The gut-joint axis: cross reactive food antibodies in rheumatoid arthritis.

BACKGROUND AND AIMS: Patients with rheumatoid arthritis (RA) often feel there is an association between food intake and rheumatoid disease severity. To investigate a putative immunological link between gut immunity and RA, food antibodies were measured in serum and perfusion fluid from the jejunum of RA patients and healthy controls to determine the systemic and mucosal immune response. METHODS: IgG, IgA, and IgM antibodies to dietary antigens were measured in serum and jejunal perfusion fluid from 14 RA patients and 20 healthy subjects. The antigens originated from cow's milk (alpha-lactalbumin, beta-lactoglobulin, casein), cereals, hen's egg (ovalbumin), cod fish, and pork meat. RESULTS: In intestinal fluid of many RA patients, all three immunoglobulin classes showed increased food specific activities. Except for IgM activity against beta-lactoglobulin, all other IgM activities were significantly increased irrespective of the total IgM level. The RA associated serum IgM antibody responses were relatively much less pronounced. Compared with IgM, the intestinal IgA activities were less consistently raised, with no significant increase against gliadin and casein. Considerable cross reactivity of IgM and IgA antibodies was documented by absorption tests. Although intestinal IgG activity to food was quite low, it was nevertheless significantly increased against many antigens in RA patients. Three of the five RA patients treated with sulfasalazine for 16 weeks had initially raised levels of intestinal food antibodies; these became normalised after treatment, but clinical improvement was better reflected in a reduced erythrocyte sedimentation rate. CONCLUSIONS: The production of cross reactive antibodies is strikingly increased in the gut of many RA patients. Their food related problems might reflect an adverse additive effect of multiple modest hypersensitivity reactions mediated, for instance, by immune complexes promoting autoimmune reactions in the joints.

A randomised placebo controlled 12 week trial of budesonide and prednisolone in rheumatoid arthritis.

OBJECTIVES: To compare budesonide, a locally acting glucocorticoid with minimal systemic exposure, with conventional glucocorticoid treatment and placebo in rheumatoid arthritis. METHODS: A double blind, randomised, controlled trial over 12 weeks in 143 patients with active rheumatoid arthritis, comparing budesonide 3 mg daily, budesonide 9 mg daily, prednisolone 7.5 mg daily, and placebo. Particular attention was paid to the pattern of clinical response and to changes in the four week period following discontinuation of treatment. RESULTS: There were improvements in tender joint count and swollen joint count on budesonide 9 mg compared with placebo (28% for tender and 34% for swollen joint counts, p<0.05). Prednisolone 7.5 mg gave similar results, while budesonide 3 mg was less effective. ACR20 response criteria were met by 25% of patients on placebo, 22% on budesonide 3 mg, 42% on budesonide 9 mg, and 56% on prednisolone 7.5 mg. A rapid and significant reduction in symptoms and signs in response to budesonide 9 mg and prednisolone 7.5 mg was evident by two weeks and maximal at eight weeks. There was no evidence that budesonide provided a different pattern of symptom control from prednisolone, or that symptoms became worse than placebo treatment levels after discontinuation of glucocorticoid treatment. Adverse effects attributable to glucocorticoids were equally common in all groups. CONCLUSIONS: The symptomatic benefits of budesonide 9 mg and prednisolone 7.5 mg are achieved within a short time of initiating treatment, are maintained for three months, and are not associated with any rebound in symptoms after stopping treatment.

Predisposing factors in sulphasalazine-induced systemic lupus erythematosus.

