Isotretinoin-induced myositis.

Retinoid-induced myositis is a phenomenon recognised in multiple case reports. We report a case of isotretinoin-induced myositis in an 18-year-old male patient. This case adds to the published literature as it demonstrates (i) myositis may occur after extended periods of isotretinoin use, (ii) should be considered as a differential diagnosis even when presenting asymmetrically and (iii) can continue to progress clinically and biochemically initially following the suspension of isotretinoin before being effectively treated with corticosteroids.

TNFα inhibitors reduce bone loss in rheumatoid arthritis independent of clinical response by reducing osteoclast precursors and IL-20.

OBJECTIVES: About half of RA patients treated with TNFα inhibitors either do not respond or lose their initial therapeutic response over time. The clinical response is measured by reduction in DAS28, which primarily reflects inflammation. However, other effects of TNFα inhibitors, such as impact on bone erosion, are not assessed by DAS28. We aimed to examine the effect of TNFα inhibitors on bone density, bone biomarkers and cytokine production in responder and non-responder patients and assessed mechanisms of action. METHODS: BMD in the lumbar spine and femur neck of 117 RA patients was measured by DEXA scan. Bone turnover biomarkers CTX, osteoprotegerin (OPG), osteocalcin and RANKL were measured by ELISA. Levels of 16 cytokines in plasma and in tissue culture supernatants of ex vivo T cells were measured by multiplex assays and ELISA. The effect of treatment with TNFα inhibitors on blood mononuclear cell (MNC) differentiation to osteoclast precursors (OCP) was measured flow cytometry and microscopy. RESULTS: TNFα inhibitors improved lumbar spine BMD but had modest effects on blood bone biomarkers, irrespective of patients' clinical response. Blood OCP numbers and the ability of monocytes to differentiate to OCP in vitro declined after treatment. Treatment also reduced RANK expression and IL-20 production. BMD improvement correlated with reduced levels of IL-20 in responder patients. CONCLUSION: This study reveals that TNFα inhibitors reduce lumbar spine bone loss in RA patients irrespective of changes in DAS28. The reduction in bone loss is associated with reduction in IL-20 levels in responder patients.

Response to Treatment with TNFα Inhibitors in Rheumatoid Arthritis Is Associated with High Levels of GM-CSF and GM-CSF+ T Lymphocytes.

Biologic TNFα inhibitors are a mainstay treatment option for patients with rheumatoid arthritis (RA) refractory to other treatment options. However, many patients either do not respond or relapse after initially responding to these agents. This study was carried out to identify biomarkers that can distinguish responder from non-responder patients before the initiation of treatment. The level of cytokines in plasma and those produced by ex vivo T cells, B cells and monocytes in 97 RA patients treated with biologic TNFα inhibitors was measured before treatment and after 1 and 3 months of treatment by multiplex analyses. The frequency of T cell subsets and intracellular cytokines were determined by flow cytometry. The results reveal that pre-treatment, T cells from patients who went on to respond to treatment with biologic anti-TNFα agents produced significantly more GM-CSF than non-responder patients. Furthermore, immune cells from responder patients produced higher levels of IL-1ß, TNFα and IL-6. Cytokine profiling in the blood of patients confirmed the association between high levels of GM-CSF and responsiveness to biologic anti-TNFα agents. Thus, high blood levels of GM-CSF pre-treatment had a positive predictive value of 87.5% (61.6 to 98.5% at 95% CI) in treated RA patients. The study also shows that cells from most anti-TNFα responder patients in the current cohort produced higher levels of GM-CSF and TNFα pre-treatment than non-responder patients. Findings from the current study and our previous observations that non-responsiveness to anti-TNFα is associated with high IL-17 levels suggest that the disease in responder and non-responder RA patients is likely to be driven/sustained by different inflammatory pathways. The use of biomarker signatures of distinct pro-inflammatory pathways could lead to evidence-based prescription of the most appropriate biological therapies for different RA patients.

Harnessing the Therapeutic Potential of Th17 Cells.

Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon γ (IFNγ). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases.

Early metacarpal bone mineral density loss using digital x-ray radiogrammetry and 3-tesla wrist MRI in established rheumatoid arthritis: a longitudinal one-year observational study.

Objectives. Early change in rheumatoid arthritis (RA) is characterised by periarticular osteopenia. We investigated the relationship of early metacarpal digital X-ray radiogrammetry bone mineral density (DXR-BMD) change rate (RC-BMD, mg/cm(2)/month) to longitudinal changes in hand and feet radiographic and wrist MRI scores over 1 year. Materials and Methods. 10 RA patients completed the study and had wrist 3T-MRI and hand and feet X-rays at various time points over 1 year. MRI was scored by RAMRIS, X-ray was done by van der Heijde modified Sharp scoring, and RC-BMD was analysed using dxr-online. Results. There was good correlation amongst the two scorers for MRI measures and ICC for erosions: 0.984, BME: 0.943, and synovitis: 0.657. Strong relationships were observed between RC-BMD at 12-week and 1-year change in wrist marrow oedema (BME) (r = 0.78, P = 0.035) but not with erosion, synovitis, or radiographic scores. Conclusion. Early RC-BMD correlates with 1-year wrist BME change, which is a known predictor of future erosion and joint damage. However, in our pilot study, early RC-BMD did not show relationships to MRI erosion or radiographic changes over 1 year. This may reflect a slower kinetic in the appearance of MRI/radiographic erosions, generating the hypothesis that RC-BMD may be a more sensitive and early structural prognostic marker in RA follow-up.

Bacterial and human peptidylarginine deiminases: targets for inhibiting the autoimmune response in rheumatoid arthritis?

Peptidylarginine deiminases (PADs) convert arginine within a peptide (peptidylarginine) into peptidylcitrulline. Citrullination by human PADs is important in normal physiology and inflammation. Porphyromonas gingivalis, a major pathogen in periodontitis, is the only prokaryote described to possess PAD. P. gingivalis infection may generate citrullinated peptides, which trigger anti-citrullinated peptide antibodies. In susceptible individuals, host protein citrullination by human PADs in the joint probably perpetuates antibody formation, paving the way for the development of chronic arthritis. Blockades of bacterial and human PADs may act as powerful novel therapies by inhibiting the generation of the antigens that trigger and sustain autoimmunity in rheumatoid arthritis.

Digital vasculitis: a late complication of anti-tumour necrosis factor alpha therapy.

Anti-tumour necrosis factor alpha therapy has led to significant advancement in the treatment of rheumatological disease. Rarely, anti-TNFalpha antagonists have been associated with vasculitis, predominantly cutaneous leukocytoclastic vasculitis. We present the first case of angiographically-confirmed digital vasculitis occurring as a late complication of etanercept therapy. Our case adds to the limited repertoire of case reports of anti-TNFalpha induced vasculitis and highlights the potential risk of this serious complication occurring up to several years after initiation of these agents.

A case of longitudinally extensive transverse myelitis (LETM): neuromyelitis optica.

Neuromyelitis optica (NMO), characterised by longitudinally extensive transverse myelitis (LETM), was previously thought to be a variant of multiple sclerosis. Transverse myelitis may be a manifestation of autoimmune connective tissue diseases and NMO is now recognised to be a humorally mediated autoimmune disease. We present a case of NMO associated with non-organ-specific autoantibodies and the absence of the characteristic NMO-IgG antibody. Our case provides an opportunity to review the diagnostic criteria of NMO and its distinction from other autoimmune and demyelinating conditions. We report successful treatment with plasmapheresis and rituximab in NMO-IgG-negative relapsing disease.