Rheumatoid Arthritis: Sacco S

De Vita S, De Marchi G, Sacco S, Gremese E, Fabris M, Ferraccioli G. · Division of Rheumatology, DPMSC, University of Udine, Italy. · Blood Cells Mol Dis. · Pubmed #11778660 No free full text.

Abstract: A classification of nonmalignant lymphoproliferation in Sjögren's syndrome is presented, based on the results of international meetings regarding Sjögren's syndrome-associated lymphomagenesis and on our results of a clinico-pathologic and molecular study and long-term follow-up in well-characterized patients. Sjögren's syndrome pathobiology has similarities to hepatitis C virus-related B-cell lymphoproliferation. Antigen stimulation with the preferential expansion of rheumatoid factor-positive clones and specific immunoglobulin gene expression and recombination represent key biologic events in lymphoproliferation. This classification is based on the coupling of molecular and histological studies and may result in more selective treatment approaches.

De Vita S, Zaja F, Sacco S, De Candia A, Fanin R, Ferraccioli G. · University of Udine, Udine, Italy. · Arthritis Rheum. · Pubmed #12209504 links to  free full text

Abstract: OBJECTIVE: The pathogenetic role of B cells in rheumatoid arthritis (RA) is under debate, but it is currently believed to be marginal. The availability of selective anti-B cell treatment provides a unique opportunity to clarify this issue. This study was undertaken to investigate the effects of B cell blockade in the treatment of refractory RA, and to evaluate the implications with regard to the role of B cells in the disease. METHODS: Five female patients with active, evolving erosive RA were treated with rituximab, an anti-CD20 chimeric monoclonal antibody. All 5 patients had been nonresponders to combination therapy with methotrexate plus cyclosporin A. Two of the 5 had also failed to respond to anti-tumor necrosis factor alpha therapy. All of these treatments were discontinued 1 month before institution of anti-CD20 therapy. RESULTS: Marked clinical improvement was observed in 2 patients (American College of Rheumatology 70% response [ACR70] and ACR50, respectively), starting at the end of the second month after institution of anti-CD20 therapy (month 2) and lasting until month 10 in 1 patient (articular relapse) and month 12 in the other (last followup). ACR20 response was observed in 2 additional patients, lasting until month 5 and month 7, respectively (articular relapse in both). Decrease or normalization of serum C-reactive protein and rheumatoid factor levels were observed in these patients. In contrast, patient 3 had no response to the treatment. RA synovitis and evolving erosive damage were decreased in patients exhibiting a major response, as demonstrated by imaging studies. CONCLUSION: Our finding of the clinical efficacy of selective B cell blockade indicates that B cells play a critical role in rheumatoid synovitis, at least in a subset of patients. Qualitative or quantitative differences in B cell commitment in RA pathobiology might have a function in the different responses observed.

Saviola G, Abdi Ali L, Shams Eddin S, Coppini A, Cavalieri F, Campostrini L, Sacco S, Bucci M, Cirino G, Rossini M. · Rheumatology and Rehabilitation Unit, Salvatore Maugeri Foundation IRCCS, 46042 Castel Goffredo, Mantua, Italy. · Rheumatology (Oxford). · Pubmed #17384176 links to  free full text

Abstract: OBJECTIVE: To evaluate: (i) a correct equivalence ratio of clinical efficacy between low-dose deflazacort (DFZ) and methyl prednisolone (MP); and (ii) bone metabolic effects of low-dose DFZ and MP in the treatment of male RA and PsA. METHODS: A total of 21 male patients with active RA or PsA, naive to steroid treatment were chosen for the study. Group I: 10 patients treated for 6 months with DFZ 7.5 mg, calcium, cholecalciferol and a DMARD; for the following 6 months with MP 4 mg, calcium, cholecalciferol and a DMARD. Group II: 11 patients treated for 6 months with MP 4 mg, calcium, cholecalciferol and a DMARD; for the following 6 months with DFZ 7.5 mg, calcium, cholecalciferol and a DMARD. At day 0, 90, 180, 240 and 360 evaluation of ACR improvement criteria; a blood sample for total and bone-specific ALP, calcium, phosphorus, PTH, SHBG, estradiol, ACTH, osteocalcin, LH, OPG; a sample of urine for calcium, phosphorus, creatinine and DPD. RESULTS: 13/21 patients (6/10 Group I; 7/11 Group II) reached ACR 20 at 6 months; 14/21 (7/10 Group I, 7/10 Group II) at 12 months. Only at the third month we observed in Group II vs Group I a reduction of OPG (24% vs 6%, P = n.s.); ALP (P < 0.001) and osteocalcin (P = 0.006) decreased in both groups from the third month; DPD decreased in both groups only from the sixth month (P = 0.002). CONCLUSIONS: The correct equivalence ratio of DFZ to MP is 1.875:1, and of DFZ to prednisolone 1.5:1. We found a relative prevalence of bone resorption compared to bone formation in the first 6 months of treatment. The trend of OPG requires further investigation.