The aim of this study was to define predisposing factors in patients with sulphasalazine-induced systemic lupus erythematosus (SLE). Eleven patients with onset of SLE or SLE-like syndromes during sulphasalazine treatment are reported. Before the onset of SLE, five of the patients suffered from rheumatoid arthritis (RA), one from psoriatic arthropathy (PsoA), two from juvenile chronic arthritis (JCA) and three from ulcerative colitis (UC). At the time of diagnosis of drug-induced SLE, analysis of antinuclear antibodies (ANA), anti-double-stranded DNA antibodies (anti-dsDNA), anti-histone antibodies (anti-histones), acetylator status of the enzyme N-acetyltransferase 2 (NAT2) and HLA classification were performed. All patients were anti-DNA positive at disease onset and were determined to be slow acetylators. HLA A1 occurred in 4/10 patients, B8 in 5/10. HLA DR 3 was represented in one patient and DR 3(17) in five patients. The DQA1* 0501 allele was observed in 7/10 patients and DQB1 0201* in 6/10. Persistent SLE and development of nephritis were noted in patients with long duration of treatment and high cumulative dose of sulphasalazine (> 1000 g). In sulphasalazine-induced SLE, slow acetylator genotype and HLA haplotypes associated with idiopathic SLE seem to predict disease induction. Further, as the risk of developing persistent SLE and nephritis increases with long-standing sulphasalazine medication, it is of importance to monitor the patients with regard to signs of SLE during the entire treatment period.

Enhanced jejunal production of antibodies to Klebsiella and other Enterobacteria in patients with ankylosing spondylitis and rheumatoid arthritis.

OBJECTIVE: To measure gut immunity directly in jejunal fluid in patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA). METHODS: Antibodies against three different Enterobacterias were measured in jejunal perfusion fluids (collected by a double balloon perfusion device) of 19 patients with AS, 14 patients with RA, and 22 healthy controls using enzyme linked immunosorbent assay. RESULTS: The AS patients had significantly increased jejunal fluid concentrations of IgM, IgG, and IgA class antibodies against Klebsiella pneumoniae, and IgM and IgA class antibodies against Escherichia coli and Proteus mirabilis compared with healthy controls. When compared with the patients with RA, the AS patients had higher concentrations of IgA and IgG class antibodies only against K pneumoniae. The RA patients had higher IgM class antibody concentrations against all three studied Enterobacterias, when compared with the healthy controls, suggesting an enhanced mucosal immune response in these patients. A three month treatment with sulphasalazine did not decrease enterobacterial antibody concentrations in the 10 patients with AS. CONCLUSION: There is strong direct evidence for an abnormal mucosal humoral immune response particularly to K pneumoniae in patients with AS.

Evidence for differential effects of sulphasalazine on systemic and mucosal immunity in rheumatoid arthritis.

OBJECTIVE: To study the effects of sulphasalazine (SASP) on the systemic and mucosal humoral immune systems in patients with rheumatoid arthritis (RA). METHODS: Serum concentrations of interleukin 6 (IL-6), class and subclass specific IgG, IgA and IgM, IgA and IgG antigliadin antibodies and rheumatoid factors (RF) of IgG, IgA (including IgA1 and IgA2 subclasses) and IgM isotypes were measured before and 16 weeks after sulphasalazine (SASP) therapy in 15 female and three male patients with RA. Amounts of immunoglobulins in saliva and jejunal fluid were measured as estimates of mucosal humoral immunity. RESULTS: Serum concentrations of IgA and IgG decreased significantly during SASP therapy and correlated with reduced concentrations of IL-6. In addition, levels of circulating IgA RF, IgA anti-gliadin antibodies and IgM RF decreased significantly after the treatment. In contrast, immunoglobulin levels in saliva and jejunal fluid were unaltered. CONCLUSION: SASP exerts powerful but selective inhibitory effects on systemic immunoglobulin production, whereas no effects on mucosal immunoglobulin production were observed. The decreased systemic B cell activity may be mediated by downregulation of the production of IL-6, a cytokine with Ig switching properties.

Effect of sulphasalazine on gastrointestinal microflora and on mucosal heat shock protein expression in patients with rheumatoid arthritis.

This study was performed in order to elucidate a possible association between mucosal heat shock protein expression, the gastrointestinal microflora and disease activity in 17 patients with RA before and after 16 weeks of sulphasalazine (SASP) treatment. The duodenal-jejunal mucosal binding of the monoclonal antibody ML30, recognizing the 65 kDa heat shock protein of mycobacteria, was increased (P = 0.048) in the untreated RA patients compared to controls, but did not correlate to disease, activity or microflora and was not altered by SASP therapy. There was no convincing evidence for bacterial overgrowth in the jejunum and the faecal microflora was normal. SASP treatment altered the faecal microflora, with significant reductions of the total aerobic bacteria, Escherichia coli and Bacteroides, and increased numbers of Bacillus. SASP had only minor effects on the jejunal microflora. A high carriage frequency of Candida albicans was found in saliva and the counts correlated negatively with the unstimulated whole salivary secretion rate. These results suggest that the gut may be involved in the aetiopathogenesis of RA but do not substantiate the hypothesis that the anti-rheumatic effects of SASP are mediated via its anti-microbial properties. However, the possibility that a micro-organism, not detected in this study, may be of crucial importance in RA, cannot be ruled out.

