Aike A. Kruize

Infection rate and use of antibiotics in patients with rheumatoid arthritis treated with methotrexate

OBJECTIVE--To investigate prospectively the frequency and type of infections and the use of antibiotics among patients with rheumatoid arthritis (RA) on methotrexate (MTX) and patients with RA without MTX. METHODS--Every three months for one year 77 patients on MTX and 151 patients without MTX were asked about infections and the use of antibiotics by means of a standardised questionnaire. Medication was checked with the pharmacist. RESULTS--In the MTX group there were significantly more infections and more antibiotic therapy. The relative risks for patients on MTX of infection or antibiotics use were 1.52 (95% Confidence Interval (CI) 1.04-2.22) and 1.49 (95% CI 1.04-2.13), respectively. The relative risk of MTX for respiratory tract infections was 1.43 (95% CI 0.96-2.14) and for skin infections 2.19 (95% CI 1.45-3.31). The increased risks could only partly be explained by differences in disease severity and were not related to either duration of MTX therapy or use of prednisone. Three patients in the MTX group had herpes zoster versus one in the control group. CONCLUSIONS--Treatment with MTX increases the rate of infection and thus the use of antibiotics but does not lead to serious complications necessitating discontinuation of the drug.

Aggressive treatment in early rheumatoid arthritis: a randomised controlled trial

OBJECTIVES To compare three therapeutic strategies using slow acting antirheumatic drugs (SAARDs) in early rheumatoid arthritis (RA), for their disease modifying properties, toxicity, and lag time until treatment effect. METHODS Patients with recent onset RA from six hospitals were randomly assigned to immediate initiation of one of three treatment strategies: (I) a “mild SAARD with a long lag time” (hydroxychloroquine, if necessary replaced by auranofin); (II) a “potent SAARD with a long lag time” (intramuscular gold, if necessary replaced byd-penicillamine); (III) a “potent SAARD with a short lag time” (methotrexate, if necessary replaced by sulfasalazine). Comparisons included two years of follow up. RESULTS All SAARD strategies reduced mean disease activity. A greater percentage of patients improved clinically with strategies II and III than with strategy I: percentages of patients improved on joint score with strategies II and III (79% and 82%, respectively), which was statistically different from strategy I (66%). The same was true for remission percentages: 31% and 24% v 16%, respectively). Longitudinal analysis showed significantly less disability with strategy III, and a lower erythrocyte sedimentation rate with strategy II than with strategy I. In addition, radiological damage after one and two years, was significantly lower in strategies II and III (at two years median scores were 11 and 10v 14 in strategy I, p<0.05). Toxicity was increased in strategy II compared with the other strategies. CONCLUSION Strategy III, comprising methotrexate or sulfasalazine, produced the best results weighing effectiveness and toxicity. Strategy I (hydroxychloroquine or auranofin) was slightly less effective, and strategy II (intramuscular gold or d-penicillamine) was associated with increased toxicity.

High-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with rheumatoid arthritis: Results of an open study to assess feasibility, safety, and efficacy

OBJECTIVE To assess the feasibility, safety, and efficacy of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT) in patients with severe, refractory rheumatoid arthritis (RA). METHODS Fourteen patients (3 male, 11 female, mean age 43 years, mean disease duration 10 years) with active, destructive, refractory RA entered the study. Autologous hematopoietic stem cells were collected by leukapheresis after mobilization with a single infusion of cyclophosphamide (CYC; 4 gm/m2) and subcutaneous injections of filgrastim (granulocyte colony-stimulating factor). Immunomagnetic selection of CD34+ cells from the leukapheresis products was performed to deplete potentially autoreactive lymphocytes. The conditioning regimen consisted of intravenous administration of high doses of CYC (cumulative dose 200 mg/kg), with subsequent reinfusion of the graft. Patients were monitored for disease activity, disability, adverse effects, and hematopoietic and immunologic reconstitution. RESULTS All 14 patients completed the mobilization and leukapheresis procedures successfully, and 12 proceeded to receive conditioning and transplantation. Engraftment occurred in all of these patients, with rapid hematologic recovery. No major unexpected toxicity was observed. Marked improvement of disease activity was recorded in 8 of 12 patients at >50% of the visits, with a followup ranging from 7 months to 21 months. The clinical responders included 2 patients who had previously failed treatment with tumor necrosis factor (TNF) blocking agents. CONCLUSION High-dose chemotherapy followed by autologous HSCT is feasible and safe, and can result in long-term improvement of disease activity in patients whose condition previously did not respond to conventional antirheumatic drugs or TNF blocking agents. The persistence of active disease in some patients may reflect the heterogeneity of the underlying disease process.

