TWEAK – a novel target for rheumatoid arthritis drugs
A member of the tumor necrosis factor (TNF) family, TNF-like weak inducer of apoptosis (TWEAK), has been identified as a potential new target for the treatment of rheumatoid arthritis (RA). The finding was published in the August issue of the Journal of Immunology.
RA is a chronic, autoimmune disorder, in which the immune system attacks the joints, causing inflammation, pain and potential loss of mobility. Once triggered by an as yet undefined factor, the immune system starts to attack the synovial tissues. Early mediators include proinflammatory cytokines, such as TNF-α, interleukin (IL)-1, -6, -8 and -15, inhibition of which is a current approach to RA treatment.
TWEAK has been identified by a group of researchers from Biogen Idec (MA, USA) and the University of Adelaide (Australia) and has a role in promoting the production of inflammatory cytokines, stimulating the secretion of damaging enzymes while inhibiting the repair of cartilage and bone.
Serum TWEAK levels increased dramatically during collagen-induced arthritis (CIA) in a mouse model. However, a monoclonal antibody that neutralized TWEAK could reduce the clinical severity of CIA significantly. The research team also showed a reduction in serum levels of inflammatory cytokines and joint-damaging enzymes using the anti-TWEAK therapy.
“Our investigative research suggests that TWEAK contributes to the disease through multiple mechanisms, and inhibiting the TWEAK pathway may represent a new set of opportunities for treatment,” said Timothy Zheng of Biogen Idec. “Our research is part of a broader effort to identify the role of the TWEAK pathway in several autoimmune diseases,” added Linda Burkly, the TWEAK program leader at Biogen Idec.
Anakinra can improve neonatal-onset multisystem inflammatory disease
Patients with neonatal-onset multisystem inflammatory disease (NOMID) may now benefit from anakinra (Kineret®, Amgen Inc., CA, USA), an approved drug for treating RA, the New England Journal of Medicine revealed in August.
NOMID is a rare but often fatal autoinflammatory disease in children and young adults, which causes fever, skin rash, joint damage, vision and hearing loss and mental retardation. The disease starts with a skin rash in infants approximately 6 weeks of age followed by inflammatory disorder of multiple organs. Despite various available anti-inflammatory treatments, only 80% of patients survive through childhood.
The exact cause of NOMID is not well established; however, approximately 60% of patients have a mutation in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene that encodes cryopyrin, an inflammation-regulating protein. The mutations lead to an abnormal level of IL-1.
Anakinra is an IL-1 receptor antagonist and is currently used as a RA-modulating drug. A research team led by Raphaela Goldbach-Mansky of the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has tested the drug on 18 NOMID patients, 12 of whom have CIAS1 mutations.
Anakinra was administered daily through subcutaneous injections. All patients responded positively with the drug and skin rash disappeared within 3 days of treatment. Other disease markers (serum amyloid A, C-reactive protein and erythrocyte sedimentation rate) also decreased significantly and remained low for the duration of the treatment. More than half of the patients had reductions in hearing loss, headaches, CNS lesions and corticosteroid dose after 6 months of the treatment. Disease relapsed quickly within days in 11 patients when the treatment was stopped after 3 months, however, when anakinra was restarted, control of the disease was regained. No major drug-related adverse effects were observed.
“This study demonstrates the efficacy of anakinra in improving major organ manifestations and helps confirm the role of IL-1β in many features of the disease, most importantly, the central nervous system,” said Goldbach-Mansky.
“NOMID is a devastating disease for which previously there was little understanding or effective treatment. This study not only provides hope, in the way of an already available agent, but it also provides a better understanding of the mechanism of the disease’s damaging effects,” added NIAMS director Stephen Katz.
Living further from the equator can predispose susceptible patients to multiple sclerosis
Patients susceptible to multiple sclerosis (MS) have an increased risk of developing the disease if they live further north of the equator compared with those living near the equator, the Annals of Neurology revealed last month.
A team led by Thomas Mack of the University of Southern California (CA, USA) has studied 418 pairs of identical twins and 380 pairs of same-sex nonidentical twins.
The concordance (both twins diagnosed with MS) in nonidentical twins was significantly (two- to three-times) less than in identical twins, suggesting that genetic factors play an important role in MS development.
In identical twins, the concordance was 18.6% in patients living above 41o north (in Canada and adjacent US states), almost twice as high as the concordance in those living further south (9.5%). This latitude effect was not observed in nonidentical twins.
