Matrix metalloproteinases (MMPs), also called matrixins, function in the extracellular environment of cells and degrade both matrix and non-matrix proteins. They play central roles in morphogenesis, wound healing, tissue repair and remodelling in response to injury, e.g. after myocardial infarction, and in progression of diseases such as atheroma, arthritis, cancer and chronic tissue ulcers. They are multi-domain proteins and their activities are regulated by tissue inhibitors of metalloproteinases (TIMPs). This review introduces the members of the MMP family and discusses their domain structure and function, proenyme activation, the mechanism of inhibition by TIMPs and their significance in physiology and pathology.

Structure and function of matrix metalloproteinases and TIMPs

Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.

10 Years of GWAS Discovery: Biology, Function, and Translation

An Expanded View of Complex Traits: From Polygenic to Omnigenic

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior.

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Partitioning heritability by functional annotation using genome-wide association summary statistics.

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

/pdf/genetics-of-rheumatoid-arthritis-contributes-to-biology-and-4wuv6x8yle.pdf

Genetics of rheumatoid arthritis contributes to biology and drug discovery

Recent advances in medication choices have strikingly improved the management of rheumatoid arthritis. However, medication alone cannot place back already deformed joints. Thus, to prevent metacarpophalangeal (MP) joint destruction, joint deformity correction should be considered since mechanical stress induced by finger motions will eventually destruct the undestructed joint, with a possibility of recurrence and future implant arthroplasty in mind since RA still remains as a progressive disease. We report a modified metacarpal shortening osteotomy for correcting MP joint deformity. The advantage of our technique over previous osteotomies is that it easily allows for subsequent implant arthroplasty even after the recurrence of joint deformity/destruction. Major modifications include that the metacarpal is shortened at its mid-shaft and the osteotomy is performed vertical to the shaft and fixed with surgical wiring. We believe that combination therapy consisting of medication and surgery is preferable to prevent joint destruction, even in this age of biological agents.

Modified metacarpal shortening osteotomy of the midcarpal bone for preserving metacarpophalangeal joints in patients with rheumatoid arthritis.

Deformities of the feet are common in patients with rheumatoid arthritis (RA). We investigated whether there was any correlation among forefoot deformities, flat foot or articular destruction of the midfoot and hindfoot, in 146 feet of 73 RA patients whose age varied from 26 to 81 years (mean 58.5 years). In all patients, anteroposterior (AP) and lateral radiographs of the feet with weight bearing were obtained. The hallux valgus angle (HVA), the intermetatarsal angle between the 1st and 2nd metatarsals (M 1 M 2), and the intermetatarsal angle between the 1st and 5th metatarsals (M 1 M 5) were measured on AP radiographs. On slateral radiographs, the height of the arch was measured and articular destruction of the talocalcaneal, talocrural, talonavicular, cuneonavicular and cuneometatarsal joints was measured and classified using Steinbrocker's classification. The average HVA was 23.4 degrees, the average M 1 M 2 was 11.1 degrees, and the average M 1 M 5 was 28.4 degrees. There was no correlation between forefoot deformities and flat foot. There were significant correlations between arthritic destruction of the cuneometatarsal joint and HVA, M 1 M 2 and M 1 M 5. The correlations between arthritic destruction of the cuneonavicular joint and HVA or M 1 M 2 were also significant, although weaker. Thas, we found some relationships between forefoot deformity and arthritics destruction of midfoot joints. Especially, the correlations between arthritic destruction of the cuneonavicular and cuneometatarsal joints and forefoot deformities were significant. Many radiographic methods for the assessment of RA have been reported, however, it is difficult to assess sarthritic destruction of rheumatoid feet with the existing methods. Accordingly, a new method should be established.