The Role of Ectopic Germinal Centers in the Immunopathology of Primary Sjögren's Syndrome: A Systematic Review

OBJECTIVES To determine whether the presence of germinal centers (GCs) in salivary glands of patients with primary Sjögrens syndrome (pSS) is related to the severity of disease course and distinct immunopathology features. METHODS A systematic search was performed in September 2011 for terms and synonyms of Sjögrens syndrome and germinal centers. A total of 80 articles were retrieved, of which 16 were included for (meta-) analysis. RESULTS GC morphology was present in a mean ± SD 25.1 ± 5.0% of pSS patients. Mean lymphocyte focus scores were 1.25 points higher in patients with GCs as compared to those without GCs. Saliva production was reduced in patients with GCs, although this did not reach statistical significance. Percentages of patients positive for rheumatoid factor, anti-Sjögrens syndrome A (SSA), and anti-Sjögrens syndrome B (SSB) antibodies were significantly higher in patients with GCs (mean increase, 15%, 18%, and 18%, respectively). Additionally, patients with GCs were characterized by enhanced levels of local and systemic proinflammatory mediators. Importantly, these patients have a higher risk of lymphoma development (14% versus 1%). CONCLUSIONS Patients with GCs are characterized by more severe disease, although the small number of studies and their design hamper generalizability of results. The precise mechanisms that contribute to the development and persistence of germinal centers in pSS are largely unknown. This and the strongly increased risk of lymphoma development warrant intensive studies for the role of germinal centers in the immunopathology of pSS.

Validation of EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI)

Objectives To validate the two recently developed disease activity indexes for assessment of primary Sjögrens syndrome (SS): the European League Against Rheumatism (EULAR) SS Patient Reported Index (ESSPRI) and the EULAR SS Disease Activity Index (ESSDAI). Methods A prospective international 6-month duration validation study was conducted in 15 countries. At each visit, physicians completed ESSDAI, SS disease activity index (SSDAI), Sjögrens Systemic Clinical Activity Index (SCAI) and physician global assessment (PhGA); and patients completed ESSPRI, Sicca Symptoms Inventory (SSI), Profile of Fatigue and Discomfort (PROFAD) and patient global assessment (PGA). Psychometric properties (construct validity, responsiveness and reliability) were evaluated and compared between scores. Results Of the 395 patients included, 145 (37%) and 251 (64%) had currently active or current or past systemic manifestations, respectively. EULAR scores had higher correlation with the gold standard than other scores (ESSDAI with PhGA: r=0.59; ESSRPI with PGA: r=0.70). Correlations between patient and systemic scores were very low (ranging from 0.07 to 0.29). All systemic scores had similar large responsiveness in improved patients. Responsiveness of patient scores was low but was significantly higher for ESSPRI compared with SSI and PROFAD. Reliability was very good for all scores. Conclusions ESSDAI and ESSPRI had good construct validity. All scores were reliable. Systemic scores had a large sensitivity to change in patients whose disease activity improves. Patient scores had a small sensitivity to change, however, significantly better for ESSPRI. Systemic and patient scores poorly correlated, suggesting that they are 2 complementary components that should be both evaluated, but separately.

