduced the histologic severity of synovitis and bone damage in the WT mice, but exerted no inhibitory effects in the Anx-1(-/-) mice, and also significantly reduced the serum levels of anti-mBSA IgG and the numbers of peripheral blood neutrophils and lymphocytes in WT mice, but had no such effect in Anx-1(-/-) mice. Anx-1 exerts endogenous antiinflammatory effects on AIA via the regulation of cytokine gene expression, and also mediates the antiinflammatory actions of dexamethasone in AIA.

Development of inflammation in proteoglycan-induced arthritis is dependent on Fc gamma R regulation of the cytokine/chemokine environment.

FcgammaRs are specialized cell surface receptors that coordinately regulate immune responses. Although FcgammaR expression is a prerequisite for the development of several immune complex-mediated diseases, the mechanism responsible for FcgammaR-dependent regulation in autoimmunity remains unclear. Therefore, we assessed FcgammaR-dependent regulation of inflammation in proteoglycan-induced arthritis (PGIA) using FcgammaR(-/-) mice. FcgammaRIIb(-/-) mice developed arthritis at an earlier time point and with a greater severity than wild-type (WT) mice. In gamma-chain(-/-) (FcgammaRI(-/-) and FcgammaRIII(-/-)) mice, no clinical or histological evidence of inflammation was observed. Exacerbation of arthritis in FcgammaRIIb(-/-) mice correlated with enhanced PG-specific Ab production, but did not significantly affect PG-specific T cell priming. In gamma-chain(-/-) mice, the absence of arthritis did not correlate with serum Ab responses, as PG-specific Ab production was normal. Although PG-specific T cell proliferation was diminished, spleen cells from gamma-chain(-/-) mice successfully adoptively transferred arthritis into SCID mice. Our studies indicated that the mechanism responsible for FcgammaR regulation of PGIA development was at the level of inflammatory cytokine and beta-chemokine expression within the joint. FcgammaRIIb regulated the development of PGIA by controlling the initiation of cytokine and chemokine expression within the joint before the onset of arthritis, whereas the expression of FcgammaRI and or FcgammaRIII controlled cytokine and chemokine expression late in the development of PGIA during the onset of disease. These results suggest that FcgammaRs are critical for the development of inflammation during PGIA, possibly by maintaining or enhancing inflammatory cytokine and beta-chemokine production.

IL-4 and IL-12 regulate proteoglycan-induced arthritis through Stat-dependent mechanisms.

IL-4, a well-recognized modulator of macrophage activation, is perceived as an anti-inflammatory cytokine; however, under certain circumstances IL-4 may function as a proinflammatory cytokine. We have previously demonstrated that IL-4 treatment of mice with proteoglycan-induced arthritis (PGIA) inhibited the development of disease. To determine whether the capacity of IL-4 to inhibit disease is dependent on IL-4-mediated regulation of IL-12, we assessed the requirement for IL-4 in modulating development of PGIA. Immunization of mice, lacking IL-4 and Stat6, with proteoglycan results in a significant increase in arthritis severity in comparison to wild-type controls, suggesting that arthritis severity is regulated by IL-4 through a Stat6-dependent mechanism. Concomitant with exacerbated disease in IL-4(-/-) mice, there is a significant increase in the systemic production of proinflammatory cytokines IL-12, TNF-alpha, and IFN-gamma and in levels of mRNA transcripts for proinflammatory cytokines and chemokines in joints. Disease is suppressed in Stat4(-/-) mice indicating that elevated levels of IL-12 contribute to exacerbation of arthritis and that suppression is accompanied by reduced levels of IFN-gamma production. In support of this, IFN-gamma(-/-) mice are protected from PGIA and the degree of inflammation is similar to Stat4(-/-) mice. The decrease in disease severity in IFN-gamma(-/-) and Stat4(-/-) mice correlates with diminished TNF-alpha levels but there is no switch to a Th2-type response. Taken together, these results suggest that IL-4 regulates the severity of disease in PGIA by controlling IL-12 production, which in turn regulates the magnitude of IFN-gamma expression through a Stat4-dependent pathway.

Exacerbation of acute inflammatory arthritis by the colony-stimulating factors CSF-1 and granulocyte macrophage (GM)-CSF: evidence of macrophage infiltration and local proliferation.

