Three poor normally does not make one rich - or does it ?

A new meta-analytical study in rheumatoid arthritis confirms superiority of Methotrexate, Sulfasalazine and Hydroxychloroquin combination therapy over  Methotrexate alone and shows that it is not statistically different from the expensive  biological therapy

Rheumatoid arthritis (RA) is a progressive inflammatory joint disease of unknown etiology. In recent decades its therapy with synthetic and biological Disease-Modifying AntiRheumatic Drugs (DMARDs) has produced a major breakthrough. By now, nearly all rheumatoid patients’ disease activity can be effectively controlled with DMARDs, resulting a significant improvement in their impairment, disability and handicap.

Previous meta-analyses have shown that most biological DMARDs combined with methotrexate are superior to methotrexate alone for controlling disease activity, however, the benefits of combining methotrexate with conventional synthetic DMARDs, such as sulfasalazine and hydroxychloroquine, are uncertain, in spite of the fact that biological therapy costs 10-20 times more than most conventional synthetic DMARDs.

A new Cochrane Network meta-analytic study has been recently conducted by researchers from the University of Calgary in Alberta, Canada and an abridged version of the study was published in the BMJ in April 2016.1

The meta-analysis included 158 trials with more than 37 000 patients.

’Triple therapy’ (methothrexate plus sulfasalazine plus hydroxychloroquine) was superior to methotrexate alone and not statistically different from methotrexate plus any biological DMARDs for controlling disease activity, either as initial therapy or additional treatment after an inadequate response to methotrexate.

These findings support that triple therapy should be either an intial treatment option or an additional  one after an inadequate reponse to methotrexate in rheumatoid arthritis.

Reference:

1.

Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe D, Bombardier C: Methotrexate monotherapy and methotrexate combination therapy with traditional and biological disease modifying antirheumatic drugs for rheumatoid arthritis: abridges Cochrane systematic review and network meta-analysis. BMJ 2016;353:i1777

Paleopathology reveals new genetic markers in Ankylosing Spondylitis

Ankylosing spondylitis (AS) is an inflammatory spine disease with involvement of the sacroiliacal joints, the apophyseal joints and other fibroblastic structures, such as tendons and ligaments (syndesmophyte formation, enthesitis). The end result is full spinal bony fusion, hence is the designation of ‘ankylosis’. One third of patients suffer from additional peripheral joint arthritis.

The condition has the strongest genetic link in medicine: 95-97% of axial spondyloarthritis patient are homozygous for the HLA-B27 gene, however, there are other genes, both within and outside the Main Histocompatibility Complex  (MHC), that are involved in the pathogenesis of AS. An indirect proof is that the B27 allele has been found not only in AS patients, but also in about 10% of the general population. As only 2-4% of these individuals ever develop a clinically manifest disease entity, some other genetic factors should play a role in the disease process.

Researcher from the University of the Basque Country in Biscay, Spain, studied this uniques genetic background in an individual’s skeleton from a 16th century medieval burial site in Basque Country in Spain.1

They analysied the tissue samples taken from the ribs for HLA-B27 allele and single nucleotid polymorphism (SNP) in interleukin 23R (IL-23R) and ERAP-1 genes.

The study confirmed previous studies for the genetic polymorphism. In addition, they alos found that the IL23R and ERAP1 genes and the HLA-B*27:90:01 subtype definitely play a role in the development of this unique inflammatory spine condition.

They also propose the use of the HLA-B*27:90:01subtype in the early diagnosis of ankylosing spondylitis.

Reference:

1.

Laza IM, Hervella M and De-La-Rúa C: Genetic markers in a medieval case of Ankylosing Spondylitis. J Rheumatol 2016;43:679-680

’Something on the loose’ - new insights to the mammalian uricase story

Uricase is an enzyme involved in purin catabolism, converting highly insoluble uric acid into 5-hydroxy-isourate. Multiple, independent evolutionary events led to the silencing or pseudogenisation of the uricase gene in ansestral apes, resulting the development of overproduction or underexcretion type of hyperuricaemia in humans, with the consequence of gouty arthritis, tumor lysis syndrome and various other conditions, including liver involvement and gouty nephropathy.