Effect of dehydroepiandrosterone administration on fatigue, well-being, and functioning in women with primary Sjögren syndrome: a randomised controlled trial

Objective: Dehydroepiandrosterone (DHEA) administration has been reported to improve fatigue, psychological distress, and physical disability. These are common features of primary Sjögren syndrome (pSS). We investigated the effects of DHEA administration on fatigue, well-being, and functioning in women with pSS. Methods: In a double-blind, randomised placebo-controlled clinical trial, 60 female patients with pSS received 200 mg oral DHEA or placebo. Primary outcome measures were general fatigue, depressive mood, mental well-being, and physical functioning. In addition, pain, sicca complaints and disease activity parameters were measured. Patients were assessed before treatment, after 3, 6, and 12 months on study medication, and 6 months after cessation of treatment. Results: Patients from both the DHEA- and placebo-treated group improved on general fatigue (p<0.001), mental well-being (p = 0.04), and depressive mood (p = 0.008). Physical functioning did not change (p = 0.44). Of the secondary outcome variables, complaints of a dry mouth diminished during treatment in both groups (p = 0.006), the erythrocyte sedimentation rate showed a decrease for the DHEA group (p = 0.02), and complaints of dry eyes improved in the placebo group (p = 0.01). The belief to have used DHEA was a stronger predictor for improvement of fatigue and well-being than the actual use of DHEA. Conclusions: Our study does not support a superior effect of DHEA over placebo in female patients with pSS. Both DHEA and placebo induce improvement of fatigue and well-being. This may suggest possibilities for cognitive behavioural interventions.

Defining disease activity states and clinically meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI)

Objectives To define disease activity levels, minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) with the primary Sjögrens syndrome (SS) disease activity indexes: European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and EULAR SS patient-reported index (ESSPRI). Methods For 790 patients from two large prospective cohorts, ESSDAI, physician evaluation of disease activity, ESSPRI and patients’ satisfaction with their current health status were recorded. Receiver operating characteristic curve analyses and anchoring methods were used to estimate disease activity levels of ESSDAI and the PASS of ESSPRI. At follow-up visit, patients and physicians assessed, respectively, whether symptoms and disease activity have improved or not. An anchoring method based on this evaluation was used to estimate MCII of ESSDAI and ESSPRI. Results Low-activity (ESSDAI<5), moderate-activity (5≤ESSDAI≤13) and high-activity (ESSDAI≥14) levels were defined. MCII of ESSDAI was defined as an improvement of at least three points. The PASS estimate was defined as an ESSPRI<5 points and MCII as a decrease of at least one point or 15%. Conclusions This study determined disease activity levels, PASS and MCII of ESSDAI and ESSPRI. These results will help designing future clinical trials in SS. For evaluating systemic complications, the proposal is to include patients with moderate activity (ESSDAI≥5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI≥5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable.

Safety and efficacy of leflunomide in primary Sjögren’s syndrome: a phase II pilot study

Background: For invalidating symptoms in primary Sjögren’s syndrome (pSS), there is still a need for easy-to-administer, cost-effective and well-tolerated systemic treatment. Leflunomide (LEF) is structurally unrelated to other immunomodulatory drugs and might be efficacious in pSS, given its characteristic immunoregulatory modes of action. Objective: To investigate the safety and efficacy of LEF in pSS in a phase II open-label pilot study. Methods: 15 patients with pSS with early and active disease received LEF 20 mg once daily for 24 weeks. Tolerability, safety and efficacy of LEF were evaluated every 8 weeks. Additional safety visits were performed every fortnight. Results: Mild gastrointestinal discomfort (including diarrhoea) and hair loss were mainly reported. Five patients developed lupus-like skin lesions on the face, arms or trunk, responding well to topical corticosteroids, nevertheless causing the withdrawal of one patient. Two patients with pre-existing hypertension had to increase dosages of anti-hypertensive drugs. Increased levels of alanine aminotransferase normalised after dose reduction in two patients. A decrease in general fatigue and an increase in physical functioning were observed after 24 weeks. Serum IgG levels decreased from 8 weeks onwards. Schirmer test values increased, not reaching statistical significance, whereas sialometry values did not change. In four of five repeated biopsies, the lymphocytic focus score decreased at the rate of 1 focus/4 mm2. A remarkable amelioration of leucocytoclastic vasculitis was observed in three patients. Conclusions: Although the safety profile seems fairly acceptable, the observed indications for efficacy were modest and may be doubtful in justifying a randomised controlled trial of LEF in pSS.

