Jiska Meijer

Effectiveness of Rituximab Treatment in Primary Sjogren's Syndrome A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE To study the efficacy and safety of B cell depletion with rituximab, a chimeric murine/human anti-CD20 monoclonal antibody, in patients with primary Sjögrens syndrome (SS) in a double-blind, randomized, placebo-controlled trial. METHODS Patients with active primary SS, as determined by the revised American-European Consensus Group criteria, and a rate of stimulated whole saliva secretion of > or =0.15 ml/minute were treated with either rituximab (1,000 mg) or placebo infusions on days 1 and 15. Patients were assigned randomly to a treatment group in a ratio of 2:1 (rituximab:placebo). Followup was conducted at 5, 12, 24, 36, and 48 weeks. The primary end point was the stimulated whole saliva flow rate, while secondary end points included functional, laboratory, and subjective variables. RESULTS Thirty patients with primary SS (29 female) were randomly allocated to a treatment group. The mean +/- SD age of the patients receiving rituximab was 43 +/- 11 years and the disease duration was 63 +/- 50 months, while patients in the placebo group were age 43 +/- 17 years and had a disease duration of 67 +/- 63 months. In the rituximab group, significant improvements, in terms of the mean change from baseline compared with that in the placebo group, were found for the primary end point of the stimulated whole saliva flow rate (P = 0.038 versus placebo) and also for various laboratory parameters (B cell and rheumatoid factor [RF] levels), subjective parameters (Multidimensional Fatigue Inventory [MFI] scores and visual analog scale [VAS] scores for sicca symptoms), and extraglandular manifestations. Moreover, in comparison with baseline values, rituximab treatment significantly improved the stimulated whole saliva flow rate (P = 0.004) and several other variables (e.g., B cell and RF levels, unstimulated whole saliva flow rate, lacrimal gland function on the lissamine green test, MFI scores, Short Form 36 health survey scores, and VAS scores for sicca symptoms). One patient in the rituximab group developed mild serum sickness-like disease. CONCLUSION These results indicate that rituximab is an effective and safe treatment strategy for patients with primary SS.

Health-related quality of life, employment and disability in patients with Sjögren's syndrome

OBJECTIVE To compare health-related quality of life (HR-QOL), employment and disability of primary and secondary SS (pSS and sSS, respectively) patients with the general Dutch population. METHODS HR-QOL, employment and disability were assessed in SS patients regularly attending the University Medical Center Groningen (n = 235). HR-QOL, employment and disability were evaluated with the Short Form-36 questionnaire (SF-36) and an employment and disability questionnaire. Results were compared with Dutch population data (matched for sex and age). Demographical and clinical data associated with HR-QOL, employment and disability were assessed. RESULTS Response rate was 83%. SS patients scored lower on HR-QOL than the general Dutch population. sSS patients scored lower on physical functioning, bodily pain and general health than pSS patients. Predictors for reduced HR-QOL were fatigue, tendomyalgia, articular involvement, use of artificial saliva, use of anti-depressants, comorbidity, male sex and eligibility for disability compensation (DC). Employment was lower and DC rates were higher in SS patients compared with the Dutch population. CONCLUSION SS has a large impact on HR-QOL, employment and disability.

Treatment of primary Sjögren syndrome with rituximab: extended follow-up, safety and efficacy of retreatment

We previously reported that B cell depletion therapy with rituximab (4 weekly infusions of 375 mg/m2, premedication: 25 mg prednisolone intravenously) in eight patients with early primary Sjogren syndrome (pSS) and seven patients with mucosa-associated lymphatic tissue (MALT)/pSS was effective in reducing subjective and objective symptoms after 12 weeks of follow-up.1 Three patients with early pSS developed serum sickness-like disease, of whom one patient declined to further participate. The MALT component of six of the seven patients with MALT/pSS was initially effectively treated with rituximab, one of these six patients was successfully retreated 9 months after the first treatment and all six patients are …

Clinical and Histologic Evidence of Salivary Gland Restoration Supports the Efficacy of Rituximab Treatment in Sjogren's Syndrome