Researchers from Atlanta, Denver and Columbia1 recently have resurrected the ancient protein and found a reason why this enzyme activity is on the loose in humans: climate changes at the end of Oligocene period forced our ancestors to adopt from energy-rich rainforests of Europe and Asia to the temperate forests, metabolising fat from fructose and making uricase ‘dormant’.  Furthemore, they were able to inject the evolutionary-engineered ancient uricase enzyme into rodents, raising the hope that primary prevention may be a realistic perspective in hyperuricaemia-related conditions, including gout and tumor-lysis syndrome.

Reference:

1.

Kratzer JT, Lanaspa MA, Murphy MN et al: Evolutionary history and metabolic insights of ancient mammalian uricases. Proceedings of the National Academy of Sciences (PNAS), 2014;111:3763-3768

’Two for the price of one’ - clinical subsets in fibromyalgia

Fibromyalgia is a central sensitisation syndrome characterised by chronic widespread pain, profound fatigue, non-restorative sleep, autonomous nervous system disturbance and cognitive dysfunction.

It is a frequent condition, affecting 5-10 % of the adult population and often causes significant health impairment, disability and handicap.

A group of researchers from the University of Nevada and the National Instutue of Health recently performed a clinical subcluster analysis and found that the condition can be divided  into two subsets or subclusters, such as cluster 1 and 2.1

Cluster one (78% of patients) is characterised by widespread pain, unrefreshed waking and somatic symptoms, whereas subcluster 2 (22 % of total subjects) is defined by fatigue and cognitive dysfunction with less severe and widespread pain.

Overall, subcluster 1 has more intense symptoms than subcluster 2.

In summary, fibromyalgia may be categorised into 2 clinical subclusters.

Reference:

1.

Lukkahatal N, Walit B, Espina A, Gelio A and Saligan LN: Understanding the Association of Fatigue with Other Symptoms of Fibromyalgia: Development of a Cluster Model. Arthritis Care & Research 2016;68:99-107

’From black and white to technicolor’ - new advances in scleroderma research

Scleroderma (systemic sclerosis, SSc) is a heterogeneous, progressive, connective tissue disease (CTD) with distinctive skin changes, vasculopathy and autoimmune profile. Traditionally a dichotomised pattern with two main groups within the scleroderma spectrum disorder have been recognised, such as limited and diffuse cutaneous pattern SSc.

Researchers from Australia1 analysed the autoantibody pattern of 505 scleroderma patients fulfilling the ACR/EULAR 2013 classification criteria for SSc and come up with a new, 5 subcluster pattern, which are:

CENP, with autoantibodies to centromare protein on ANA analysis

RNA-III strong, with RNA Polymerase III, epitopes 11 and 155

RNA-III week, with RNA Polymerase III, epitopes 11 and 155

Topoisomerase - 1

Other

In short, the first 4 would classify for limited cutaneous scleroderma but with various clinical patterns.

The editorial in the same issue of Arthritis and Rheumatology2  summarises these finding and puts the whole in the context of scleroderma clinical patterns: we are now moving from the dichotomous, ‘black-and white’ pattern to a ‘technicolor-type’ disease clustering, where various clinical subsets could be matched with the help of the distinctive autoimmune profiling.

References:

1.

Patterson KA, Roberts-Thomson PJ, Lester S et  al: Interpretation of an Extended Autoantibody Profile in a Well-Characterized Australian Systemic Sclerosis (Scleroderma) Cohort UsingPrincipal Component Analysis. Arthritis and Rheumatology 2015;67:3234-3244

2.

Ligon CA, Wigley FM: Scleroderma: Bringing a Disease From Black-andWhite Into Technicolor. Editorial. Arthritis and Rheumatology 2015;67:3101-3103