CSF-1 and GM-CSF have been implicated in the pathogenesis of rheumatoid arthritis. We report the effects of CSF-1 and GM-CSF in the development of an acute methylated bovine serum albumin (mBSA)-induced murine arthritis model. Examination of histopathological features revealed that the systemic administration of CSF-1 or GM-CSF following mBSA administration into the knee resulted in the exacerbation of arthritis. This included synovial hyperplasia and joint inflammation, most evident at 7 and 14 days post-mBSA administration, and the appearance of erosive pannus tissue. The exacerbation by CSF-1 and GM-CSF was not sustained but declined in incidence and severity by 21 days post-mBSA administration, similar to the effects of IL-1beta in this model, reported here and previously. Macrophages expressing Mac-2 and F4/80 were a prominent feature of the pathology observed, particularly the infiltration of Mac-2+ macrophages seen in all mice administered CSF-1, GM-CSF or IL-1beta. Present in inflamed knees was a locally dividing population of cells which included Mac-2+ and F4/80+ macrophages. These studies demonstrate that CSF-1 and GM-CSF can exacerbate and prolong the histopathology of acute inflammatory arthritis and lend support to monocytes/macrophages being a driving influence in the pathogenesis of inflammatory arthritis.

Unmethylated oligo-DNA containing CpG motifs aggravates collagen-induced arthritis in mice.

To investigate the effects of an intradermal injection of an unmethylated oligodeoxynucleotide (ODN) containing CpG motifs on the severity of collagen-induced arthritis (CIA). CIA was induced in DBA/1 LacJ mice by immunization with bovine type II collagen (CII) in Freund's complete adjuvant followed 3 weeks later by immunization with CII in Freund's incomplete adjuvant (yielding CIA mice). Unmethylated ODN containing a CpG motif was injected intradermally into DBA/1 LacJ mice at a dosage of 20 microg (yielding CpG-CIA mice) 1 week prior to the first immunization with CII. Unmethylated ODN containing a GpC motif instead of a CpG motif and ODN containing a methylated CpG motif were used to produce controls (GpC-CIA mice and mCpG-CIA mice, respectively). After the second immunization with CII, arthritis scores were measured weekly up to the eighth week. At the eighth week, the mice were killed, histopathologic changes in the ankle joints were examined, and titers of interferon-gamma (IFNgamma) in the supernatants of splenocytes (1 x 10(7)) stimulated in culture by CII for 3 days were determined by enzyme-linked immunosorbent assay. CpG-CIA mice had significantly higher arthritis scores than CIA mice. CpG-CIA mice had more severe histopathologic changes than CIA mice and mCpG-CIA mice. Moreover, splenocytes in CpG-CIA mice produced higher IFNgamma titers in response to CII than did splenocytes in CIA mice and mCpG-CIA mice. Injection of unmethylated oligo-DNA containing CpG motifs aggravated CIA through activation of the Th1-type immune response, suggesting that microbial infection could be one of the mechanisms for aggravation or exacerbation of arthritis or, alternatively, that such infection could be an adjuvant in the induction of arthritis in rheumatoid arthritis.

Dual role of IL-12 in early and late stages of murine collagen type II arthritis.

IL-12 can promote Th1 responses, and early administration of IL-12 during immunization was shown to enhance expression of autoimmune collagen-induced arthritis (CIA). We now studied the impact of IL-12 at the stage of disease expression and during established CIA in DBA-1 mice. Accelerated onset and enhanced severity were provoked when i.p. injections of 100 ng of murine IL-12 (mIL-12) were given around the time of arthritis onset. Moreover, the onset of CIA could be ameliorated with anti-mIL-12 Abs, indicating that IL-12 is a pivotal mediator in the expression of CIA. In addition, the effect of anti-mIL-12 treatment was analyzed in established CIA. Continued treatment did not suppress established arthritis. Instead, these mice showed an impressive exacerbation of arthritis shortly after cessation of anti-mIL-12 treatment, indicative of impairment of endogenous control. Exaggerated disease was characterized by massive granulocyte influx and enhanced expression of IL-1 beta and TNF-alpha mRNA in the synovial tissue. Subsequently, we treated established collagen arthritis with recombinant mIL-12 for 7 days. Profound suppression of the arthritis score was noted, including reduced influx of cells and diminished cartilage damage. Tenfold enhanced levels of IL-10 were detected in sera of mIL-12-treated mice, and up-regulated mRNA levels of IL-10, IFN-gamma, and IL-12 were measured in synovial tissue. Finally, the anti-inflammatory effect of IL-12 on CIA could be reversed by coadministration of anti-IL-10 Abs. This study indicates that IL-12 has a stimulatory role in early arthritis expression, whereas it has a suppressive role in the established phase of collagen arthritis.

