Deva Situnayake

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.

Birmingham SLE cohort: outcomes of a large inception cohort followed for up to 21 years

OBJECTIVE The aim of this study was to describe the outcomes and predictors for development of damage in a large inception cohort of SLE patients. METHODS This was a prospective longitudinal study of a cohort of SLE patients. SLE patients were included if they were recruited within 3 years of achieving the fourth ACR criterion for SLE. Data were collected on disease activity, damage and treatment. Information on death was provided by the Office for National Statistics. The censoring date for analysis was 31 December 2010. A standardized mortality ratio was calculated. Poisson regression was used to determine the incidence rate for damage accrual. Multistate Markov modelling was used to determine predictors for development of damage. RESULTS There were 382 patients (92.4% females, 51.6% Caucasian, 22% South Asian, 20.7% Afro-Caribbean) with 12 072 assessments and total follow-up of 2958 patient-years. There were 300 items of damage (in 143 patients) and 37 deaths. The overall standardized mortality ratio was 2.0 (95% CI 1.5, 2.8) and the most common causes of death were infection (37.8%), cardiovascular (27%) and malignancy (13.5%). The predictors for damage accrual were higher prior damage, older age at diagnosis, active disease, systemic corticosteroid exposure and CYC exposure. Patients were more likely to develop new damage earlier in their disease than later. Ethnicity was not predictive of damage accrual or death in this cohort. CONCLUSION SLE patients have premature mortality. Active disease, corticosteroid exposure and CYC exposure were independently associated with the development of damage. Damage accrual is more likely to occur in early disease.

Genetics of Behçet's disease.

Purpose of reviewThis article discusses recent genetic and epigenetic associations involved in the pathogenesis of Behçets disease. Recent findingsGenetic studies have supported the strong association of human leukocyte antigen-B and Behçets disease, and high production of tumour necrosis factor and low production of interleukin (IL)-10, which have led to therapy based on controlling these effects. Polymorphisms that affect the response to pathogens (TLR and FUT2) are leading to increased interest in responses to microbiomes. Inflammation in Behçets disease results in vascular damage and several single nucleotide polymorphisms in chemokine and adhesion molecules may be involved in this process. Increased levels of inflammatory cytokines including IL-1&bgr; and IL-17 have been linked to altered expression of microRNAs, miR155, miR21 and miR23b. DNA methylation changes in monocytes and lymphocytes have been described that affect the function of these cells. SummaryGenetic and epigenetic changes affecting cells and molecules involved in Behçets disease offer new pathways for research, including cytoskeletal protein function, that will provide new targets for therapy, and potentially address the ethnic differences seen in validation of gene studies.

Ten-year experience of pulsed intravenous cyclophosphamide and methylprednisolone protocol (PICM protocol) in severe ocular inflammatory disease

Aims Severe ocular inflammation is a blinding ophthalmological emergency. This study evaluates the efficacy and patient tolerance of a validated regime of pulsed intravenous cyclophosphamide and methylprednisolone (‘PICM protocol’) for these patients. Methods 26 patients with severe inflammatory eye disease (43 eyes: 22 uveitis, 21 scleritis/sclerokeratitis; median age 52 years (IQR 40.25–62.25)) presenting to a regional tertiary referral centre were recruited over a 10-year period (January 2002–December 2011) into the PICM protocol, comprising intravenous cyclophosphamide 15 mg/kg, intravenous methylprednisolone 10 mg/kg, maximum nine pulses over 20 weeks supplemented with low-dose continuous oral prednisolone. Data were captured pretreatment and at 6 and 12 months follow-up. Primary outcome measures were control of inflammation according to standard criteria and reduction in systemic glucocorticoid to ≤10 mg prednisolone/day. Results A median of six pulses (IQR 5–6) were administered over a median of 3 months (IQR 2.25–4). In the scleritis/sclerokeratitis group, 15/21(71%) achieved success or partial success at 6 and 12 months versus 9/22 (41%) for the same time points in the uveitis group (χ2=4.058, p=0.044). Two patients had adverse events requiring treatment withdrawal. Conclusions This PICM protocol is a well-tolerated regimen for managing severe ocular inflammation and appears particularly useful in patients with scleritis/sclerokeratitis.

Refractory multisystem sarcoidosis responding to infliximab therapy

Chronic progressive multisystem granulomatous disease is seen in 10–30% of patients with sarcoidosis and can result in end organ damage. Corticosteroids are the mainstay of treatment with the addition of cytotoxic agents in severe cases. Some patients are refractory to such treatment and, therefore, management is a challenge. There is currently limited evidence for biological agents such as infliximab, a monoclonal anti-tumor necrosis factor-α antibody in the treatment of multisystem sarcoidosis. We report outcomes of three patients with extensive multisystem sarcoidosis refractory to conventional treatment and treated at our center. Clinical assessment and radiographic imaging were used to assess the response to infliximab treatment. Infliximab therapy induced clinical remission in all three patients, and this clinical response correlated with radiographic evidence of the resolution of granulomatous disease. Serum ACE level was reduced in all cases, and daily steroid dosage was reduced. We propose that infliximab can be an effective treatment in patients with multisystem complex sarcoidosis refractory to conventional drug therapy and can result in sustained clinical remission. Our experience supports the urgent need for randomized controlled clinical trials of anti-TNF therapy in refractory systemic sarcoidosis.