OBJECTIVE To assess the effect of rituximab (anti-CD20 antibody) therapy on the (immuno)histopathology of parotid tissue in patients with primary Sjögrens syndrome (SS) and the correlation of histologic findings with the flow rate and composition of parotid saliva. METHODS In a phase II study, an incisional parotid biopsy specimen was obtained from 5 patients with primary SS before and 12 weeks after rituximab treatment (4 infusions of 375 mg/m(2)). The relative amount of parotid parenchyma, lymphocytic infiltrate, and fat, and the presence/quantity of germinal centers and lymphoepithelial duct lesions were evaluated. Immunohistochemical characterization was performed to analyze the B:T cell ratio of the lymphocytic infiltrate (CD20, CD79a, CD3) and cellular proliferation in the acinar parenchyma (by double immunohistologic labeling for cytokeratin 14 and Ki-67). Histologic data were assessed for correlations with the parotid flow rate and saliva composition. RESULTS Four patients showed an increased salivary flow rate and normalization of the initially increased salivary sodium concentration. Following rituximab treatment, the lymphocytic infiltrate was reduced, with a decreased B:T cell ratio and (partial) disappearance of germinal centers. The amount and extent of lymphoepithelial lesions decreased in 3 patients and was completely absent in 2 patients. The initially increased proliferation of acinar parenchyma in response to inflammation was reduced in all patients. CONCLUSION Sequential parotid biopsy specimens obtained from patients with primary SS before and after rituximab treatment demonstrated histopathologic evidence of reduced glandular inflammation and redifferentiation of lymphoepithelial duct lesions to regular striated ducts as a putative morphologic correlate of increased parotid flow and normalization of the salivary sodium content. These histopathologic findings in a few patients underline the efficacy of B cell depletion and indicate the potential for glandular restoration in SS.

B Cell Reconstitution and T Helper Cell Balance After Rituximab Treatment of Active Primary Sjogren's Syndrome A Double- Blind, Placebo-Controlled Study

Objective To assess the phenotype of reconstituting B cells after B cell depletion, and to assess the effect of reconstitution on the balance of Treg cells and effector T cells in patients with active primary Sjogrens syndrome (SS). Methods Twenty-eight patients with primary SS were treated on days 1 and 15 with either rituximab (n = 19) or placebo (n = 9). The frequencies and absolute numbers of circulating B cell subsets, Treg cells, and effector T cells were examined in fresh blood samples by 4-color flow cytometry at baseline and 5, 12, 24, 36, and 48 weeks after the first infusion. The results in rituximab-treated patients were compared with those in patients receiving placebo and with those in age- and sex-matched healthy controls (n = 10). Results At baseline, patients with primary SS displayed several abnormalities in B cell homeostasis, including a significant reduction of CD27+ B cells and expansion of CD27– B cells, compared with healthy controls. At week 48 after rituximab treatment, the majority of emerging B cells exhibited a phenotype of transitional B cells. Although recovery of CD27+ memory B cells was delayed after rituximab treatment, a significant increase in Ig class–switched memory B cells within the memory pool was observed. In addition, percentages and absolute numbers of Treg cells and effector T cells, as well as ratios of effector T cells to Treg cells, did not change significantly after rituximab treatment. Conclusion The characteristics of reconstituted B cells in patients with primary SS following depletion by rituximab treatment showed dominance of transitional B cells during the early recovery phase, which corresponds to bone marrow–derived repopulation. The depletion of B cells did not influence the balance of peripheral Treg cells and effector T cells.

