Intensive short-term treatment with rituximab, cyclophosphamide and methylprednisolone pulses induces remission in severe cases of SLE with nephritis and avoids further immunosuppressive maintenance therapy.

BACKGROUND: B cells play a central role in systemic lupus erythematosus (SLE). Rituximab is expected to induce apoptosis of all the CD20-positive B cells. A proportion of patients are refractory or intolerant to standard immunosuppression. These are candidate to new therapeutic options. METHODS: Eight patients [six women, two men, mean age 41-year-old (27-51), with severe multiorgan involvement (kidney, skin, nervous system, polyarthritis, polyserositis, antiphospholipid antibody syndrome)] were considered eligible for an intensive combination therapy including rituximab. Rituximab was administered (dose 375 mg/m(2)) on Days #2, 8, 15 and 22. Two more doses were administered 1 and 2 months following the last weekly infusion. This treatment was combined with two pulses of 750 mg cyclophosphamide (Days #4 and 17) and three pulses of 15 mg/kg (Days #1, 4 and 8) methylprednisolone followed by oral prednisone, 50 mg for 2 weeks rapidly tapered until 5 mg in 2 months. Response was evaluated by assessing the changes in clinical signs and symptoms [Systemic Lupus Erythematosus Disease Activity Index (SLEDAI score)] and laboratory parameters for at least 12 months. RESULTS: Levels of erythrocyte sedimentation rate and anti-double-strand DNA antibodies significantly decreased (P < 0.01 at 12 months), whereas C3 and mainly C4 values increased at 6 months (P < 0.01 for C4). Proteinuria improved in the cases with renal involvement (P < 0.01 at 3, 6 and 12 months). SLEDAI score improved moving from the mean 17.3 (12-27) before therapy to 3.1 (1-5) after rituximab treatment. Constitutional symptoms including arthralgia, weakness and fever disappeared in all the previously affected patients; paresthesia improved in the four patients with polyneuropathy and skin lesions gradually resolved in the patients with necrotizing skin ulcers at presentation. Drug side effects were negligible. CONCLUSIONS: Long-lasting remissions were obtained in patients with severe SLE and major organ involvement by this intensive administration of rituximab combined with low doses of intravenous cyclophosphamide and methylprednisolone pulses followed by a rapid tapering of prednisone to 5 mg/day as a sole maintenance therapy.

A 3-Year Observational Study of Patients with Progressive Systemic Sclerosis Treated with an Intensified B Lymphocyte Depletion Protocol: Clinical and Immunological Response.

BACKGROUND: B-cells have been suggested to play a role in the pathogenesis of systemic sclerosis (SSc), representing, therefore, a potential therapeutic target. OBJECTIVES: We aimed at investigating the 36-month outcomes of 20 SSc patients who underwent an intensified B-depletion therapy (IBCDT) scheme, including both Rituximab (RTX) and cyclophosphamide (CYC). METHODS: Data from 20 severe patients (18 females and 2 males, mean age 66.7 ± 11.0 years) with diffuse SSc (anti-topoisomerase I antibody in 95%) patients with multiorgan involvement including interstitial lung disease (ILD) treated with an IBCDT were prospectively collected. IBCDT comprehended: RTX 375 mg/m2 administered for four weekly doses (on days 1, 8, 15, and 22), followed by two additional doses after 30 and 60 days, in addition to two administrations of 10 mg/kg of intravenous CYC plus three methylprednisolone pulses (15 mg/kg) and subsequently followed by oral prednisone rapidly tapered to low minimum dosage of 5 mg daily. In addition, 10 patients with more severe functional respiratory impairment at baseline were also treated with RTX 500 mg every 4 months during the first year and two times a year during the second and the third year. RESULTS: After 36 months of follow-up, we recorded significant amelioration in N-terminal-pro-brain natriuretic peptide (NT-proBNP) levels (mean 385.4 ± 517 pg/mL at baseline to 279 ± 543 after 36 months). In addition, a significant radiological improvement of ILD in 20% of patients (4/20) and a radiological stabilization with no sign of progression of interstitial involvement in 13/20 (65%) were documented. A total of 3 out of 20 (15%) patients experienced a worsening of the ILD. No patient showed further decrease in functional respiratory parameters, including forced vital capacity, forced expiratory volume in one second, and mean values of diffusing capacity for carbon monoxide Moreover, no patient showed any change in the ejection fraction and pulmonary artery pressure when comparing values at baseline and after 24 and 36 months of observation. No severe infection, renal flare, RTX-related side effects were observed. No patient died. CONCLUSIONS: Our findings support that the IBCDT was well tolerated and might be a promising therapeutic option for the management of SSc, especially in those subjects with multiorgan involvement that includes ILD.

How I treat patients with adult onset Still's disease in clinical practice.

