Reviewing the Pathophysiology Behind the Advances in the Management of Giant Cell Arteritis.

Improving understanding of the underlying pathophysiology of giant cell arteritis (GCA) is transforming clinical management by identifying novel avenues for targeted therapies. One key area of concern for both clinicians and patients with GCA is glucocorticoid (GC) morbidity. The first randomised controlled trials of targeted treatment to reduce cumulative GC use in GCA have been published, with tocilizumab, an interleukin (IL)-6 receptor inhibitor, now the first ever licensed treatment for GCA. Further potential therapies are emerging owing to our enhanced understanding of the pathophysiology of the disease. Other improvements in the care of our patients are rapid access pathways and imaging techniques, such as ultrasound, which are becoming part of modern rheumatology practice in the UK, Europe and beyond. These have been highlighted in the literature to reduce delay in diagnosis and improve long-term outcomes for those investigated for GCA.

Defective removal of ribonucleotides from DNA promotes systemic autoimmunity.

Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE- and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.

Predicting persistent inflammatory arthritis amongst early arthritis clinic patients in the UK: is musculoskeletal ultrasound required?

INTRODUCTION: Analyses of large clinical datasets from early arthritis cohorts permit the development of algorithms that may be used for outcome prediction in individual patients. The value added by routine use of musculoskeletal ultrasound (MSUS) in an early arthritis setting, as a component of such predictive algorithms, remains to be determined. METHODS: The authors undertook a retrospective analysis of a large, true-to-life, observational inception cohort of early arthritis patients in Newcastle upon Tyne, UK, which included patients with inflammatory arthralgia but no clinically swollen joints. A pragmatic, 10-minute MSUS assessment protocol was developed, and applied to each of these patients at baseline. Logistic regression was used to develop two "risk metrics" that predicted the development of a persistent inflammatory arthritis (PIA), with or without the inclusion of MSUS parameters. RESULTS: A total of 379 enrolled patients were assigned definitive diagnoses after ≥12 months follow-up (median 28 months), of whom 162 (42%) developed a persistent inflammatory arthritis. A risk metric derived from 12 baseline clinical and serological parameters alone had an excellent discriminatory utility with respect to an outcome of PIA (area under receiver operator characteristic (ROC) curve 0.91; 95% CI 0.88 to 0.94). The discriminatory utility of a similar metric, which incorporated MSUS parameters, was not significantly superior (area under ROC curve 0.91; 95% CI 0.89 to 0.94). Neither did this approach identify an added value of MSUS over the use of routine clinical parameters in an algorithm for discriminating PIA patients whose outcome diagnosis was rheumatoid arthritis (RA). CONCLUSIONS: MSUS use as a routine component of assessment in an early arthritis clinic did not add substantial discriminatory value to a risk metric for predicting PIA.

Immunity 12 years after alemtuzumab in RA: CD5⁺ B-cell depletion, thymus-dependent T-cell reconstitution and normal vaccine responses.

OBJECTIVES: Lymphocyte depleting therapies have been used to treat refractory autoimmune disease, including RA, but treatment may be associated with long-term lymphopenia. It is unclear whether delayed reconstitution preferentially affects lymphocyte subsets, how this modulates immune challenges and whether thymic function influences the outcome. These questions are now addressed in a detailed analysis of RA patients 12 years after alemtuzumab (anti-CD52) treatment. METHODS: Blood was obtained from 20 RA patients 12 years after alemtuzumab treatment. Lymphocyte subsets were enumerated by flow cytometry. T-cell receptor excision circles (TRECs)/ml were determined to quantify thymic function, and serological responses to neoantigens and recall antigens were assessed. RESULTS: RA patients remained lymphopenic 12 years after their first dose of alemtuzumab. CD5(+) B cells, which may be associated with autoantibody production, were significantly reduced in alemtuzumab-treated patients compared with age-matched disease controls. In addition, naïve and memory CD4(+) T-cell subsets were present in altered proportions in patients who had received alemtuzumab, with increased effector memory CD4(+) T cells, and decreased naïve and central memory CD4(+) T cells. TRECs were detectable in alemtuzumab-treated patients and correlated with CD4(+) lymphocyte counts. Vaccine responses to neoantigens and recall antigens fell within the normal range for an ageing population. CONCLUSIONS: Alemtuzumab therapy resulted in long-term alterations in lymphocyte subsets. The significance of these changes remains uncertain but patients respond normally to antigenic challenges. Thymic function remains an important determinant of T-cell reconstitution even several years after lymphocytotoxic therapy.