Serum levels of BAFF, but not APRIL, are increased after rituximab treatment in patients with primary Sjögren's syndrome: data from a placebo-controlled clinical trial

B cell depletion therapy with rituximab (RTX; 2 weekly infusions of 1000 mg, premedication: 100 mg prednisolone) in primary Sjogrens syndrome (pSS) patients is effective in reducing subjective and objective symptoms.1 As B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are important cytokines involved in B cell survival and activation, we assessed in pSS patients included in a double-blind, randomised, placebo-controlled trial1 the effects of RTX on serum BAFF and APRIL levels up to 48 weeks after RTX. Serum concentrations of BAFF and APRIL were measured by ELISA using kits from RD median 1277 pg/ml (range 907–3802 pg/ml)) compared with healthy controls (n=10; median 983 pg/ml (range 600–1564 pg/ml)); p<0.01; figure 1A). Also, baseline serum APRIL levels were significantly higher in pSS patients (median 15 098 pg/ml (range 1891–228 591 pg/ml)) than in healthy controls (median 1965 pg/ml (range 889–4567 pg/ml); p<0.05; …

Sjögren's syndrome and localized nodular cutaneous amyloidosis: coincidence or a distinct clinical entity?

OBJECTIVE To report 8 patients with Sjögrens syndrome (SS) and localized nodular cutaneous amyloidosis and to examine serologic and immunohistologic findings that may link the 2 diseases. METHODS The databases for 3 amyloidosis centers were searched for patients with localized nodular cutaneous amyloidosis and SS. Eight patients with this combination were identified, and clinical, serologic, and histologic parameters were retrospectively evaluated. RESULTS Among the 8 patients with a clinical diagnosis of SS, 6 fulfilled the American-European Consensus Group criteria for SS. All of the patients were women in whom SS had been diagnosed at a median age of 47 years (range 30-61 years) and amyloid had been diagnosed at a median age of 60 years (range 42-79 years). The presence of the immunoglobulin light chain type of amyloid (AL amyloid) was confirmed in 4 patients. In 3 of these 4 patients as well as 2 other patients, a light chain-restricted plasma cell population was observed near the amyloid deposits. Progression to systemic amyloidosis was not observed in any patient during a median followup of 3.5 years. CONCLUSION SS should be considered in patients with cutaneous amyloidosis. The combination of cutaneous amyloidosis and SS appears to be a distinct disease entity reflecting a particular and benign part of the polymorphic spectrum of lymphoproliferative diseases related to SS.

The Future of Biologic Agents in the Treatment of Sjögren’s Syndrome

The gain in knowledge regarding the cellular mechanisms of T and B lymphocyte activity in the pathogenesis of Sjögren’s syndrome (SS) and the current availability of various biological agents (anti-TNF-α, IFN- α, anti-CD20, and anti-CD22) have resulted in new strategies for therapeutic intervention. In SS, various phase I and II studies have been performed to evaluate these new strategies. Currently, B cell-directed therapies seem to be more promising than T cell-related therapies. However, large, randomized, placebo-controlled clinical trials are needed to confirm the promising results of these early studies. When performing these trials, special attention has to be paid to prevent the occasional occurrence of the severe side effects.

The n‐ vs. u‐serration is a learnable criterion to differentiate pemphigoid from epidermolysis bullosa acquisita in direct immunofluorescence serration pattern analysis

Serration pattern analysis of direct immunofluorescence (DIF) allows the differentiation of epidermolysis bullosa acquisita from other subtypes of pemphigoid. In daily practice its use is limited due to lack of experience and unfamiliarity.

Antilichaamtherapie bij het syndroom van Sjögren

Het syndroom van Sjogren (SS) komt wereldwijd voor. De prevalentie van SS wordt geschat op 0,5-1% van de bevolking. Deze hoge prevalentie maakt SS, op reumatoide artritis (RA) na, tot de meest voorkomende reumatologische aandoening. SS kan primair en secundair voorkomen. Primair SS wordt gekenmerkt door de combinatie van droge ogen, droge mond en vaak ook een zwelling van de speekselklieren. Bij secundair SS is naast deze trias sprake van een tweede auto-immuun gerelateerde aandoening, zoals RA of systemische lupus erythematodes (SLE). In iets meer dan de helft van de gevallen is er sprake van secundair SS. De ziekte komt vaker voor bij vrouwen dan bij mannen, in de verhouding 9 : 1 en openbaart zich over het algemeen tussen het 20ste en 40ste levensjaar (Fox, 2005).