Evidence of a local intestinal immunomodulatory effect of sulfasalazine in rheumatoid arthritis.

OBJECTIVE: To analyze whether the intestinal mucosa in rheumatoid arthritis (RA) is immunologically abnormal and whether sulfasalazine (SSZ) possesses any local intestinal immunoregulatory effect. METHODS: Lymphocyte subpopulations and HLA-DR expression were evaluated in biopsy specimens from the duodenal-jejunal mucosa and in peripheral blood samples obtained from 17 patients with RA, both before and after 16 weeks of SSZ treatment. The same mucosal assays were also performed in 7 controls. RESULTS: The mucosa of the small intestine in RA patients showed no differences in morphology, HLA-DR expression, or the amounts and distribution of CD3+, CD4+, CD8+, and gamma/delta + lymphocytes compared with the control group. However, there was a reduction in mucosal CD3+ and gamma/delta + lymphocyte numbers after SSZ therapy, which did not correspond to a change in peripheral blood CD3+ lymphocyte number. SSZ treatment also tended to diminish the peripheral blood CD4+:CD8+ cell ratio (P = 0.05). CONCLUSION: No signs of inflammation or immunologic abnormalities were seen in RA duodenal-jejunal mucosa. In this part of the intestine, however, SSZ exerted immunoregulatory effects that were not encountered in the peripheral blood.

Effects of antirheumatic treatment on gastric secretory function and salivary flow in patients with rheumatoid arthritis.

Many patients with rheumatoid arthritis have impaired gastric acid secretion and dysfunction of the lacrimal and salivary glands, conditions which have been proposed to be due to glandular atrophy. The hypothesis that the rheumatoid inflammation by itself has a depressive effect on these secretory functions was tested on 20 patients with active rheumatoid arthritis who underwent 16 weeks of sulphasalazine therapy. The patients responded well to the treatment, with reduction of joint indices and acute phase reactants. The resting and stimulated whole salivary secretion rate increased in 9/10 and 8/10 patients, respectively. The maximal gastric acid output increased in those patients who had a moderate reduction in acid output prior to treatment. When estimated by s-pepsinogen I, the gastric secretory capacity increased in all patients but one. In a group of auranofin treated patients, s-pepsinogen I rose only in those who responded to treatment with reduced disease activity. These results support the idea that the impaired secretory functions are at least partially reversible and probably also partly inflammatory mediated.

Treatment of drug-induced agranulocytosis with recombinant GM-CSF.

A 53-year male patient, treated for rheumatoid arthritis with sulphasalazine, developed a total agranulocytosis. When this state had prevailed for at least 10 d no bone marrow granulocyte progenitor cells were detectable. Intravenous GM-CSF treatment was initiated 5 d later, and the patient recovered within the next 6 d. GM-CSF treatment for severe agranulocytosis deserves further investigation.

Effect of sulphasalazine and sulphapyridine on neutrophil superoxide production: role of cytosolic free calcium.

As the neutrophil granulocyte plays an important part in rheumatoid inflammation the effect of sulphasalazine on neutrophil function was studied. The results show that sulphasalazine, and its metabolite sulphapyridine, inhibit neutrophil superoxide production elicited by the receptor mediated stimulus N-formyl-methionyl-leucyl-phenyl-alanine (fMLP) and by the calcium ionophore A23187. This effect seems to be dependent on inhibition of intracellular Ca++ increase as both substances reduce this increase upon cell activation with fMLP and A23187. Sulphasalazine and sulphapyridine do not inhibit superoxide production after stimulation with the ester phorbol myristate acetate, a stimulus response coupling which is independent of intracellular Ca++ increase. The reported inhibition of superoxide generation may explain, at least partly, the antirheumatic property of sulphasalazine.