Heidemarie Becker

Mycophenolate sodium treatment in patients with primary Sjögren syndrome: a pilot trial

The aim of this study was to evaluate the efficacy and safety of mycophenolate sodium (MPS) in patients with primary Sjögren syndrome (pSS) refractory to other immunosuppressive agents. Eleven patients with pSS were treated with MPS up to 1,440 mg daily for an observation period of 6 months in this single-center, open-label pilot trial. At baseline, after 3 months, and after 6 months, we examined the clinical status, including glandular function tests, as well as different laboratory parameters associated with pSS. In addition, subjective parameters were determined on the basis of different questionnaires. Treatment with MPS was well tolerated in 8 of 11 patients. Due to vertigo or gastrointestinal discomfort, two patients did not complete the trial. One patient developed pneumonia 2 weeks after treatment and was withdrawn. In the remaining patients, MPS treatment resulted in subjective improvement of ocular dryness on a visual analogue scale and a reduced demand for artificial tear supplementations. However, no significant alterations of objective parameters for dryness of eyes and mouth were observed, although a substantial improvement of glandular functions occurred in two patients with short disease duration. In addition, treatment with MPS resulted in significant reduction of hypergammaglobulinemia and rheumatoid factors as well as an increase of complement levels and white blood cells. MPS promises to be an additional therapeutic option for patients with pSS, at least in those with shorter disease duration. Further investigations about the efficacy and safety of MPS in pSS have to be performed in larger numbers of patients.

Differential effects of cyclophosphamide and mycophenolate mofetil on cellular and serological parameters in patients with systemic lupus erythematosus

IntroductionDisease activity and therapy show an impact on cellular and serological parameters in patients with systemic lupus erythematosus (SLE). This study was performed to compare the influence of mycophenolate mofetil (MMF) and cyclophosphamide (CYC) therapy on these parameters in patients with flaring, organ-threatening disease.MethodsSLE patients currently receiving CYC (n = 20), MMF (n = 25) or no immunosuppressive drugs (n = 22) were compared using a cross-sectional design. Median disease activity and daily corticosteroid dose were similar in these treatment groups. Concurrent medication, organ manifestations, and disease activity were recorded, and cellular and serological parameters were determined by routine diagnostic tests or flow cytometric analysis. In addition follow-up data were obtained from different sets of patients (CYC n = 24; MMF n = 23).ResultsAlthough both drugs showed a significant effect on disease activity and circulating B cell subsets, only MMF reduced circulating plasmablasts and plasma cells as well as circulating free light chains within three months of induction therapy. Neither MMF nor CYC were able to reduce circulating memory B cells. MMF lowered IgA levels more markedly than CYC. We did not observe a significant difference in the reduction of IgG levels or anti-dsDNA antibodies comparing patients receiving MMF or CYC. In contrast to MMF, induction therapy with CYC was associated with a significant increase of circulating CD8+ effector T cells and plasmacytoid dendritic cells (PDCs) after three months.ConclusionsThe results indicate differences between MMF and CYC with regard to the mechanism of action. MMF, but not CYC, treatment leads to a fast and enduring reduction of surrogate markers of B cell activation, such as circulating plasmablasts, plasma cells and free light chains but a comparable rate of hypogammaglobulinemia.

Etanercept tolerance in a patient with previous infliximab-induced hepatitis

Dear Editor, We read with great interest the report by Harada et al. [1], who described the first case of autoimmune hepatitis exacerbated by etanercept administration in a patient with rheumatoid arthritis (RA). Hepatitis is a rare complication of treatment with tumor necrosis factor (TNF)-α antagonists. Several cases associated with infliximab therapy have been described [2]. To further contribute to the understanding of the mechanisms that lead to hepatitis induction by both TNF-a antagonists, we would like to present our observation in a RA patient who developed hepatitis during infliximab therapy and was subsequently treated with etanercept without recurrence. A 41-year-old woman with a history of rheumatoid factornegative, erosive RA since 1999 presented to our outpatient clinic in 2001. Since sulfasalazine, methotrexate, and a combination of methotrexate with leflunomide were not effective and the patient had progressive disease, infliximab was started (3 mg/kg body weight), in addition to methotrexate (15 mg/ week subcutaneously), with folic acid supplementation and prednisolone (10 mg/day). She received repeated infliximab infusions after 2 and 6 weeks, and then every 6 to 8 weeks. As the patient improved, prednisolone was gradually tapered to 5 mg/day. She had normal liver enzymes. In 2004, increased levels of alanine aminotransferase (ALT, 1061 U/l), aspartate aminotransferase (AST, 2019 U/l), and alkaline phosphatase (244 U/l) were detected. Consequently, all medications were withdrawn, except prednisolone. Laboratory testing showed an increase in the antinuclear antibody (ANA) titer previously present at 1/160 to 1/640 and positive anti-smooth muscle antibodies (ASMA). Tests for antibodies against doublestranded DNA, mitochondria, liver–kidney microsomes, and soluble liver antigen/liver pancreas antigen, as well as for hepatitis A, B, and C and cytomegalovirus, were negative. Liver biopsy revealed lymphoplasmacytic inflammatory cell infiltration predominating the portal areas, necrosis of hepatocytes, and mild periportal fibrosis. Prednisolone was started (initial dose of 1 mg kg day), and within 4 weeks, normalization of ALT (17 U/l) and AST (29 U/l) was observed. When prednisolone was reduced to 12.5 mg/day after 2 months, the patient developed a severe flare of her joint symptoms. Since treatment options were limited at that time, etanercept was started (2×25 mgweekly). Joint symptoms improved and prednisolone was tapered to 5 mg/day. During a follow-up period of more than 3 years on etanercept, significantly increased ALT and AST values have not recurred, while low titers of ANA and ASMA remained positive. Likewise, Goldenberg and Jorizzo [3] have treated a patient with pyoderma gangrenosum and autoimmune hepatitis with etanercept and reported no adverse effects. Our observation of etanercept tolerance in a patient who had previous liver disease with features of autoimmune hepatitis during infliximab therapy suggests that both TNF antagonists might exert different effects on mechanisms that result in liver inflammation. Etanercept might be tolerated in patients at risk of exacerbation of autoimmune hepatitis. However, it remains to be clarified whether non-TNF-α biologicals might be safer still for these patients.

