The Kaiser Permanente Shoulder Arthroplasty Registry: Results from 6,336 primary shoulder arthroplasties

Background and purpose

Shoulder arthroplasty is being performed in the United States with increasing frequency. We describe the medium-term findings from a large integrated healthcare system shoulder arthroplasty registry.

Patients and methods

Shoulder arthroplasty cases registered between January 2005 and June 2013 were included for analysis. The registry included patient characteristics, surgical information, implant data, attrition, and patient outcomes such as surgical site infections, venous thromboembolism, and revision procedures.

Results

During the study period, 6,336 primary cases were registered. Median follow-up time for all primaries was 3.3 years; 461 cases were lost to follow-up by ending of health plan membership. Primary cases were predominantly female (56%) and white (81%), with an average age of 70 years. The most common reason for surgery was osteoarthritis in 60% of cases, followed by acute fracture (17%) and rotator cuff tear arthropathy (15%). In elective shoulder arthroplasty procedures, 200 all-cause revisions (4%) were reported, with glenoid wear being the most common reason.

Interpretation

Most arthroplasties were elective procedures: over half performed for osteoarthritis. Glenoid wear was the most common reason for revision of primary shoulder arthroplasty in elective cases.In the period 2000 through 2010, over 200,000 shoulder arthroplasties were performed in the USA for osteoarthritis (Trofa et al. 2014). With the increasing use of shoulder arthroplasty (SA) over the past decade (Kim et al. 2011) and projections that future growth rates of SA may exceed those of hip and knee arthroplasty (Day et al. 2010), the need to track the outcomes of SA is becoming increasingly important.Arthroplasty registries provide an important mechanism for tracking surgical outcomes. In the fields of total hip arthroplasty and total knee arthroplasty, registries have demonstrated their importance in monitoring revisions, complications, and mortality, identifying outlier prostheses, and improving quality of care (Graves et al. 2004, Herberts and Malchau 2000, de Steiger et al. 2013, Paxton et al. 2010). SA registries have also provided critical information about demographics, survival, and outlier implants, though there have been considerably fewer publications from the younger national SA registries than from the more established hip and knee registries (Clitherow et al. 2014, Young et al. 2013, Rasmussen et al. 2012a, Rasmussen et al. 2014a and b, Fevang et al. 2009, Fevang et al. 2013). The lack of a national US registry emphasizes the need to use existing US registries to conduct international comparisons of SA patients, implants, surgical techniques, and outcomes. We present the medium-term findings of a large integrated healthcare system SA registry.     

Lolium perenne peptide immunotherapy is well tolerated and elicits a protective B‐cell response in seasonal allergic rhinitis patients

Background

Systemic allergic reactions are a risk for allergen immunotherapy that utilizes intact allergen preparations. We evaluated the safety, efficacy and immune mechanisms of short‐course treatment with adjuvant‐free Lolium perenne peptides (LPP) following a 6‐week dose‐escalation protocol.

Methods

In a prospective, dose‐escalation study, 61 grass pollen–allergic patients received 2 subcutaneous injections of LPP once weekly for 6 weeks. Safety was assessed evaluating local reactions, systemic reactions and adverse events. The clinical effect of LPP was determined by reactivity to the conjunctival provocation test (CPT). Specific IgE, IgG₄ and blocking antibodies were measured at baseline (V1), during (V6) and after treatment (V8).

Results

No fatality, serious adverse event or epinephrine use was reported. Mean wheal diameters after injections were <0.6 cm and mean redness diameters <2.5 cm, independent of dose. Transient and mostly mild adverse events were reported in 33 patients. Two patients experienced a grade I and 4 patients a grade II reaction (AWMF classification). At V8, 69.8% of patients became nonreactive to CPT. sIgG₄ levels were higher at V6 (8.1‐fold, P < .001) and V8 (12.2‐fold, P < .001) than at V1. The sIgE:sIgG₄ ratio decreased at V6 (?54.6%, P < .001) and V8 (?71.6%, P < .001) compared to V1. The absolute decrease in IgE‐facilitated allergen binding was 18% (P < .001) at V6 and 25% (P < .001) at V8.

