[Swiss registry for TNF-alpha blockers in children and adolescents with rheumatological diseases]

We created a registry to evaluate long term outcome, efficacy and adverse events for children treated wit TNF-alpha inhibitors in Switzerland. 106 patients (68 female/38 male) were included. 61 patients were treated with Etanercept (Enbrel) and 45 with Infliximab (Remicade). Concomitant treatment at baseline included corticosteroids in 26% and Methotrexate in 75% of the patients. Subjective disease activity three months after initiation of TNF-alpha was better in 81%, worse in 4% and stable in 15% of the patients. In total 24 adverse events in 21 patients were reported. Treatment with TNF-alpha inhibitors seems to be safe and effective for children and adolescents with rheumatologic diseases.

The Combination of Interferon-Beta and HMG-CoA Reductase Inhibition in Multiple Sclerosis: Enthusiasm Lost too Soon?

Recent studies support the notion that statins, widely prescribed cholesterol-lowering agents, may target key elements in the immunological cascade leading to inflammation and tissue damage in the pathogenesis of multiple sclerosis (MS). Compelling experimental and observational clinical studies highlighted the possibility that statins may also exert immunomodulatory synergy with approved MS drugs, resulting in several randomized clinical trials testing statins in combination with interferon-beta (IFN-?). Some data, however, suggest that this particular combination may not be clinically beneficial, and might actually have a negative effect on the disease course in some patients with MS. In this regard, a small North American trial indicated that atorvastatin administered in combination with IFN-? may increase disease activity in relapsing-remitting MS. Although other trials did not confirm this finding, the enthusiasm for studies with statins dwindled. This review aims to provide a comprehensive overview of the completed clinical trials and reports of the interim analyses evaluating the combination of IFN-? and statins in MS. Moreover, we try to address the evident question whether usage of this combination routinely requires caution, since the number of IFN-?-treated MS patients receiving statins for lowering of cholesterol is expected to grow.

Pregnancy and reproduction in autoimmune rheumatic diseases

Despite evidence for the important role of oestrogens in the aetiology and pathophysiology of chronic immune/inflammatory diseases, the previous view of an unequivocal beneficial effect of oestrogens on RA compared with a detrimental effect on SLE has to be reconsidered. Likewise, the long-held belief that RA remits in the majority of pregnant patients has been challenged, and shows that only half of the patients experience significant improvement when objective disease activity measurements are applied. Pregnancies in patients with SLE are mostly successful when well planned and monitored interdisciplinarily, whereas a small proportion of women with APS still have adverse pregnancy outcomes in spite of the standard treatment. New prospective studies indicate better outcomes for pregnancies in women with rare diseases such as SSc and vasculitis. Fertility problems are not uncommon in patients with rheumatic disease and need to be considered in both genders. Necessary therapy, shortly before or during the pregnancy, demands taking into account the health of both mother and fetus. Long-term effects of drugs on offspring exposed in utero or during lactation is a new area under study as well as late effects of maternal rheumatic disease on children.

Is IgG galactosylation the relevant factor for pregnancy-induced remission of rheumatoid arthritis?

During pregnancy, most patients with rheumatoid arthritis (RA) experience spontaneous improvement of their disease activity. Among the soluble candidates that have been investigated in search for the most relevant disease-remitting factor are the galactosylation levels of immunoglobulin G (IgG). In RA, a higher percentage of IgG lacking the terminal galactose residues, thought to play a pro-inflammatory role, is found. During pregnancy, however, IgG galactosylation levels increase and correlate with improved disease activity. The question remains whether the increase in IgG galactosylation during pregnancy is a mere epiphenomenon or a true remission-inducing factor.

Measurement issues in trials of pediatric acute diarrheal diseases: a systematic review

BACKGROUND: Worldwide, diarrheal diseases rank second among conditions that afflict children. Despite the disease burden, there is limited consensus on how to define and measure pediatric acute diarrhea in trials. OBJECTIVES: In RCTs of children involving acute diarrhea as the primary outcome, we documented (1) how acute diarrhea and its resolution were defined, (2) all primary outcomes, (3) the psychometric properties of instruments used to measure acute diarrhea and (4) the methodologic quality of included trials, as reported. METHODS: We searched CENTRAL, Embase, Global Health, and Medline from inception to February 2009. English-language RCTs of children younger than 19 years that measured acute diarrhea as a primary outcome were chosen. RESULTS: We identified 138 RCTs reporting on 1 or more primary outcomes related to pediatric acute diarrhea/diseases. Included trials used 64 unique definitions of diarrhea, 69 unique definitions of diarrhea resolution, and 46 unique primary outcomes. The majority of included trials evaluated short-term clinical disease activity (incidence and duration of diarrhea), laboratory outcomes, or a composite of these end points. Thirty-two trials used instruments (eg, single and multidomain scoring systems) to support assessment of disease activity. Of these, 3 trials stated that their instrument was valid; however, none of the trials (or their citations) reported evidence of this validity. The overall methodologic quality of included trials was good. CONCLUSIONS: Even in what would be considered methodologically sound clinical trials, definitions of diarrhea, primary outcomes, and instruments employed in RCTs of pediatric acute diarrhea are heterogeneous, lack evidence of validity, and focus on indices that may not be important to participants.

Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series

OBJECTIVE: To evaluate the effect of IL-6 blockade using tocilizumab in inducing remission of arterial large vessel vasculitides (LVV). METHODS: Five consecutive patients with giant-cell arteritis (GCA) and two with Takayasu’s arteritis (TA) were treated by tocilizumab infusions (8 mg/kg). Tocilizumab was given every other week for the first month and once monthly thereafter. Clinical symptoms of disease activity, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level and glucocorticoid (GC) dosage necessary to maintain remission were prospectively assessed. MR angiography was performed to monitor local inflammation. RESULTS: Of the seven patients three were newly diagnosed and four showed GC resistance, i.e. GC could not be lowered to less than 7.5 mg/day. The mean follow-up time was 4.3 months (range 3–7 months). All patients achieved a rapid and complete clinical response and normalisation of the acute phase proteins. Remarkably, prednisone dosage could be reduced within 12 weeks to a mean of 2.5 mg/day (range 0–10 mg/day). No relapse and no drug-related side effects were noted. CONCLUSION: Collectively the data suggest that IL-6 blockade using tocilizumab qualifies as a therapeutic option to induce rapid remission in large vessel vasculitides.

Eculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findings

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy associated with defective regulation of the alternative complement pathway. The prognosis for patients with aHUS is poor, and plasma exchange represents the first-line therapy. Eculizumab is a humanized monoclonal anti-C5 antibody that prevents the activation of the terminal complement pathway. Here, we report the case of a 9-year-old girl with frequent relapsing aHUS due to heterozygous factor H mutation who was initially treated with plasma exchange three times per week with 150% plasma exchange volume. This treatment frequently caused allergic reactions and school absences. Because any reduction in the frequency of plasma exchange immediately induced relapses of the aHUS, treatment with eculizumab, 600 mg every 2 weeks, was started and plasma exchange completely stopped. On this drug regimen the patient showed no evidence of disease activity during a period of more than 24 months. Renal function improved, proteinuria disappeared, the number of antihypertensive medications could be decreased, and the quality of life increased substantially. The inhibition of the terminal complement pathway by eculizumab was also confirmed by renal biopsy, which showed the absence of thrombotic microangiopathy 2 months after the initiation of eculizumab therapy. This case illustrates the long-term favorable outcome of aHUS with eculizumab treatment.

Influence of pregnancy on the adipocytokine and peroxisome proliferator-activated receptor pathways in peripheral blood mononuclear cells from healthy donors and rheumatoid arthritis patients

To identify candidate genes that are regulated by human pregnancy and have the potential to modulate rheumatoid arthritis (RA) disease activity.

Serum cytokine profile in patients with active lupus nephritis

Determination of disease activity of lupus nephritis remains challenging. Since cytokines play a role as inflammatory mediators extending renal injury, measuring serum cytokine levels might help in the clinical assessment of patients with lupus nephritis. Therefore, the aim of this study was to determine the diagnostic value of a panel of serum cytokines in patients with active lupus nephritis.

Pregnancy mediated improvement of rheumatoid arthritis

To investigate pregnancy related changes of rheumatoid factor (RF) isotypes and anti-citrullinated protein antibodies (ACPA) and their association with disease activity and therapy in patients with rheumatoid arthritis.

Eosinophilic esophagitis in adults--no clinical relevance of wheat and rye sensitizations

BACKGROUND: Eosinophilic esophagitis (EE) is often associated with concomitant atopic diseases. In children with EE in whom food allergens have been identified as causative factors, elemental and elimination diets result in an improvement or resolution of symptoms. Most adult EE patients are sensitized to aeroallergens, which cross-react with plant-derived food allergens, most commonly to grass pollen and cereals. AIMS OF THE STUDY: To investigate the clinical relevance of the sensitization to wheat and rye, and the efficacy of an allergen-specific elimination diet in adult EE patients. METHODS: Six patients (five men, one women) with permanently active EE sensitized to grass pollen and the cereals wheat and rye underwent a double-blind placebo-controlled food challenge and were kept on an elimination diet avoiding wheat and rye for 6 weeks. RESULTS: The challenge tests with wheat and rye did not provoke any EE symptoms in all patients. The elimination diet failed in reducing disease activity. Although one patient noticed an improvement of symptoms, endoscopic and histopathologic findings remained unchanged. CONCLUSIONS: In adult EE patients, sensitization to wheat and rye does not seem causative for EE. Elimination diet is not a reliable and efficient therapeutic measure in EE patients sensitized to wheat and rye. Low specific immunoglobulin-E levels to wheat and rye may be a consequence of the underlying grass pollen allergy.

