Human leukocyte antigen (HLA)-DM is an unconventional major histocompatibility complex (MHC) class II heterodimer that is important for B-cell-mediated antigen processing and presentation to MHC class II-restricted T cells. HLA-DM is encoded by two genes, DMA and DMB, which map to the MHC class II region, and shares some homology with MHC class I and class II proteins. Here we define the biochemical role of HLA-DM. Recombinant soluble HLA-DM heterodimers have been purified from culture supernatants of insect cell transformants. At pH 5.0, they induce the dissociation of a subset of peptides bound to HLA-DR, including a nested set of class-II-associated invariant chain peptides (CLIP). This process liberates HLA-DR and leads to the enhanced binding of exogenous peptides.

Phosphodiesterase 4 (PDE4) is a key enzyme in the degradation of cyclic adenosine monophosphate and is centrally involved in the cytokine production of inflammatory cells, angiogenesis, and the functional properties of other cell types such as keratinocytes. In this review article, apremilast, a novel small molecule inhibitor of PDE4, is introduced. Apremilast has profound anti-inflammatory properties in animal models of inflammatory disease, as well as human chronic inflammatory diseases such as psoriasis and psoriatic arthritis. Apremilast blocks the synthesis of several pro-inflammatory cytokines and chemokines, such as tumor necrosis factor alpha, interleukin 23, CXCL9, and CXCL10 in multiple cell types. In contrast to the biologics, which neutralize pro-inflammatory mediators at the protein level, apremilast modulates production of these mediators at the level of mRNA expression. Apremilast also interferes with the production of leukotriene B4, inducible nitric oxide synthase, and matrix metalloproteinase and reduces complex inflammatory processes, such as dendritic cell infiltration, epidermal skin thickening, and joint destruction. As this novel PDE4 inhibitor interferes with several key processes of inflammation, it may emerge as a promising new drug for the treatment of chronic inflammatory diseases such as those of the skin and the joints.

Objective. Bisphosphonates inhibit osteoclast activity, which is central to the development of bone damage in rheumatoid arthritis (RA). The aim of this study was to assess whether treatment with zoledronic acid, compared with placebo, could achieve a >50% reduction in the development of new erosions on magnetic resonance imaging (MRI) in patients with early RA.Methods. In this proof-of-concept study, 39 patients with early RA and clinical synovitis of the hand/ wrist were randomized to receive infusions with either zoledronic acid (5 mg) or placebo, administered at baseline and week 13. Patients in both groups received methotrexate (MTX) at a dosage of 7.5-20 mg/week. MRI and plain radiography were performed at baseline and week 26.Results. At week 26, the mean ؎ SD change in MRI hand and wrist erosions was 61% lower in the zoledronic acid group compared with the placebo group (0.9 ؎ 1.63 versus 2.3 ؎ 3.09; P ‫؍‬ 0.176). The mean ؎ SD increase in the number of hand and wrist bones with erosions was 0.3 ؎ 0.75 for zoledronic acid compared with 1.4 ؎ 1.77 for placebo (P ‫؍‬ 0.029). The proportion of patients in whom new MRI-visualized bone edema developed was smaller in the zoledronic acid group compared with the placebo group (33% versus 58%; P ‫؍‬ 0.121). The zoledronic acid group had a mean change in the number of radiographic erosions of 0.1 compared with 0.5 for the placebo group (P ‫؍‬ 0.677). The safety profile of zoledronic acid was similar to that of placebo.Conclusion. The results of this study suggest a structural benefit associated with zoledronic acid therapy in patients with RA, as demonstrated by consistent results in structural end points in favor of zoledronic acid plus MTX compared with MTX alone.

HLA-DM catalyzes the release of invariant chain fragments from newly synthesized major histocompatibility complex (MHC) class II molecules, stabilizes empty class II molecules, and edits class II-associated peptides by preferentially releasing those that are loosely bound. The ability of HLA-DM to carry out these functions in vitro is pH dependent, with an optimum at pH 4.5-5.5 and poor activity at pH 7. The structural basis for these properties of HLA-DM is unknown. Sequence homology suggests that HLA-DM resembles classical, peptidebinding MHC class II molecules. In this study, we examined whether HLA-DM has a secondary structure composition consistent with an MHC fold and whether HLA-DM changes conformation between pH 5 and pH 7. Far-UV circular dichroism (CD) spectra of recombinant soluble HLA-DM (sDM) indicate that HLA-DM belongs to the ␣/␤ class of proteins and structurally resembles both MHC class I and class II molecules. The CD peak around 198 nm increases upon going from neutral to endosomal pH and drops sharply upon denaturation below pH 3.5, distinguishing at least three states of sDM: the denatured state and two highly similar folded states. Fluorescence emission spectra show a slight blue-shift and a Ϸ20% drop in intensity at pH 5 compared with pH 7. Unfolding experiments using guanidinium chloride show that the stability of sDM is somewhat reduced but not lost at pH 5. These results indicate that sDM undergoes a pH-dependent conformational change between neutral and endosomal pH. The change seems to involve both hydrogen bonding patterns and the hydrophobic core of sDM and may contribute to the pH dependence of DM activity. Major histocompatibility complex (MHC)1 encoded glycoproteins bind antigenic peptides and display them on the surface of antigen-presenting cells for inspection by T lymphocytes bearing ␣␤ antigen receptors. MHC molecules can be divided into class I and class II molecules, which share a common tertiary fold with a characteristic peptide binding groove but differ in their domain connectivity, specificity requirements for peptide, and ability to stimulate selectively CD8 ϩ and CD4 ϩ lymphocytes, respectively (1). These highly polymorphic "classical" MHC molecules belong to a larger family, which includes more distantly related and less polymorphic molecules encoded in the class II and class Ib regions of the MHC and elsewhere in the genome (2). Among the functions identified for such "nonclassical" MHC molecules are antigen presentation to unconventional T cells, accessory functions in MHC class II antigen presentation, and other, unrelated functions. Classical MHC class II molecules load peptides in endosomal compartments, and this process is regulated by at least three additional molecules: invariant chain (Ii), HLA-DM, and HLA-DO (3, 4). Ii, which lacks homology to MHC molecules, associates with class II molecules in the endoplasmic reticulum, facilitates their assembly, and targets them to endosomes. Here, Ii is degraded, leaving Ii-derived peptides in the antigen binding groo...

Lumiracoxib 100 mg od provided effective relief from the pain of knee OA, with efficacy similar to celecoxib 200 mg od, and was well tolerated.

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A randomised, double-blind study was performed to assess the efficacy and tolerability of lumiracoxib in patients with rheumatoid arthritis (RA). Patients received lumiracoxib 200mg once daily (o.d.) (n= 280), lumiracoxib 400mg o.d. (n= 281), naproxen 500 mg twice daily (n= 279) or placebo (n= 284) for 26 weeks. The primary efficacy variable was response to treatment according to ACR20 criteria (adjusted for prohibited concomitant or excessive rescue medication use and discontinuations due to unsatisfactory therapeutic response) at week 13. Safety and tolerability was also assessed. Significantly more patients receiving lumiracoxib than placebo were responders according to ACR20 criteria at week 13 (41.1 and 42.7% for lumiracoxib 200 and 400 mg o.d., respectively; 32.4% for placebo; both p < 0.05). The proportion responding to naproxen (39.1%) was not significantly different from placebo. Prespecified gastrointestinal adverse events were more frequent with naproxen than with either lumiracoxib dose or placebo. Lumiracoxib is therefore an effective and well-tolerated therapy for RA.

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