Conclusion

Increasing doses of subcutaneous LPP appeared safe, substantially diminished reactivity to CPT and induced blocking antibodies as early as 4 weeks after treatment initiation. The benefit/risk balance of LPP immunotherapy remains to be further evaluated in large studies.

     

AID Biology: A pathological and clinical perspective

Activation-induced cytidine deaminase (AID), primarily expressed in activated mature B lymphocytes in germinal centers, is the key factor in adaptive immune response against foreign antigens. AID is responsible for producing high-affinity and high-specificity antibodies against an infectious agent, through the physiological DNA alteration processes of antibody genes by somatic hypermutation (SHM) and class-switch recombination (CSR) and functions by deaminating deoxycytidines (dC) to deoxyuridines (dU), thereby introducing point mutations and double-stranded chromosomal breaks (DSBs). The beneficial physiological role of AID in antibody diversification is outweighed by its detrimental role in the genesis of several chronic immune diseases, under non-physiological conditions. This review offers a comprehensive and better understanding of AID biology and its pathological aspects, as well as addresses the challenges involved in AID-related cancer therapeutics, based on various recent advances and evidence available in the literature till date. In this article, we discuss ways through which our interpretation of AID biology may reflect upon novel clinical insights, which could be successfully translated into designing clinical trials and improving patient prognosis and disease management.     