The antibody response in experimental ocular toxoplasmosis

BACKGROUND: The dynamics of the humoral immune response in ocular toxoplasmosis (OT) are poorly understood. We therefore investigated this process in a rabbit model of the disease. MATERIALS AND METHODS: Of 24 infection-naïve adult rabbits, 12 were left untreated and 12 were systematically infected with 5,000 tachyzoites of the non-cyst-forming BK strain of Toxoplasma gondii. Three months later, all rabbits were inoculated transvitreally with 5,000 tachyzoites of Toxoplasma gondii. Paired samples of aqueous humor and serum were analyzed temporally for their total and specific IgG contents. RESULTS: In infection-naïve rabbits with primary OT, specific IgG reached detectable levels in the inoculated eyes between 5 and 15 days after inoculation. In infection-immunized rabbits with secondary OT, a significant increase in specific IgG was regularly detected after 5 days. The antibody ratio C was diagnostic (>/=3) from day 15 onward in primary OT and from day 21 onward in secondary OT. In the uninfected partner eyes, the antibody ratio C was found sporadically diagnostic from day 15 onward in primary OT, but at no time in secondary OT. Specific IgG persisted both locally and in the serum until the end of the monitoring period (100 days). CONCLUSION: Our findings relating to the rabbit model of OT reveal three features of clinical relevance: a diagnostic window precedes the establishment of a humoral immune response; specific antibodies persist long after the cessation of disease activity; and in primary OT, the antibody ratio C may also increase in the uninfected partner eye.

The -308 tumour necrosis factor-alpha gene polymorphism predicts therapeutic response to TNFalpha-blockers in rheumatoid arthritis and spondyloarthritis patients

OBJECTIVE: To examine whether the G-to-A polymorphism at position -308 in the promoter of the tumour necrosis factor-alpha (TNFalpha) gene influences the therapeutic response to TNFalpha-blockers in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS). METHODS: A total of 54 patients with RA, 10 with PsA and 22 with AS were genotyped by polymerase chain reaction for the -308 TNFalpha promoter polymorphism. They were treated with infliximab (n = 63), adalimumab (n = 10) or etanercept (n = 13). Clinical response was assessed after 24 weeks by the Disease Activity Score in 28 joints (DAS28) for RA and PsA, and the Bath Ankylosing Spondylitis Activity Index (BASDAI) for AS patients. RESULTS: All patients with the A/A genotype (n = 3, all RA) and two patients with the A/G genotype (AS) failed to respond to anti-TNF treatment. Irrespective of the underlying disease, moderate response (n = 44) was predominantly associated with the A/G genotype (A/G 18/22, G/G 4/22), whereas good response (n = 59) was exclusively seen in patients with the G/G genotype. The average improvement in the DAS28 score was 0.83 in the A/A, 1.50 in the A/G and 2.64 in the G/G group of RA and PsA patients (P < 0.0001). The BASDAI score in AS improved on average by 1.21 in the A/G and by 3.30 in the G/G group (P < 0.005). CONCLUSIONS: The data suggest that humans with a TNFalpha -308 G/G genotype are better responders to anti-TNFalpha treatment than those with A/A or A/G genotypes independent of the treated rheumatic disease (RA, PsA or AS).

Anti-inflammatory and immunosuppressive drugs and reproduction

Rheumatic diseases in women of childbearing years may necessitate drug treatment during a pregnancy, to control maternal disease activity and to ensure a successful pregnancy outcome. This survey is based on a consensus workshop of international experts discussing effects of anti-inflammatory, immunosuppressive and biological drugs during pregnancy and lactation. In addition, effects of these drugs on male and female fertility and possible long-term effects on infants exposed to drugs antenatally are discussed where data were available. Recommendations for drug treatment during pregnancy and lactation are given.

[Pregnancy in patients with rheumatoid arthritis and inflammatory spondylarthropathies]

The activity of a rheumatic disease can be influenced by pregnancy and puerperium. Prospective studies have shown an improvement in joint involvement in rheumatoid arthritis in two thirds to three quarters of pregnancies. After birth, an exacerbation is common. In spondylarthropathies there is no relevant change in disease activity. The fetal outcome is not impaired in patients with rheumatoid arthritis and inflammatory spondylarthropathies. Every pregnancy in women with a rheumatic disease should be considered as high-risk, and such pregnancies require close collaboration between rheumatologists and obstetricians.