Mycoplasma genitalium in the joints of two patients with arthritis

Mycoplasma genitalium was sought in synovial fluids from 13 patients, of whom five had Reiter's syndrome, four had rheumatoid arthritis, and one each had systemic lupus erythematosus, psoriatic arthritis, rheumatic fever and undefined arthritis. The mycoplasma was detected by a PCR assay in the knee joint of a 25-year-old man with Reiter's syndrome, from whom urethral ureaplasmas were isolated and whose synovial fluid mononuclear cells responded to ureaplasmal antigens in a proliferation assay. Mycoplasma genitalium was also detected in the knee joint during an exacerbation of arthritis in a 58-year-old man who had had seronegative juvenile polyarthritis that had evolved to seronegative rheumatoid arthritis.

Exacerbation of Established Collagen‐Induced Arthritis in Mice Treated with An Anti—T Cell Receptor Antibody

To investigate the effect of T cell depletion on established collagen-induced arthritis (CIA) in mice, using monoclonal antibodies (MAb) to T cell receptor alpha/beta (TCR alpha/beta). In addition, experiments using anti-CD3 MAb were performed for comparison. CIA was induced in male DBA/1 mice by immunizing them twice with bovine type II collagen (CII). The arthritis score and anti-CII antibody titers were examined serially. Proportions of T cells were determined by fluorescence-activated cell sorter (FACS) analysis on spleen cells or peripheral blood cells. When anti-TCR alpha/beta MAb was injected on the day of CII priming, no arthritis was detected in association with depressed anti-CII antibody titers. Unexpectedly, however, when MAb was given after arthritis was established, a rapid exacerbation of arthritis was observed, which resulted in ankylosis of most joints. Anti-CII antibody titers were not affected. The addition of anti-TCR gamma/delta MAb had no effect on the augmented arthritis. T cell depletion by anti-CD3 MAb during established CIA also caused an enhancement of arthritis, which was, however, weak and only transient. FACS analysis revealed that the early improvement of arthritis after the transient augmentation seen in the mice treated with anti-CD3 MAb paralleled the early recovery of alpha/beta T cells in the periphery. The present results support the concept that alpha/beta T cells, in general, may play a regulatory role in the clinical course of murine CIA after disease onset. Therefore, caution is recommended when using intensive T cell-targeted therapy in patients with rheumatoid arthritis.

Triggering and exacerbation of autoimmune arthritis by the Mycoplasma arthritidis superantigen MAM.

It has been postulated that superantigens might play a role in the human rheumatic diseases, by activation of self-reactive T cells or by induction of autoantibodies. The Mycoplasma arthritidis superantigen MAM, which is derived from a naturally occurring murine arthitogenic mycoplasma, uses certain V beta chains of the murine T cell receptor (TCR) that have been proposed to be involved in murine collagen-induced arthritis (CIA). The present study was designed to determine whether MAM influences the course of arthritis mediated by immunization with porcine type II collagen (PII). MAM or phosphate buffered saline (PBS) was injected locally or systemically into mice convalescing from CIA or mice suboptimally immunized with collagen. In contrast to PBS, MAM caused an exacerbation of arthritis in mice that were recovering from CIA. MAM also triggered arthritis onset in mice that had been suboptimally immunized with PII up to 160 days previously. Injection of MAM during the onset phase of CIA also triggered and enhanced the severity of arthritis in mice given low doses of PII. MAM can both trigger and exacerbate murine autoimmune arthritis induced by immunization with type II collagen. Since T cells bearing the same V beta TCRs as are used by MAM have been found to comprise a major portion of the activated cells in the synovial tissue of patients with rheumatoid arthritis, it is possible that superantigens similar to MAM may play a role in this human disease.

The triggering role of physical injury in the onset of peripheral arthritis in seronegative spondyloarthropathy

Three more cases of B27-positive patients who developed peripheral arthritis immediately after trauma are reported. The first had an exacerbation of arthritis in the right hip after falling from her motor-bike. The second had arthritis of the distal interphalangeal (DIP) joint of the right forefinger after shutting his finger in the door of his car. The third had arthritis of the right sternoclavicular joint after a road-accident while fastening her safety belt.

