Salivary gland and peripheral blood T helper 1 and 2 cell activity in Sjögren's syndrome compared with non-Sjögren's sicca syndrome.

OBJECTIVES: To investigate whether differences in T helper (Th) 1 and Th2 cell activity in salivary glands ("local") or ("peripheral") blood can discriminate between Sjögren's syndrome (SS) and non-Sjögren's sicca syndrome (nSS-sicca). Additionally, to study relationships of local and peripheral Th cell activities with each other and with disease activity measures. METHODS: 62 sicca patients (32 with SS, 30 with nSS-sicca) were studied. Local Th1 (interferon gamma (IFNgamma)) and Th2 (interleukin (IL) 4) activity were determined using immunohistochemistry. T cell production of IFNgamma and IL4 in peripheral blood (PB) was determined by ELISA. Erythrocyte sedimentation rate (ESR) and serum IgG were considered disease activity measures. RESULTS: ESR and serum IgG were higher in patients with SS than in patients with nSS-sicca. Local Th1 cell activity was higher and PB Th1 activity lower in patients with SS than in those with nSS-sicca. Th2 cell activity did not differ significantly between the patient groups. The ratio IFNgamma/IL4 was higher in salivary glands and lower in PB in patients with SS than in patients with nSS-sicca. Local and peripheral Th1 and Th2 cell activities correlated with ESR and serum IgG levels. ESR, serum IgG, and local or peripheral Th1 or Th2 cell activity did not discriminate between patients with SS and nSS-sicca. CONCLUSIONS: An imbalance between Th1 and Th2 activity in sicca patients is clearly related to the severity of disease, but cannot be used to distinguish between patients with SS and those with nSS-sicca.

Age-related decrease in susceptibility of human articular cartilage to matrix metalloproteinase-mediated degradation: the role of advanced glycation end products.

OBJECTIVE: Progressive destruction of articular cartilage is a hallmark of osteoarthritis (OA) and rheumatoid arthritis (RA). Age-related changes in cartilage may influence tissue destruction and thus progression of the disease. Therefore, the effect of age-related accumulation of advanced glycation end products (AGEs) on cartilage susceptibility to proteolytic degradation by matrix metalloproteinases (MMPs) present in synovial fluid (SF) of OA and RA patients was studied. METHODS: Cartilage was incubated with APMA-activated SF obtained from OA or RA patients, and tissue degradation was assessed by colorimetric measurement of glycosaminoglycan (GAG) release. Cartilage degradation was related to the level of AGEs in cartilage from donors of different ages (33-83 years) and in cartilage with in vitro-enhanced AGE levels (by incubation with ribose). MMP activity in SF was measured using a fluorogenic substrate. AGE levels were assessed by high-performance liquid chromatography measurement of the glycation product pentosidine. RESULTS: In cartilage from donors ages 33-83 years, a strong correlation was found between the age-related increase in pentosidine and the decrease in MMP-mediated tissue degradation (r = -0.74, P < 0.0005). Multiple regression analysis showed pentosidine to be the strongest predictor of the decreased GAG release (P < 0.0005); age did not contribute (P > 0.8). In addition, decreased MMP-mediated GAG release was proportional to increased pentosidine levels after in vitro enhancement of glycation (r = -0.27, P < 0.01). This was demonstrated for both OA and RA SF (for control versus glycated, P < 0.002 for all SF samples tested). CONCLUSION: Increased cartilage AGEs resulted in decreased cartilage degradation by MMPs from SF, indicating that aged cartilage is less sensitive than young cartilage to MMP-mediated cartilage degradation, such as occurs in OA and RA. Therefore, the level of cartilage glycation may influence the progression of these diseases.

Relation of plasma dexamethasone to clinical response.

OBJECTIVE: The clinical effects of high dosage pulse glucocorticosteroid (GS) infusion as a treatment for rheumatoid arthritis (RA) differ considerably between patients. The aim of the present study was to gain more insight into these differences in clinical response. METHODS: Twenty-three RA patients (6 M/17 F) with treatment-resistant active erosive disease were treated with GS pulse therapy, consisting of 3 infusions of 200 mg dexamethasone at 3-day intervals. Plasma dexamethasone and plasma cortisol levels, as well as the mononuclear cell glucocorticosteroid receptor density, were determined on days 0, 2, 6, 12 and 40 after the start of therapy. Clinical evaluation consisted of the Thompson articular index, the erythrocyte sedimentation rate (ESR), and the serum concentration of C reactive protein (CRP). RESULTS: Plasma dexamethasone levels in RA patients determined during pulse therapy revealed the existence of two groups. One group reached significantly (p < 0.05) higher plasma levels than another group comparable for age and sex. The CRP, ESR and Thompson joint score prior to the start of pulse therapy were all higher (p < 0.05) for the high plasma dexamethasone group. The decrease in ESR, CRP and the Thompson joint score was also significantly greater (all p < 0.05) for the high plasma dexamethasone group. Plasma cortisol, as well as the GS receptor density at the start of treatment, did not differ between the two groups; both decreased after the first pulse in both groups and returned to pre-treatment values shortly after the last infusion. CONCLUSION: The treatment of refractory RA with dexamethasone pulse therapy is, on average, beneficial. The high plasma dexamethasone levels reached might depend on the greater severity of the disease in these patients prior to the start of the treatment, and result in greater changes in the disease parameters. Glucocorticosteroid receptor density measurements made during and directly after high dose pulse dexamethasone treatment proved to be unreliable because of the high plasma dexamethasone levels.