Role of RAG1 autoubiquitination in V(D)J recombination

The variable domains of Ig and T-cell receptor genes in vertebrates are assembled from gene fragments by the V(D)J recombination process. The RAG1–RAG2 recombinase (RAG1/2) initiates this recombination by cutting DNA at the borders of recombination signal sequences (RSS) and their neighboring gene segments. The RAG1 protein is also known to contain a ubiquitin E3 ligase activity, located in an N-terminal region that is not strictly required for the basic recombination reaction but helps to regulate recombination. The isolated E3 ligase domain was earlier shown to ubiquitinate one site in a neighboring RAG1 sequence. Here we show that autoubiquitination of full-length RAG1 at this specific residue (K233) results in a large increase of DNA cleavage by RAG1/2. A mutational block of the ubiquitination site abolishes this effect and inhibits recombination of a test substrate in mouse cells. Thus, ubiquitination of RAG1, which can be promoted by RAG1’s own ubiquitin ligase activity, plays a significant role in governing the level of V(D)J recombination activity.V(D)J recombination plays a central role in the production of antigen receptors by recombining V, D, and J gene segments from their genomic clusters to give rise to the highly varied populations of immunoglobulins and T-cell receptors (1). Recombination starts with the introduction of double-strand breaks by the RAG1/RAG2 protein complex at a pair of recombination signal sequences (RSS) (2, 3), distinguished by the length of the spacer DNA separating their conserved heptamer and nonamer elements. Recombination requires one RSS with a 12-base pair spacer and another with a 23-base pair spacer. Each pair of breaks is then processed by the nonhomologous DNA end-joining group of proteins to produce a junction of two segments of coding sequence (a coding joint) and a junction of the two RSSs (a signal joint) (4). The purified RAG1/2 protein complex displays the correct specificity for pairs of RSSs (5, 6), and has thus been used as a model for the initiation of V(D)J recombination. Until recently, the RAG proteins used for these studies have generally been minimal “core” regions of RAG1 and RAG2 (amino acids 384–1,008 of 1,040 in mouse RAG1 and 1–387 of 527 in RAG2), which are sufficient for specific binding and cleavage activity in a purified cell-free system. Ectopic expression of these truncated proteins supports V(D)J recombination in suitable cell lines, although with differences from the full-length proteins that will be discussed here.A complex composed of core RAG1 and RAG2 is more active than its full-length counterpart in cleavage of extrachromosomal substrates in a hamster cell line, but overall recombination is reported to be lower (7), indicating a defect in the stages of recombination subsequent to DNA cleavage. Similarly, mice or pre-B cells missing the RAG2 C-terminal noncore region are defective in the V to DJ recombination step of Ig heavy chain joining, although the earlier D to J joining step is normal (8). The mice also display an increased prevalence of lymphomas (9). A plant homeo domain (PHD) within the RAG2 C terminus is known to bind to chromatin, and specifically to histone 3 trimethylated on lysine 4 (H3K4me3), which is presumably an important step in directing RAG1/2 to loci bearing this “activating” modification (10). The lack of this domain may largely explain the defective functions of the RAG2 core protein. Similarly, although core RAG1 can support D to J rearrangement at the Ig heavy chain locus in RAG1^−/− pro-B cells, the level is reduced compared with that of full-length RAG1 (FLRAG1) (11), and deletions of certain smaller regions within the RAG1 N terminus have even greater effects (11). Some naturally occurring truncations of the RAG1 N terminus lead to human immunodeficiency (12). The functions of the parts of RAG1 and RAG2 outside of the catalytically essential cores have been reviewed (13). There is also evidence that the RAG1 and RAG2 C termini interact: DNA cleavage by RAG1/2 combinations containing both regions was greatly reduced but was restored upon addition of an H3K4me3-containing peptide (14). Relief of this autoinhibition may synergize with the chromatin-binding effect of the PHD domain to target recombination to the appropriate loci.The significant modulation of recombination in cells, and/or of DNA cleavage in vitro, by these “dispensable” regions of both RAG1 and RAG2 is further modified by covalent modifications of the proteins, which affect their stability or activity. RAG2 becomes phosphorylated at a specific site in its C terminus (T490) at the G1/S stage of the cell cycle, and is then ubiquitinated by the Skp2-SCF ubiquitin ligase, a central regulator of cell cycle progression, leading to its degradation in S phase (15, 16). Phosphorylation of RAG1 at residue S528 by the AMP-dependent protein kinase has also been described (17), in this case leading to increased activity of RAG1/2 both for cell-free DNA cleavage and for recombination in cells.The N terminus of RAG1 contains a Zn-binding motif (amino acids 264–389) that includes a C₃HC₄ RING (really interesting new gene) finger motif closely associated with an adjacent C₂H₂ Zn finger. This domain was shown to have ubiquitin ligase (E3) activity (18, 19), a common feature of RING finger domains, when combined with ubiquitin, the ubiquitin-activating (E1) enzyme, and an appropriate ubiquitin-conjugating (E2) enzyme. A naturally occurring human mutation in this RING finger motif (C328Y) was found to cause the primary immunodeficiency disease Omenn’s syndrome (20). A study of the equivalent mutation in mouse RAG1 (C325Y) showed that it greatly reduced recombination of an extrachromosomal plasmid, as did mutation of the neighboring residue (P326G) (21). Other RING finger residues critical for ubiquitin ligase activity appeared to contribute to robust recombination of extrachromosomal substrates (22). In biochemical experiments carried out with an N-terminal fragment of RAG1 (residues 218–389), the principal site of autoubiquitination was found to be a residue neighboring the RING finger, K233; mutation of this residue (K233M) essentially abolished autoubiquitination of the fragment (18).In this article, we assess the site or sites and extent of autoubiquitination of RAG1, the consequences of this modification for RAG1/RAG2 activity in a cell-free system and in cells, and the functional relationship between this modification and the histone-recognizing PHD domain of RAG2. We prepare FLRAG1 in complex with either full-length RAG2 (FLRAG2) or core RAG2 and find that FLRAG1 undergoes autoubiquitination specifically at K233. The ubiquitination of RAG1 protein enhances coupled cleavage by the RAG1/RAG2 complex of a 12/23 RSS pair by about fivefold. RAG1 autoubiquitination also ap-pears to be important for supporting V(D)J recombination in cells.