Constant darkness enhances autoimmunity to type II collagen and exaggerates development of collagen-induced arthritis in DBA/1 mice

The humoral function of the pineal gland is known to be strongly dependent on environmental lighting. Melatonin, the best characterized of the photo-dependent pineal hormones, has been reported to affect immune responses in mice. It has been hypothesized that the development of some types of psychosomatic and autoimmune disease could be due to a disturbed release of this hormone. The present investigation was performed in order to evaluate effects of constant darkness (physiological stimulation of pineal melatonin synthesis) and constant light (physiological suppression of pineal melatonin synthesis) on the course of an experimental autoimmune model, the type II collagen-induced arthritis (CIA) in DBA/1 female mice. Mice kept in darkness develop more severe arthritis than those kept in constant light or in a normal dark/light rhythm (12 h light/12 h dark). Levels of anti-type II collagen antibodies were higher in mice kept in darkness, and the spleens of these animals were enlarged. Since castration of female DBA/1 mice enhances the severity of CIA, and since melatonin is known to exert effects on gonadal function, the experiment was repeated using oophorectomized mice. The same difference in arthritis severity between darkness- and light-exposed mice was obtained in this second experiment. We conclude that the exacerbation of arthritis in darkness is due to a darkness-induced change in levels of critical neurohumoral compound(s), that via gonadal independent mechanisms affect the autoimmune response. The exaggerated severity and chronicity of arthritis may be due to higher levels of melatonin in these animals.

Exacerbation of arthritis by IL-1 in rat joints previously injured by peptidoglycan-polysaccharide.

The arthropathic activity of mouse recombinant IL-1 (mrIL-1) after intraarticular (i.a.) injection into rat ankles was investigated. Nanogram quantities of either mrIL-1 alpha or mrIL-1 beta induced an acute transient arthritis. Arthritis induced by i.a. mrIL-1 developed more rapidly and was more severe in ankles previously injured by i.a. injection of group A streptococcal peptidoglycan-polysaccharide (PG-APS) fragments. In addition, a protracted pain response, as judged by severe limping, occurred 60 to 90 min after mrIL-1 injection into joints previously injured by PG-APS or 4 to 6 h after mrIL-1 injection into naive joints. The severity of arthritis was related to the mrIL-1 dose. Arthropathic activity of mrIL-1 alpha was neutralized by goat anti-mouse IL-1 alpha IgG, and the activity of both the alpha and beta preparations was heat labile. Repeated episodes of acute inflammation were induced by repeated i.a. injection of mrIL-1. In naive ankles this led to chronic synovitis without histologic evidence of erosions. However, in joints previously injured by PG-APS, repeated mrIL-1 injection induced a more severe chronic synovitis with a 50% incidence of early pannus formation and limited marginal erosions of cartilage and subchondral bone. Thus, mrIL-1 induces an acute exacerbation of arthritis in joints previously injured by PG-APS and repeated exposure of these joints to mrIL-1 promotes chronic erosive synovitis. These studies provide evidence for an in vivo function of IL-1 and are consistent with its role as one of the mediators in the local regulation of inflammation in recurrences of arthritis induced by bacterial cell wall polymers.

PLATELET SEROTONIN RELEASE IN RHEUMATOID ARTHRITIS: A STUDY IN FOOD-INTOLERANT PATIENTS

Serotonin and 5-hydroxyindoleacetic acid levels in platelet-rich plasma were determined in serial samples obtained before and up to 6 h after food-challenge in 7 patients showing inflammation of the joints after ingestion of certain foods. Exacerbation of arthritis was associated with a fall in serotonin levels and a subsequent increase in 5-hydroxyindoleacetic acid. These data suggest that serotonin may be released from platelets during food challenges and that platelet serotonin release may contribute to joint inflammation.

Adult-onset Still's disease. Twenty-year followup and further studies of patients with active disease.