Increased expression of interleukin-7 in labial salivary glands of patients with primary Sjögren's syndrome correlates with increased inflammation

OBJECTIVE To study the expression levels and immunostimulatory capacities of interleukin-7 (IL-7) in primary Sjögrens syndrome. METHODS Labial salivary gland (LSG) IL-7 expression was determined by immunohistochemistry, using a quantitative scoring system, in 30 patients with sicca syndrome: 15 patients with primary Sjögrens syndrome (SS) and 15 patients with non-SS sicca syndrome. The correlation of IL-7 expression in LSGs with parameters of local and peripheral disease was studied, and serum and salivary IL-7 levels were determined. Additionally, the effects of IL-7 on cytokine production by peripheral blood mononuclear cells (PBMCs) from patients with primary SS were determined in vitro by Luminex multicytokine assay and compared with the effects in control subjects. RESULTS The expression of IL-7 in LSGs was higher in patients with primary SS compared with that in patients with non-SS sicca syndrome. IL-7 was observed primarily in the vicinity of lymphocytic infiltrates. Salivary IL-7 levels in patients with primary SS were higher than those in control subjects. In all 30 patients with sicca syndrome, IL-7 expression in LSGs correlated with parameters of both local and peripheral disease. Furthermore, IL-7 stimulated T cell-attracting and T cell-differentiating cytokines (monokine induced by interferon-gamma [IFNgamma], IFNgamma-inducible 10-kd protein, IL-12, and IL-15), as well as Th1 (IFNgamma), Th2 (IL-4), Th17 (IL-17A), proinflammatory (tumor necrosis factor alpha and IL-1alpha), and regulatory (IL-10 and IL-13) cytokine production by PBMCs. All of these cytokines were previously shown to be associated with primary SS. The IL-7-induced increase in IL-10 production in patients with primary SS was reduced compared with that in control subjects. CONCLUSION The correlation between LSG IL-7 expression and (local) disease parameters in primary SS as well as the IL-7-mediated induction of inflammatory cytokines indicate that IL-7 might contribute to the immunopathology of primary SS.

Salivary gland and peripheral blood T helper 1 and 2 cell activity in Sjögren’s syndrome compared with non-Sjögren’s sicca syndrome

Objectives: To investigate whether differences in T helper (Th) 1 and Th2 cell activity in salivary glands (“local”) or (“peripheral”) blood can discriminate between Sjögren’s syndrome (SS) and non-Sjögren’s sicca syndrome (nSS-sicca). Additionally, to study relationships of local and peripheral Th cell activities with each other and with disease activity measures. Methods: 62 sicca patients (32 with SS, 30 with nSS-sicca) were studied. Local Th1 (interferon γ (IFNγ)) and Th2 (interleukin (IL) 4) activity were determined using immunohistochemistry. T cell production of IFNγ and IL4 in peripheral blood (PB) was determined by ELISA. Erythrocyte sedimentation rate (ESR) and serum IgG were considered disease activity measures. Results: ESR and serum IgG were higher in patients with SS than in patients with nSS-sicca. Local Th1 cell activity was higher and PB Th1 activity lower in patients with SS than in those with nSS-sicca. Th2 cell activity did not differ significantly between the patient groups. The ratio IFNγ/IL4 was higher in salivary glands and lower in PB in patients with SS than in patients with nSS-sicca. Local and peripheral Th1 and Th2 cell activities correlated with ESR and serum IgG levels. ESR, serum IgG, and local or peripheral Th1 or Th2 cell activity did not discriminate between patients with SS and nSS-sicca. Conclusions: An imbalance between Th1 and Th2 activity in sicca patients is clearly related to the severity of disease, but cannot be used to distinguish between patients with SS and those with nSS-sicca.