Interferon-γ Is Increased in Patients with Primary Sjogren's Syndrome and Raynaud's Phenomenon

OBJECTIVES To determine the prevalence of Raynauds phenomenon (RP) in patients with primary Sjogrens syndrome (pSS) and to identify clinical and immunological characteristics associated with this manifestation. Since increased interferon-gamma (INF-gamma) has been associated with RP, we also compared the INF-gamma production in pSS patients with or without RP. METHODS RP was diagnosed if pSS patients presented with characteristic sequence of skin color changes of the digits. In uncertain cases noninvasive vascular tests were performed by ultrasound examination. The secretion of INF-gamma by peripheral blood mononuclear cells was assessed by enzyme-linked immunospot analysis. Further, we examined the expression of different lymphocyte activation markers (CD25, CD45RO, CD69) on CD4+ T-cells by flow cytometric analysis. RESULTS Thirty-six of 108 patients with pSS had RP. In these patients we found a significantly increased number of INF-gamma-secreting peripheral blood mononuclear cells compared with patients without RP or to healthy controls. Further, in patients with RP a significantly increased percentage of CD25-positive T-helper cells was detectable. In addition we found an association of leukopenia, thyroiditis, and lower C3 levels with RP in pSS patients. CONCLUSIONS These results suggest a pathogenic role of INF-gamma in pSS patients with RP. Whether the RP is immune-mediated or whether INF-gamma directly causes vasospasm still remains to be elucidated.

Increased serum levels of macrophage migration inhibitory factor in patients with primary Sjögren's syndrome

The objective of this study was to analyse levels of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) in patients with primary Sjögrens syndrome (pSS) and to examine associations of MIF with clinical, serological and immunological variables. MIF was determined by ELISA in the sera of 76 patients with pSS. Further relevant cytokines (IL-1, IL-6, IL-10, IFN-γ and TNF-α) secreted by peripheral blood mononuclear cells (PBMC) were determined by ELISPOT assay. Lymphocytes and monocytes were examined flow-cytometrically for the expression of activation markers. Results were correlated with clinical and laboratory findings as well as with the HLA-DR genotype. Healthy age- and sex-matched volunteers served as controls. We found that MIF was increased in patients with pSS compared with healthy controls (p < 0.01). In particular, increased levels of MIF were associated with hypergammaglobulinemia. Further, we found a negative correlation of MIF levels with the number of IL-10-secreting PBMC in pSS patients (r = -0.389, p < 0.01). Our data indicate that MIF might participate in the pathogenesis of primary Sjögrens syndrome. MIF may contribute to B-cell hyperactivity indicated by hypergammaglobulinemia. The inverse relationship of IL-10 and MIF suggests that IL-10 works as an antagonist of MIF in pSS.

Emerging Treatment Strategies and Potential Therapeutic Targets in Primary Sjogrens Syndrome

Primary Sjögrens syndrome (pSS) is a common autoimmune disease which can lead to considerable complications and diminished quality of life. Recent insights into disease mechanisms and the advent of biological agents have provided new options for the treatment of pSS. In particular, B cell targeted intervention has shown promising results. In this review, we focus on emerging treatment strategies and therapeutic targets beyond B cells. Interference with proinflammatory cytokines and mechanisms that link innate and adaptive immunity offers new options in the treatment of pSS. Approaches directed against interleukin (IL)-1beta, Toll-like receptors and the inflammasome are emerging. Targeting IL-12, IL-18, the IL-23/IL-17 system, macrophage migration inhibitory factor and chemokines might be considered. The inhibition of apoptosis of glandular cells, the promotion of cell regeneration and organ-specific stem cell transplantation are potential strategies directed at preserving and restoring functional exocrine tissue. The recognition of patients who benefit most from a particular strategy might help to design more efficient therapeutic approaches. Since efficacy of many agents depends on the presence of residual functional glandular tissue, future studies should focus on patients with recent onset of pSS.

Treatment of arthralgias and spondyloarthropathy associated with inflammatory bowel disease

Joint involvement is the most frequent extraintestinal manifestation of inflammatory bowel diseases (IBDs). Arthralgias are common and spondyloarthropathy may affect peripheral joints and the axial skeleton, as well as the tendons. The broad spectrum of joint manifestations requires a therapeutic concept that takes the potential influence of agents on the underlying bowel disease into consideration. This review will focus on the current therapeutic approach to the different manifestations of IBD-related joint disease and will outline baseline treatment, the use of conventional agents and biologicals. TNF antagonists have dramatically changed the care of patients. In particular, TNF antagonists have emerged as the most effective treatment for ankylosing spondylitis, which has often been refractory to therapy in the past. For patients who fail to respond to TNF antagonists, several novel agents will provide more treatment choices in the future. Recent insights into disease mechanisms of IBD have revealed at...