Furthermore, the concordance in either twin group was independent of the patients’ genders, despite previous thoughts that MS is more prevalent in women.
The findings suggest that “there is some environmental exposure and it is interacting with the genes,” said Mack. The northern environment may lack protective factors or inhibitors of unknown viruses, which altogether predispose susceptible patients to MS. “It may even be that exposure to the sun interrupts whatever effect a virus has,” added Mack.
New role of interferon-γ in immune modulation
The finding that interferon (IFN)-γ plays an important role in activating regulatory T cells (Tregs) has appeared in the August online issue of the Journal of Clinical Investigation.
Tregs are a subpopulation of T cells that suppresses the activation of the immune system and prevents autoimmune diseases and inflammation. Tregs have been characterized recently with the exclusive expression of the forkhead box p3 (Foxp3) transcription factor.
Foxp3-expressing Tregs also express two cell-surface marker proteins, CD4 and CD25, hence they are also known as CD4+CD25+Foxp3+ T cells. Foxp3 is essential for the conversion to active Tregs from CD4+CD25- T cells.
A research team led by Jingwu Zhang (Institute of Health Sciences, China) has found that IFN-γ-deficient mice were significantly more susceptible to experimental autoimmune encephalomyelitis (EAE) than wild-type animals. The severity of EAE correlated directly with a reduction in both the number and function of CD4+CD25+Foxp3+ Tregs.
In vitro treatment of CD4+CD25- T cells with IFN-γ resulted in an increase in Foxp3 expression, leading to the conversion of these cells to functional Tregs. Furthermore, these IFN-γ-treated Tregs, when transferred to IFN-γ-deficient mice, successfully suppressed EAE development in these animals.
IFN-γ is a well-known proinflammatory cytokine that induces inflammation. This study suggests a more complex role for IFN-γ in regulating inflammation through Treg activation.
IFN-β1b delays multiple sclerosis development
Early treatment with IFN-β1b can delay the development of multiple scleroisis (MS) by half for at least 2 years following the first suggestive event of the disease. The finding appeared in the August online issue of the journal Neurology.
MS is an autoimmune disease that attacks the CNS, causing damage to the myelin sheath that covers the neuron axons, leading to disruptions in the nerve pathways, muscle weakness, loss of coordination and speech and vision impairment.
The researchers have conducted a multicenter, randomized, double-blind trial, in which 292 patients received 250 µg of IFN-β1b subcutaneously every other day while 176 others received a placebo. All patients were monitored for 2 years or until they developed clinically definite MS (CDMS).
At the end of the 2-year period, 45% of patients receiving placebo developed CDMS. The risk of developing CDMS was halved in patients receiving treatment with IFN-β1b.
“It is important for people who are experiencing symptoms of MS to see a neurologist for diagnosis and treatment,” emphasized Mark Freedman, a research team member.
“Our study provides a strong rationale for the early use of early IFN-β1b therapy after the first episode suggestive of MS,” added Freedman. “It is well established that neurological damage, including damage of the nerve fibers or axons, can occur even before MS is diagnosed. The current thinking is that by limiting the amount of axonal damage through early and effective therapy, we can postpone a person’s disability.”
Obstructive sleep apnea linked to asthma in women
In the August issue of the Annals of Allergy, Asthma and Immunology, scientists have revealed that women with asthma have an almost twofold risk of developing obstructive sleep apnea (OSA) compared with those who do not have asthma.
The study involved 677 young women and was carried out by researchers from the University of Cincinnati and Cincinnati Children’s Hospital Medical Center (OH, USA).
The team has found that approximately 21% of women with asthma reported snoring, twice as many as those without asthma. Women who smoked cigarettes also reported snoring more than those who did not smoke.
Snoring is the primary symptom of OSA, when the airways become narrow and eventually blocked, leading to short nonbreathing periods and low oxygen content in the blood. This then triggers brain signals that wake people up and the cycle can repeat as much as hundreds of times per night.
Treatment of OSA involves surgical removal of airway tissues and wearing pressure masks during sleep. If left untreated, OSA can lead to fatigue, memory loss, mood change, increased blood pressure and reduced heart function.
“Our study reinforces the need for awareness and early detection of the disease in women who are at increased risk for breathing disorders related to sleep,” said the research team leader, Maninder Kalra.