Fabris M, Tolusso B, Di Poi E, Tomietto P, Sacco S, Gremese E, Ferraccioli G. · Department of Rheumatology, Universita' Cattolica del Sacro Cuore School of Medicine, Rome, Italy. · J Rheumatol. · Pubmed #15940758 No free full text.

Abstract: OBJECTIVE: To analyze tumor necrosis factor-alpha (TNF-alpha) synthesis by mononuclear cells stimulated with lipopolysaccharide (LPS) in patients with rheumatoid arthritis (RA). METHODS: TNF-alpha molecular expression and extracellular release were assessed in the peripheral blood mononuclear cells (PBMC) of 27 RA patients and 16 healthy blood donor controls during 8 hours of LPS stimulation. We also analyzed the mRNA expression of tristetraprolin (TTP), the major TNF-alpha mRNA destabilizing factor. TNF receptor p75 (TNFR 2) plasma concentrations were also tested in all patients. RESULTS: Controls and patients demonstrated a comparable wide range of TNF-alpha release capability, but patients achieved the peak value of protein release more quickly. Defining the median TNF-alpha release in controls as the cutoff value to distinguish high and low LPS-induced TNF-alpha-releasing phenotypes, patients with early RA (disease duration < 1 yr) belonged mainly to the low TNF-alpha producer subgroup, whereas patients with long-standing RA (> 1 yr) were prevalently high TNF-alpha producers. TTP molecular expression was higher in patients with shorter, than in patients with longer, disease duration. The profile of TNF-alpha release in patients with early RA changed significantly when retested after 6 months of therapy, while patients with long-standing disease maintained the same behavior as at baseline. Finally, a baseline low TNF-alpha-producer phenotype predisposed to a better responsiveness to disease modifying antirheumatic drugs. CONCLUSION: The LPS-induced TNF-alpha-releasing phenotype differs between cells obtained from RA patients with different disease durations and seems to influence the therapeutic outcome.

Tolusso B, Sacco S, Gremese E, La Torre G, Tomietto P, Ferraccioli GF. · Division of Rheumatology, UCSC, Catholic University of Rome, Rome, Italy. · Hum Immunol. · Pubmed #15603867 No free full text.

Abstract: OBJECTIVE: To assess the relationship between tumor necrosis factor receptor II (TNF-RII) gene polymorphisms and sTNFRII plasma levels in healthy blood donors (HBDs) and in rheumatoid arthritis (RA) patients. 113 HBDs and 49 RA patients were genotyped for the T/G polymorphism in exon 6 of the TNF-RII gene. In the same cases, sTNF-RII plasma levels were determined by an enzyme-linked immunosorbent assay (ELISA) procedure. sTNF-RII levels were higher in RA patients than in HBDs (p < 0.0001). No difference in sTNF-RII levels arose between RA patients on low oral doses of glucocorticoids versus those not taking glucocorticoids. In healthy controls, we observed lower levels of the sTNF-RII in carriers of the TT genotype compared to TG/GG genotype (p = 0.04). In RA there was the same behaviour between TT and TG/GG carriers, even though the difference was not statistically significant. When analyzing the correlation between sTNF-RII plasma levels and disease activity parameters, significant correlations were seen with disease activity score (r = 0.40, p = 0.01), swollen joint count (r = 0.38, p = 0.01), and tender joint count (r = 0.42, p = 0.01), but not with erythrocyte sedimentation rate (r = 0.22, p = ns) nor with C-reactive protein (r = 0.14, p = NS). The correlation remained significant only in the RA subgroup carrying the TT genotype. Healthy donors carrying the TT genotype showed lower sTNF-RII plasma levels than carriers of the TG/GG genotypes, while in RA patients we observed only a trend.

