Devesh Mewar

Independent associations of anti-cyclic citrullinated peptide antibodies and rheumatoid factor with radiographic severity of rheumatoid arthritis

Several recent publications have established a strong association between anti-cyclic citrullinated peptide antibody (anti-CCP)-positive rheumatoid arthritis (RA) and carriage of shared epitope (SE) alleles. Although anti-CCP have also been associated with more severe RA, the issue of whether this is independent of rheumatoid factor (RF) has not been addressed. To identify associations between RF, anti-CCP, SE status and radiological damage, we studied a large cross-sectional cohort with longstanding RA. Individuals (n = 872) enrolled in the study all fulfilled the American College of Rheumatology criteria for RA, had a minimum disease duration of 3 years, and at least one definite radiographic erosion was present in hands or feet. Radiographs were scored blind at study entry by a single musculoskeletal radiologist using a modified Larsens score. Anti-CCP and RF levels were determined using enzyme-linked immunosorbent assay, and DRB1 typing was performed using polymerase chain reaction based methodology. Both anti-CCP and RF levels were strongly associated with radiographic severity (P < 0.0001). In subgroups stratified for both anti-CCP and RF status, evidence of independent associations of both antibodies with radiographic outcome was found (P < 0.0001). An association of SE alleles with radiographic severity was present only in RF-negative individuals. Anti-CCP positivity was associated with SE status with evidence of a gene-dose effect, most markedly in RF-negative individuals (P < 0.01). Anti-CCP and RF status are independent severity factors for RA, with SE alleles playing at most a secondary role. Our data support the view that previously described associations between SE and radiological severity, especially in RF-negative patients, may be indirect and due to an association with anti-CCP.

Abatacept: a potential therapy in refractory cases of juvenile idiopathic arthritis-associated uveitis

BackgroundJuvenile idiopathic arthritis (JIA) is the most common of all systemic conditions associated with childhood uveitis. Visual impairment has been shown to be as high as 40% of which 10% being blind (6/60 or worse). Due to the lack of well-designed randomized control trials for paediatric uveitis and arthritis there are limited comparative data regarding the efficacy of single or combination treatments. Recently, abatacept was shown to control ocular inflammation in a case of psoriatic arthritis- associated uveitis, seven cases of JIA- associated uveitis and in JIA. We present two cases with JIA-associated uveitis who have responded dramatically to abatacept therapy following unsuccessful therapy with other immunosuppressants. Control of arthritis still represents a challenge with this treatment.MethodsProspective review of two patients with refractory JIA- associated uveitis not responding to maximum conventional treatment. Patients were regularly reviewed in the ophthalmology and rheumatology clinics. Assessment of their ocular condition was characterized according to the Standardization of Uveitis Nomenclature (SUN) group.ResultsIn case 1, ocular inflammation was brought under control after repeated abatacept infusions. Case 2 showed complete resolution of cystoids macular edema CME and improvement of 5 Snellen’s lines in best corrected visual acuity. After 9 months, the ocular condition of both patients remains in remission with steroid sparing. Joint disease was brought to clinical remission in case 2, but not in case 1.ConclusionsAbatacept is a promising alternative treatment in refractory cases of JIA uveitis but may not be as successful in controlling joint disease. Larger series with long term follow up of biological therapies in paediatric uveitis are essential to assess the efficacy and cost effectiveness.

Treatment of rheumatoid arthritis with tumour necrosis factor inhibitors

Advances in our understanding of the key mediators of chronic inflammation and tissue damage characteristic of rheumatoid arthritis (RA) have resulted in the development of novel therapies primarily targeting pro‐inflammatory cytokines. Inhibitors of tumour necrosis factor (TNF) are the most widely used of the biological therapies at present with five different agents currently available; four are based on monoclonal anti‐TNF antibodies and a soluble TNF receptor‐Fc fusion protein. Long‐term use of these molecules has proven to be highly effective in the majority of patients; however, around one‐third have a suboptimal response potentially leading to further cartilage and bone damage, furthermore these agents are expensive compared with conventional therapies such as methotrexate. Many recent studies have attempted to identify therapeutic response biomarkers of TNF inhibitors which could be used to improve therapeutic targeting. The presence of rheumatoid factor and anti‐cyclic citullinated protein antibodies, present in around 65% of RA patients, are associated with a poorer response to anti‐TNF agents. Poorer response is also associated with levels of C‐reactive protein and cartilage degradation product at initiation of treatment. Intriguingly, genetic studies of variants of TNF and of genes encoding members of the Toll‐like receptors, nuclear factor‐kappa B and p38 mitogen‐activated protein kinase signalling families have been associated with response to individual anti‐TNF agents. Continued advances in technologies such as ultra high throughput sequencing and proteomics should facilitate the discovery of additional biomarkers of response to anti‐TNF resulting in improved disease control and quality of life for RA patients and reduced costs for healthcare funders.