Successful treatment of calcinosis with infliximab in a patient with systemic sclerosis/myositis overlap syndrome

SIR, Calcinosis is a debilitating manifestation of many connective tissue diseases, particularly JDM and SSc. Little is known about the pathogenesis of this condition, and its treatment remains a challenge. Previously used measures of therapeutic response (clinical examination, X-ray and scintigraphy) have been inconsistent and insensitive. We present a case of severe calcinosis where the response to an anti-TNF agent was assessed by serial pelvic CT imaging at baseline, 7 and 41 months posttherapy. The patient was diagnosed with limited SS/myositis overlap syndrome in 2007, based on clinical features and positive immunology (ANA 1:1600, PM-Scl positive). Creatinine kinase (CK) was significantly elevated and EMG demonstrated low-grade myositis (a muscle biopsy was not performed). Although affected by arthritis, myositis and moderate pulmonary fibrosis, the patient was principally debilitated by calcinosis. Severe lesions occurred across several sites, affecting particularly the fingers and pressure areas, including the buttocks and hips. The lesions were painful and prone to ulceration and infection, and many discharged continuously. Intratendon calcification was proved radiologically, and local shortening of the triceps tendon disabled the patient by preventing the hand from reaching the mouth. Multiple therapeutic interventions failed to treat the calcinosis. CYC, NSAIDs and corticosteroids provided no benefit and the lesions continued to worsen. Minocycline and MTX improved finger lesions and rendered myositis subclinical, but calcific deposits remained severe. Surgical excision of the lesions resulted in wound dehiscence. In 2008, specialist consensus was to initiate infliximab, based on clinical experience and individual case reports. Infliximab 3 mg/kg was infused at 0, 2 and 6 weeks, and then every 8 weeks thereafter. Pelvic CT at 7 months demonstrated reduced calcification with no new lesions when compared

Birmingham Behçet’s service: classification of disease and application of the 2014 International Criteria for Behçet’s Disease (ICBD) to a UK cohort

BackgroundThis study reports on the analysis of the application and diagnostic predictability of the revised 2014 ICBD criteria in an unselected cohort of UK patients, and the ensuing organ associations and patterns of disease.MethodsA retrospective cohort study was conducted using a database of electronic medical records. Three categories were recognised: clinically defined BD, incomplete BD and rejected diagnoses of BD. We applied the ISG 1990 and ICBD 2014 classification criteria to these subgroups to validate diagnostic accuracy against the multidisciplinary assessment.ResultsBetween 2012 and 2015, 281 patients underwent initial assessment at an urban tertiary care centre: 190 patients with a confirmed diagnosis of BD, 7 with an incomplete diagnosis, and 84 with a rejected diagnosis. ICBD 2014 demonstrated an estimated sensitivity of 97.89% (95% CI: 94.70 to 99.42) and positive likelihood ratio of 1.21 (1.10 to 1.28). The strongest independent predictors were: Central nervous lesions (OR = 10.57, 95% CI: 1.34 to 83.30); Genital ulceration (OR = 9.05, 95% CI: 3.35 to 24.47); Erythema nodosum (OR = 6.59, 95% CI: 2.35 to 18.51); Retinal vasculitis (OR = 6.25, 95% CI: 1.47 to 26.60); Anterior uveitis (OR = 6.16, 95% CI: 2.37 to 16.02); Posterior uveitis (OR = 4.82, 95% CI: 1.25 to 18.59).ConclusionsThe ICBD 2014 criteria were more sensitive at picking up cases than ISG 1990 using the multidisciplinary assessment as the gold standard. ICBD may over-diagnose BD in a UK population. Patients who have an incomplete form of BD represent a distinct group that should not be given an early diagnostic label. Behçet’s disease is a complex disease that is best diagnosed by multidisciplinary clinical assessment. Patients in the UK differ in their clinical presentation and genetic susceptibility from the original descriptions. This study also highlights an incomplete group of Behçet’s patients that are less well defined by their clinical presentation.

Communicating with patients of South Asian origin: problems and solutions in the context of rheumatoid arthritis

Rheumatoid arthritis is a common chronic disease associated with significant morbidity and mortality. As with all chronic conditions, active participation by the patient, in areas ranging from accepting the diagnosis and its treatment to the implementation of coping strategies, is essential for effective management. Involving any patients in these process can be difficult; however patients of South Asian origin can present particular challenges. Many patients of South Asian origin have beliefs about disease causation and the utility of pharmacological and non‐pharmacological treatments that differ from those held by other patients. Communication difficulties can make it difficult for health care professionals to address these issues. We discuss strategies to support patients and encourage their involvement including linguistically appropriate educational material, peer support and telephone helplines.