Rheumatoid Arthritis: Secchi ME

Pizzorni C, Secchi ME, Cutolo M. · U.O. Clinica Reumatologica, Dipartimento di Medicina Interna Università di Genova, Genova, Italia. · Reumatismo. · Pubmed #17898884 links to  free full text

Abstract: Leishmaniasis represents a complex of diseases with an important clinical and epidemiological diversity. Visceral leishmaniasis is of higher priority than cutaneous leishmaniasis as it is a fatal disease in the absence of treatment. The clinical spectrum of leishmaniasis and control of the infection are influenced by the parasite-host relationship. The role of cellular immune responses of the Th1 type in the protection against disease in experimental and human leishmaniasis is well established. TNF-alpha has been implicated in cytokine-induced macrophage activation and tissue granuloma formation, two activities linked to control of intracellular visceral infection caused by Leishmania donovani. Anti-tumor necrosis factor-alpha (TNF-alpha) strategies have had a marked and substantial impact in the treatment of rheumatoid arthritis, however the clinical use of TNF-alpha antagonists has been accompanied by increased reporting of infections. Here we report the first case of visceral leishmaniasis in a patient treated for a long period of time with human anti TNF-alpha monoclonal antibody, adalimumab. Due to the low incidence rate of Mediterranean visceral leishmaniasis, a systematic screening for leishmaniasis in all patients treated with biologics may be not recommended. However, for those patients living at high risk of leishmaniasis exposure, a periodical serological monitoring should be performed during therapy with anti-TNF monoclonal antibodies.

Cutolo M, Capellino S, Sulli A, Serioli B, Secchi ME, Villaggio B, Straub RH. · Research Laboratory and Division of Rheumatology, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy. · Ann N Y Acad Sci. · Pubmed #17261796 No free full text.

Abstract: Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immune-suppressors . Several physiological, pathological, and therapeutic conditions may change the serum estrogen milieu and/or peripheral conversion rate, including the menstrual cycle, pregnancy, postpartum period, menopause, being elderly, chronic stress, altered circadian rhythms, inflammatory cytokines, and use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. In particular, cortisol and melatonin circadian rhythms are altered, at least in rheumatoid arthritis (RA), and partially involve sex hormone circadian synthesis and levels as well. Abnormal regulation of aromatase activity (i.e., increased activity) by inflammatory cytokine production (i.e., TNF-alpha, IL-1, and IL-6) may partially explain the abnormalities of peripheral estrogen synthesis in RA (i.e., increased availability of 17-beta estradiol and possible metabolites in synovial fluids) and in systemic lupus erythematosus, as well as the altered serum sex-hormone levels and ratio (i.e., decreased androgens and DHEAS). In the synovial fluids of RA patients, the increased estrogen concentration is observed in both sexes and is more specifically characterized by the hydroxylated forms, in particular 16alpha-hydroxyestrone, which is a mitogenic and cell proliferative endogenous hormone. Local effects of sex hormones in autoimmune rheumatic diseases seems to consist mainly in modulation of cell proliferation and cytokine production (i.e., TNF-alpha, Il-1, IL-12). In this respect, it is interesting that male patients with RA seem to profit more from anti-TNFalpha strategies than do female patients.

Cutolo M, Sulli A, Pizzorni C, Secchi ME, Soldano S, Seriolo B, Straub RH, Otsa K, Maestroni GJ. · Research Laboratory and Division of Rheumatology, Department of Internal Medicine, University of Genova, Viale Benedetto XV6, 16132 Genova, Italy. · Ann N Y Acad Sci. · Pubmed #16855156 No free full text.

Abstract: Circadian rhythms are driven by biological clocks and are endogenous in origin. Therefore, circadian changes in the metabolism or secretion of endogenous glucocorticoids are certainly responsible in part for the time-dependent changes observed in the inflammatory response and arthritis. More recently, melatonin (MLT), another circadian hormone that is the secretory product of the pineal gland, has been found implicated in the time-dependent inflammatory reaction with effects opposite those of cortisol. Interestingly, cortisol and MLT show an opposite response to the light. The light conditions in the early morning have a strong impact on the morning cortisol peak, whereas MLT is synthesized in a strictly nocturnal pattern. Recently, a diurnal rhythmicity in healthy humans between cellular (Th1 type) or humoral (Th2 type) immune responses has been found and related to immunomodulatory actions of cortisol and MLT. The interferon (IFN)-gamma/interleukin (IL)-10 ratio peaked during the early morning and correlated negatively with plasma cortisol and positively with plasma MLT. Accordingly, the intensity of the arthritic pain varies consistently as a function of the hour of the day: pain is greater after waking up in the morning than in the afternoon or evening. The reduced cortisol and adrenal androgen secretion, observed during testing in rheumatoid arthritis (RA) patients not treated with glucocoticoids, should be clearly considered as a "relative adrenal insufficiency" in the presence of a sustained inflammatory process, and allows Th1 type cytokines to be produced in higher amounts during the late night. In conclusion, the right timing (early morning) for the glucocorticoid therapy in arthritis is fundamental and well justified by the circadian rhythms of the inflammatory mechanisms.

Sulli A, Montecucco CM, Caporali R, Cavagna L, Montagna P, Capellino S, Fazzuoli L, Seriolo B, Alessandro C, Secchi ME, Cutolo M. · Research Laboratory and Division of Rheumatology, Department of Internal Medicine, San Martino Hospital, University of Genova, Viale Benedetto XV, 6-16132 Genova, Italy. · Ann N Y Acad Sci. · Pubmed #16855158 No free full text.