Eleven female patients with adult-onset Still's disease were followed for 7-36 years (mean 20.2 years) after the onset of their illness. Ten of these patients had a chronic course characterized by remissions and exacerbations of arthritis associated with fever and rash. Five patients had terminal interphalangeal involvement, and carpal ankylosis was demonstrated on x-ray film in 10. Two patients developed a widespread polyarthritis, and renal amyloidosis was diagnosed 10 years after disease onset in the most severely affected patient. In 4 patients studied during an exacerbation of the disease, circulating immune complexes were detected by the staphylococcal A binding assay, but not by the C1q binding assay. Synovial fluid analysis in 1 patient revealed a low C3 level and total hemolytic complement (CH50) together with immune complexes and IgG rheumatoid factor. Immune complexes were not identified in the characteristic Still's rash by immunofluorescence or electron microscopy, although mast cell degranulation, neutrophil lysis, and perivascular fibrin deposition were reminiscent of immune complex--mediated vascular injury. The clinical and laboratory features as well as the long-term course of adult- and juvenile-onset systemic Still's disease are similar, but further studies of genetic markers and immunopathology are required to establish a common pathophysiology.

Ferastral® in the Treatment of Patients with Inflammatory Anaemia

An investigation has been performed with a new parenteral iron preparation, iron-poly-(sorbitol-gluconic acid) complex (Ferastral) in the treatment with iron deficiency anaemia associated with inflammatory diseases, mainly rheumatoid arthritis. Fifteen moderately anaemic patients entered into the trial. These patients constituted a special group in whom the MCHCs were subnormal. Observations were made concerning the occurrence of side-effects. Particular attention was paid to those-side-effects which are known to be associated with the use of parenteral iron preparations in the treatment of rheumatoid subjects. Ferastral was administered by intramuscular by intramuscular injection. The single doses given on any one occasion varied from a minimum of 100 mg to a maximum of 500 mg, divided into two separate injections. The results of therapy, measured at eight weeks, showed significant increases in haemoglobin concentrations. Increases in erythrocyte count, MCHC and serum-iron concentration were also found. There were no signs of acute toxic effects with Ferastral and in no patient was there exacerbation of arthritis as has been previously reported with iron-dextran.

Roentgen Therapy for Psoriasis of the Nails and Psoriatic Arthritis

Psoriasis of the nails is usually charracterized by pitting, brownish discoloration of the nail bed, leukonychia, cracking of the free edges, and subungual hyperkeratosis. Among the remedies suggested for treatment of this lesion, the use of roentgen rays is one of the most prominent. Most writers suggest treating the nails after carefully protecting the nail base from the roentgen rays. Because of the fact that arthritis of the distal joints of the hands or feet (or both) occurs not infrequently in cases of psoriasis, we have tried, during the past five years, a different method of treatment with roentgen rays, applying them to the dorsum of the hands in a field extending from the nail tips to the wrists, and to the dorsum of the feet in a field from the tips of the nails to the ankles. We have used this method of treatment whether the individual patient did or did not have arthritis as a complication of his psoriasis. We have given treatment in 24 cases in which the diagnosis of psoriasis of the nails was unquestionable. Of these, six showed involvement of the fingernails only, and 18 showed involvement of the nails of both hands and feet. Of these 24 patients, nine had arthritis of the distal joints. The history of the patients with arthritis complicating psoriasis is interesting because, with development of psoriatic changes in the nails, there was usually a definite exacerbation of arthritis with pain and periarticular swelling. Roentgenologic studies of the joints showed no definite changes, but only some periarticular swelling. In this series of cases, the average duration of symptoms was approximately seven years. The shortest duration was three months and the longest twenty years. The method of roentgen therapy in this series of cases has been to expose the hands or feet in the manner mentioned previously. The treatments are given with roentgen rays generated at approximately 130 kv., constant potential, filtered through 4 mm. of aluminum for the hands, and through 6 mm. of aluminum for the feet. The dose for each treatment is about 300 r (measured in air). The treatments are usually repeated twice, at monthly intervals. After the third, no further treatments are given. We feel that at least three months must be allowed to elapse before the results can be definitely evaluated. In the cases in which arthritis was a complication, symptomatic improvement has been manifest after the first treatment, but at times an exacerbation of the pain and stiffness in the joints may be noted in the first few days after a treatment has been given. This exacerbation can be disregarded, as it lasts only a few days and quickly subsides. The results of treatment have been gratifying to us because in six cases complete remission of all changes in the nails occurred and no exacerbation has occurred to date.

Environmental Factors in Rheumatoid Arthritis: a Study of the Relationship between the Onset and Exacerbations of Arthritis and the Emotional or Environmental Factors

Environmental Factors in Rheumatoid Arthritis: a Study of the Relationship between the Onset and Exacerbations of Arthritis and the Emotional or Environmental Factors