Association between radiographic severity of rheumatoid arthritis and shared epitope alleles: differing mechanisms of susceptibility and protection

Objective: To investigate the association of a recently described classification of Human leukocyte antigen (HLA)-DRB1 shared epitope alleles with rheumatoid factors (RF) and anti-cyclic citrullinated peptide (CCP) production and radiological severity in rheumatoid arthritis (RA). Methods: Patients with RA (n = 962) were studied. Genotyping of DRB1 alleles and assays for RF and anti-CCP were performed. Radiological severity was measured using the modified Larsen score. Results: In accordance with previous reports, we found carriage of S2 alleles (K-R-A-A at positions 71–74) to be associated with more severe disease with a gene–dose effect (p = 0.0059), and also associated with the presence of anti-CCP and RF (p<0.001). Carriage of S1 alleles (D-E-R-A-A at positions 70–74) was associated with less severe disease (p = 0.01), however there was no association between S1 and either anti-CCP or RF, suggesting that the basis for this possible protective effect was not related to autoantibody-producing B cells. Conclusions: These data suggest that multiple biological mechanisms underlie the DRB1 association with rheumatoid arthritis severity.

Haplotype-specific gene expression profiles in a telomeric major histocompatibility complex gene cluster and susceptibility to autoimmune diseases

The telomeric class III region of the major histocompatibility complex is gene dense, but apart from the three tumour necrosis factor (TNF) superfamily members (TNF, lymphotoxin alpha and lymphotoxin beta) little is known of the expression and function of the majority of the genes. Recent genetic studies in autoimmune diseases, particularly rheumatoid arthritis (RA), have suggested a human leukocyte antigen (HLA)-DR-independent disease effect in this region. To gain further insights into these associations, we used lipopolysaccharide-stimulated human macrophages to examine inducible mRNA expression and genotype–phenotype relationships for genes in this region. Following stimulation in addition to the expected induction of TNF mRNA, a 14-fold increase of ATP6V1G2 at 18 h (P<0.001) was seen, whereas B-associated transcript (BAT)2 (P<0.001) and leucocyte-specific transcript (LST)1 (P<0.001) were both downregulated. By genotyping single-nucleotide polymorphisms spanning a 70 kb interval centred on the TNF locus, we constructed haplotypes and determined associated expression profiles for 10 genes in the cluster using quantitative real-time polymerase chain reaction. Overexpression of BAT1 mRNA was associated with carriers of a haplotype containing the LST1 marker transmitted to RA cases in a family study and also DRB1*15 associated with susceptibility to nephritis in systemic lupus erythematosus. The implications of our findings for the understanding of genetic associations with disease susceptibility in this region are discussed.

Inflammatory osteoarthritis which was precipitated by Arimidex and resolved with tamoxifen

We report the case of a 51-year-old woman who presented with an inflammatory flare of osteoarthritis of the small joints of her hands occurring in a temporal relationship with the commencement of Arimidex, prescribed to reduce systemic oestrogen levels to treat breast cancer. Following the cessation of Arimidex and the initiation of tamoxifen, a specific oestrogen receptor antagonist, this flare resolved. It has long been observed that during the menopause, as oestrogen levels decline, many women develop osteoarthritis or experience progression of the disease. However, this theory of oestrogen-dependent osteoarthritis has not been consistently demonstrated in animal models. As far as the authors are aware, this is the first case in which systemic oestrogen reduction has resulted in a severe osteoarthritis flare but targeted oestrogen receptor blockade led to a resolution of symptoms. These findings may inform the pathophysiological process underlying oestrogen-dependent osteoarthritis, although further series are needed.