Abstract: Polymyalgia rheumatica (PMR) usually exhibits a good clinical response to glucocorticoid (GC) treatment, but early clinical symptoms may create some difficulties in the differential diagnosis with elderly onset rheumatoid arthritis (EORA), particularly in patients complaining of shoulder and pelvic girdle involvement at onset (PMR-like clinical onset) (EORA/PMR). Since neuroendocrine mechanisms seem to play a pathogenetic role in these clinical conditions, the aim of this study was to evaluate hormone and cytokine responsiveness to GC treatment in these patients. Cortisol (CO), dehydroepiandrosterone sulphate (DHEAS), 17-OH-progesterone (PRG), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were evaluated at base line, and 1 month after GC treatment (prednisone 10 mg/day), in 14 PMR, 11 EORA/PMR, and 13 EORA patients (mean age 73 +/- 5 years, +/- SD, mean disease duration 3 +/- 2 months, +/- SD). No patient was taking GCs or immunosuppressive agents at base line. Following GC treatment, CO, DHEAS, and PRG decreased significantly in both PMR and EORA/PMR patients (P < 0.05), but not in EORA patients. On the contrary, IL-1Ra was significantly increased in both PMR and EORA/PMR patients (P < 0.05). IL-6 and TNF-alpha serum levels were significantly decreased in all groups of patients (P < 0.05). In conclusion, PMR and EORA/PMR seem to exhibit similar hormonal variations after GC administration, when compared to EORA patients. These differences suggest a deficient function of the hypothalamic-pituitary-adrenal (HPA) axis in PMR and EORA/PMR patients, with a related higher responsiveness to GC treatment. Interestingly, in PMR and EORA/PMR patients, GC treatment was found to downregulate PRG serum levels.

Mancarella L, Bobbio-Pallavicini F, Ceccarelli F, Falappone PC, Ferrante A, Malesci D, Massara A, Nacci F, Secchi ME, Manganelli S, Salaffi F, Bambara ML, Bombardieri S, Cutolo M, Ferri C, Galeazzi M, Gerli R, Giacomelli R, Grassi W, Lapadula G, Cerinic MM, Montecucco C, Trotta F, Triolo G, Valentini G, Valesini G, Ferraccioli GF, Anonymous00012. · Division of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy. · J Rheumatol. · Pubmed #17611987 No free full text.

Abstract: OBJECTIVE: To assess the prevalence of good clinical response and remission in rheumatoid arthritis (RA) patients with longstanding disease treated with anti-tumor necrosis factor-alpha (TNF-alpha) drugs at outpatient clinics. METHODS: Retrospective national study of 14 academic tertiary referral rheumatology medical centers. RA patients with a Disease Activity Score (DAS28) > 3.2 were defined as having active disease and could start TNF-alpha blockers. All patients received one TNF-alpha blocker plus methotrexate (10-20 mg/wk). At the third month the patients were categorized as responders or nonresponders, based on improvement of at least 0.25 of the Health Assessment Questionnaire (HAQ). Those who had improved by at least 0.25 HAQ were analyzed for possible predictors of DAS28 remission at the sixth month. RESULTS: A total of 1257 patients started TNF-alpha blockers. Of these, 591 (46.7%) reached the sixth month with an improvement of HAQ of 0.25 at the third month. In the cohort of patients reaching HAQ of 0.25, DAS28 remission was seen in 24% of rheumatoid factor (RF)-positive and 36% of RF-negative patients (p = 0.03). Logistic regression analysis for predictors of remission identified age at baseline, HAQ < 1.63, and RF negativity as positive predictors of remission at 6 months along with sex (male). CONCLUSION: We show that only a minority of patients with longstanding RA achieve a good clinical response or remission at the outpatient community level. Predictors of remission identify characteristics commonly observed in subsets with less severe RA.

Cutolo M, Otsa K, Laas K, Yprus M, Lehtme R, Secchi ME, Sulli A, Paolino S, Seriolo B. · Division of Rheumatology - Dept Internal Medicine, University of Genova, Genova, Italy. · Clin Exp Rheumatol. · Pubmed #17207389 No free full text.

Abstract: BACKGROUND: Greater intake of vitamin D has been associated with a lower risk of rheumatoid arthritis (RA) and low serum vitamin D together with higher prevalence of RA seem common among North European people when compared to Southern Europe. OBJECTIVES: To evaluate serum 25-hydroxyvitamin D [25(OH)D] levels in female RA patients from North (Estonia) and South (Italy) Europe and to correlate them with the disease activity score (DAS28) during winter and summer. METHODS: Fifty-four RA Italian patients (IP) and 64 RA Estonian patients (EP) were evaluated for serum 25(OH)D levels in winter and summer time, as well as for DAS28 score. Normal female controls (C) were 35 (IC) and 30 (EC) age-matched subjects, respectively. 25(OH)D concentrations were measured by a competitive radioimmunoassay. Statistical analysis was performed by "r" Pearson correlation, "t" Student with Bonferroni correction and by repeated ANOVA measures (summer and winter) with two factors (country and clinical status). RESULTS: 25(OH)D levels were found significantly higher in IP versus EP (p = 0.0116) both in winter and in summer time. Differences were observed also in controls. The variations (increase) of 25(OH)D levels between winter and summer were found significant (p = 0.0005) in both IP and EP. Differences were observed also in controls. No significant differences were found concerning 25(OH)D levels between RA patients and their controls in either country. Interestingly, a significant negative correlation between 25(OH)D and DAS28, was found in summer only in IP (r =-0.57, p < 0.0001) and in winter in EP (r =-0.40, p < 0.05). CONCLUSION: Significantly lower 25(OH)D serum levels were observed in RA patients from North versus South Europe with a circannual rhythm in winter and summer time. In addition, 25(OH)D values showed a significant correlation (negative) with RA clinical status (DAS28) in both North and South European RA patients, suggesting possible effects of vitamin D among other factors on disease activity.