Radiological evaluation of foot deformities in rheumatoid arthritis

Objective The following is a retrospective study on lower extremity alignment of rheumatoid arthritis (RA) patients with a history of both Total Hip Replacement (THR) and Total Knee Replacement (TKR). Methods From 1992 to 2000, our department had 26 rheumatoid arthritis patients who underwent both THR and TKR. We classified these patients into three groups based on radiographic alignment of the lower extremities in the standing position: Knock-knee (valgus deformity of the knees), Bowleg (varus deformity of the knees) and Windswept Deformity (one knee in severe varus alignment with the other in severe valgus alignment). Furthermore, we identified dominant weight bearing points of the hip as classified by the following new criteria: Central Shift, Lateral Shift, and Upward Shift. Mal-alignment was then evaluated based on these two classification systems. Results Of the 26 patients, 22 patients met our criteria and 4 did not. In mal-alignment, we had 11 cases in the knock-knee group, 5 cases in the bowleg group, and 6 cases in the Windswept deformity. Using the new criteria, central shift had 6 cases; lateral shift had 6 cases; and upward shift had 10 cases. The groups of Lateral shift and Central shift demonstrated deformities of the lower extremities were influenced by moving weight bearing points, pelvis obliquity, and adduction contractures of the hip joint. In upward shift, weight bearing lines did not change. Consequently, destruction of the joint in this group progressed symmetrically. Windswept deformity was asymmetric and had severe destruction on the other side of the knee and forefoot. Discussion Moving of weight bearing point, pelvis obliquity, and adduction contractures of the hip joint affected the severity of mal-alignment of the lower extremities.

Alignment of lower extremity in rheumatoid arthritis patients with a history of both total hip replacement and total knee replacement

OBJECTIVES
To report 24-week safety and effectiveness data of certolizumab pegol (CZP) in Japanese patients with rheumatoid arthritis (RA) from a post-marketing surveillance study.


METHODS
Enrolled patients were newly receiving CZP. All adverse events (AEs) and adverse drug reactions (ADRs) were recorded for patients who received ≥1 CZP dose. Effectiveness outcomes included: 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) and EULAR response. Missing data were imputed using last observation carried forward.


RESULTS
3,727 patients were enrolled; safety and effectiveness were evaluated in 3,586 and 1,794 patients, respectively. 24.9% of patients reported AEs (n=893/3,586) and 14.7% reported ADRs (528/3,586). Serious AEs and serious ADRs were reported in 8.3% (298/3,586) and 5.3% (190/3,586), respectively. Selected serious ADRs of interest included infections (n=110; 3.1%), tuberculosis (6; 0.2%), interstitial pneumonia (15; 0.4%), malignancy (8; 0.2%) and hepatic function disorder (7; 0.2%). No allergic reactions, autoimmune disease, cardiac failure, demyelinating diseases or pancytopenia were reported. Mean DAS28-ESR reduced from 4.8 (baseline) to 3.4 (final evaluation). At final evaluation, 34.7% of patients achieved EULAR good response.


CONCLUSIONS
These real-world safety and effectiveness results were consistent with previously reported data, with no new safety signals identified. Long-term, real-world CZP safety and effectiveness data are needed.

Safety and Effectiveness of Certolizumab Pegol in Japanese Patients with Rheumatoid Arthritis: Results from a 24-Week Post-Marketing Surveillance Study.

To the Editor,Abatacept is a biologic agent for treating rheumatoid arthritis (RA). It inhibits T-cell activation by binding to CD80/86 and modulating its interaction with CD28. In a postmarketing ...

Shigeki Momohara

Papers

Modified metacarpal shortening osteotomy of the midcarpal bone for preserving metacarpophalangeal joints in patients with rheumatoid arthritis.

Radiological evaluation of foot deformities in rheumatoid arthritis

Alignment of lower extremity in rheumatoid arthritis patients with a history of both total hip replacement and total knee replacement

Safety and Effectiveness of Certolizumab Pegol in Japanese Patients with Rheumatoid Arthritis: Results from a 24-Week Post-Marketing Surveillance Study.

The efficacy of abatacept focusing on anti-CCP antibody in Japanese patients with rheumatoid arthritis for 104 weeks.