Adult onset Still's disease (AOSD) is a rare systemic inflammatory disease of unknown etiology characterized by four cardinal signs which are almost always present in patients: high spiking fever, arthralgia (with or without synovitis), maculo-papular salmon-pink evanescent skin rash, striking leukocytosis with neutrophilia. Here, we review the clinical features of AOSD and describe the best practice approaches for its management, reviewing available guidelines and recommendations and providing experts' insights.

Mesalamine-induced lung injury in a patient with ulcerative colitis and a confounding autoimmune background: a case report.

Two years after being diagnosed with ulcerative colitis, a 57-year-old man taking oral mesalamine experienced severe respiratory distress due to left lung pleuropneumonitis. Eight months later, severe respiratory distress recurred due to right lung pneumonitis. Extraintestinal manifestations of inflammatory bowel disease or mesalamine-induced pulmonary injury were considered in the differential diagnosis, which was complicated by a history of aseptic meningitis and evidence of an ongoing autoimmune response. The implications of the case are discussed.

Rheumatoid arthritis: Biological therapy other than anti-TNF.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and is characterized by synovitis that causes joint damage. The introduction of biologic agents has made it possible to induce remission in many patients and inhibit joint damage. Activated T cells in RA patients proliferate and stimulate the production of pro-inflammatory cytokines including tumor necrosis factor (TNF) and interleukin 6 that play important roles in RA pathogenesis. The most widely used biologic agents indicated for RA inhibit the activity of TNF. However, newly developed biologic drugs targeting different pathways are now currently part of the therapeutic options to induce remission in patients with RA. The present review focuses on biologic agents directed at molecular targets different from TNF and addresses the possible advantages of these drugs.

Cost-effectiveness of biologic treatment for rheumatoid arthritis in clinical practice: an achievable target?

The burden of illness of rheumatoid arthritis (RA) falls on patients, families and society through the direct costs, indirect costs, and intangible costs. A large number of RA cost-of-illness studies have been performed in recent decades with discrepant results due to patient heterogeneity, and different health-care organization, employment rate or social support, job opportunities, and methodologies used to calculate the costs. The greatest burden of RA is the indirect and the intangible costs, but how to estimate them remains controversial. The systematic use of traditional disease modifying anti rheumatic drugs has changed the evolution of the disease. However, a considerable improvement in the management of RA has been obtained since the advent of biologic response modifiers. The use of these drugs, which have demonstrated greater efficacy than conventional therapies, have tripled the direct costs of RA, which rose from about € 4000 to roughly € 12,000, in a period of five years, from 2000 to 2005. The present paper is aimed to examine the effects of this change in therapeutic strategy.

Polymorphism of the uteroglobin gene in systemic lupus erythematosus and IgA nephropathy.

Uteroglobin (UG) is a multifunctional protein with anti-inflammatory/immunomodulatory properties. The UG gene is located on the long arm of chromosome 11 (11q12.3-q13.1) in a region linked to some immune disorders. A guanine-adenine substitution at position 38 (A38G) has been found in the noncoding region of exon 1 that is significantly correlated with an increased risk of developing immune-mediated diseases. Recently an experimental model of UG knockout mice showed that in mice, UG deficiency causes severe glomerulopathy with mesangial deposition of IgA-fibronectin complexes. To detect the presence of polymorphisms in the UG coding sequence, the DNA of 109 patients with IgA nephropathy (IgAN), and 32 patients with systemic lupus erythematosus (SLE) were tested for the nucleotide sequence of all three UG exons by heteroduplex analysis. We detected heterozygous DNA only for exon 1 due to the A38G substitution, as confirmed by sequencing. We tested for A38G polymorphism, by restriction endonuclease digestion (Sau96I), both in SLE patients and in IgAN patients. Twenty patients with either membranous nephropathy (12) or focal and segmental glomerular sclerosis and 120 healthy subjects served as controls. Compared with both healthy controls and non-IgA control patients, the frequency of the 38A allele was significantly higher in SLE patients (38 of 64 alleles versus 89 of 240 alleles, p = 0.002, and versus 7 of 40 alleles, p < 0.001). IgAN patients showed an allelic distribution similar to both control groups. A subgroup of 18 IgAN patients undergoing renal replacement therapy because of end-stage renal disease showed a significant increase in 38A allele frequency (5 of 36 38G alleles versus 31 of 36 38A alleles, p < 0.001). UG is an immunomodulatory agent that is able to (a) inhibit the activity of several phospholipase A2 (PLA2s), (b) interfere with the function of both neutrophils and monocytes, and (c) prevent immune recognition, perhaps by masking surface antigens. This could account for the role this molecule plays in SLE. The A38G polymorphism is located within a region corresponding to the rat minimal promoter that proved to be important in the transcriptional regulation of UG. Although the significance of any alterations in the UG exon 1 noncoding region in humans has yet to be clarified, initial evidence suggests that it may alter the control of immune response and of inflammation.