De Vita S, Damato R, De Marchi G, Sacco S, Ferraccioli G. · Department of Rheumatology, DPMSC, University of Udine, Udine, Italy. · Isr Med Assoc J. · Pubmed #12516900 links to  free full text

Abstract: BACKGROUND: Hepatis C virus infection is presently an exclusion criterion to classify Sjögren's syndrome; however, there are distinct clinicopathologic and biologic similarities between HCV-related and SS-related chronic inflammation of mucosa-associated lymphoid tissue and lymphoproliferation that suggest common pathogenetic pathways. OBJECTIVES: To determine whether a subset of patients with sicca syndrome and HCV infection may present a true primary SS rather than a distinct clinicobiologic entity. METHODS: We extensively characterized 20 consecutive patients with positive anti-HCV antibodies and heavy subjective dry eye and/or dry mouth symptoms, plus positive unstimulated sialometry and/or Shirmer's test. We then compared these features with those in HCV-negative primary SS controls (classified according to the latest American-European Consensus Group Classification Criteria for SS). RESULTS: Of the 20 HCV-positive patients with sicca manifestations, 12 (60%) had positive anti-SSA/SSB antibodies (3/12 by enzyme-linked immunosorbent assay and 6/12 by immunoblot) and/or positive salivary gland biopsy (at least 1 focus/4 mm2), which met the strict classification criteria for SS, as in the case of HCV-negative SS controls. Comparing the HCV-positive SS subset with HCV-negative SS controls showed similar female to male ratio (11/1 vs. 46/4), major salivary gland swelling (17% vs. 26%), positive antinuclear antibodies (75 vs. 94%) and positive rheumatoid factor (58 vs. 52%). Significant differences (P < 0.05) were seen in mean age (69 vs. 56 years), liver disease (50 vs. 2%), lung disease (25 vs. 0%), anti-SSA/SSB positivity (25 vs. 90%), and low C3 or C4 (83 vs. 36%). HCV-positive SS patients exhibited a trend for more frequent chronic gastritis (50 vs. 22%), fibromyalgia (33 vs. 14%), peripheral neuropathy (33 vs. 18%), purpura (33 vs. 19%) and cryoglobulinemia (33 vs. 6%). CONCLUSIONS: A major subset of HCV-positive patients with definite subjective sicca symptoms and positive objective tests may indeed present a true, though peculiar, subset of SS. There are strict similarities with key clinical, pathologic and immunologic findings of definite HCV-negative SS. Other features appear more characteristic of HCV infection. When also considering that HCV is sialotropic and may be treated, HCV-related chronic sialadenitis represents a unique opportunity to clarify key pathogenetic events occurring in the large majority of HCV-negative SS; and similarities to typical primary SS, rather than differences, should be taken into account.

Fabris M, Di Poi E, Sacco S, Damante G, Sinigaglia L, Ferraccioli G. · Divisione di Reumatologia, DPMSC, Università degli Studi di Udine, Italia. · Reumatismo. · Pubmed #12089610 links to  free full text

Abstract: OBJECTIVES: To study -238 and +489 TNF-alpha polymorphisms in severe-unresponsive (more than 6 swollen joints and still active disease despite at least 6 months of DMARDs combination therapy) and mild-responsive (less than 3 swollen joints and good response to MTX or other conventional DMARDs) rheumatoid arthritis (RA). METHODS: We investigated 100 RA patients (56 with severe and 44 with mild disease activity) and 45 healthy blood donors (HBDs). Genotyping was performed by PCR-restriction fragment length polymorphism procedure. Several clinical and serological parameters were also examined. RESULTS: Severe RA patients disclosed the -238 GG genotype in 100% of the cases versus 95.5% in the mild-responsive patients and 91.2% in the HBDs. The +489 GG genotype disclosed only a trend towards a prevalence in severe RA patients. However the +489 A allele seems to associates with early onset, longer disease duration and longer responsiveness to conventional therapy. CONCLUSION: The -238 AG genotype is absent in severe-unresponsive RA, but present in mild-responsive RA subjects. Thus -238 GG homozygosity associates with severity and unresponsiveness. In contrast the +489 polymorphism does not segregate differently between responsive and unresponsive RA patients.