The BILAG multi-centre open randomized controlled trial comparing ciclosporin vs azathioprine in patients with severe SLE.

OBJECTIVE: To determine whether low-dose ciclosporin was a more effective corticosteroid-sparing agent than AZA in patients with SLE. METHODS: Patients with SLE requiring a change or initiation of a corticosteroid-sparing agent and who were taking > or =15 mg of prednisolone/day were randomized to receive either ciclosporin or AZA during this 12-month open-label multi-centre trial. There were strict guidelines for the reduction of prednisolone. The primary outcome was the absolute mean change in prednisolone. RESULTS: Eighty-nine patients were randomized. Using an intention-to-treat analysis, the absolute mean change in prednisolone dose between baseline and 12 months, adjusted for baseline prednisolone dose, was 9.0 mg for ciclosporin (95% CI 7.2, 10.8) and 10.7 mg for AZA (95% CI 8.8, 12.7). The difference in the change between treatment groups was -1.7 mg (95% CI -4.4, 0.9; P = 0.2). No significant differences were detected for the secondary outcomes: change in disease activity [classic British Isles Lupus Assessment Group (BILAG) index], number of flares, development of new damage or change in quality of life. A similar number of patients in each arm stopped the study drugs due to adverse events and ineffectiveness. No patient developed severe hypertension or a persistent rise in creatinine. One patient in the ciclosporin arm developed a significant increase in proteinuria due to disease activity. CONCLUSIONS: Both drugs were effective corticosteroid-sparing agents. Ciclosporin was not a more effective corticosteroid-sparing agent. Ciclosporin may be considered in patients who are unable to tolerate AZA. Patients on ciclosporin require close monitoring of blood pressure and creatinine. TRIAL REGISTRATION: Current Controlled Trials, http://www.controlled-trials.com/, ISRCTN35919612.

Morbidity and mortality in rheumatoid arthritis patients with prolonged therapy-induced lymphopenia: twelve-year outcomes.

OBJECTIVE: To assess immunologically relevant outcomes in a cohort of rheumatoid arthritis (RA) patients with prolonged therapy-induced lymphopenia. METHODS: Morbidity (infection or malignancy) and mortality were assessed in 53 RA patients who were treated with the lymphocytotoxic monoclonal antibody alemtuzumab between 1991 and 1994. Data were obtained by interview, medical record review, and Office for National Statistics mortality monitoring. Lymphocyte subsets were enumerated by flow cytometry. A retrospective, matched-cohort study of mortality was performed with 102 control subjects selected from the European League Against Rheumatism database of patients with rheumatic disorders. RESULTS: Lymphopenia persisted in the patients: median CD3+CD4+, CD3+CD8+, CD19+, and CD56+ lymphocyte counts measured at a median followup of 11.8 years from the first administration of alemtuzumab were 0.50 x 10(9)/liter, 0.26 x 10(9)/liter, 0.11 x 10(9)/liter, and 0.09 x 10(9)/liter, respectively. Twenty-seven of 51 cases and 46 of 101 controls with available data had died, yielding a mortality rate ratio of 1.20 (95% confidence interval 0.72-1.98). Causes of death were similar to those that would be expected in a hospital-based RA cohort. No opportunistic infections were noted, and only 3 infections were documented following 36 elective orthopedic procedures. CONCLUSION: Despite continued lymphopenia 11.8 years after therapy, our patient cohort did not exhibit excess mortality or unusual infection-related morbidity, and surgery was well tolerated. These data should be reassuring for clinicians and patients who are considering lymphocytotoxic or other immunomodulatory therapy for RA.