Ann Knight

Cancer incidence in a population-based cohort of patients with Wegener's granulomatosis

Wegeners granulomatosis is necrotizing granulomatous vasculitis of unknown origin, which untreated has a high mortality within the first year of onset. The introduction of corticosteroids and cyclophosphamide in the treatment has considerably improved survival rates, but past studies have indicated an increased cancer risk, including an increased risk for urinary bladder cancer. No large assessment of the general cancer occurrence in Wegeners granulomatosis has been reported. The aim of our study was to assess the general incidence of cancer in patients with Wegeners granulomatosis and to put this in relation to the risk for bladder cancer. We identified a population‐based cohort of 1,065 patients with Wegeners granulomatosis in the Swedish In‐patient Register. Through linkage with the Swedish Cancer Register, we followed the cohort for cancer occurrence for up to 26 years. Standardized incidence ratios (SIR) between observed and expected numbers of cancers were used as a measure of relative risk. There was a 2‐fold overall increased risk for cancer in the cohort. The increase was most pronounced for bladder cancer (SIR = 4.8; 95% CI 2.6–8.1), squamous cell skin cancer (SIR = 7.3; 95% CI 4.4–12), leukemias (SIR = 5.7; 95% CI 2.3–12) and for malignant lymphomas (SIR = 4.2; 95% CI 4.2–8.3). The results confirm previous indications of an increased risk for cancer of the urinary bladder but also points to increased risks for cancer at other sites.

Beneficial Effect of Interleukin 1 Inhibition with Anakinra in Adult-onset Still's Disease. An Open, Randomized, Multicenter Study

Objective. To study the efficacy of anakinra versus disease-modifying antirheumatic drugs (DMARD) in refractory adult-onset Still’s disease (AOSD). Methods. In a 24-week study, 22 patients with AOSD taking prednisolone ≥ 10 mg/day received anakinra (n = 12) or DMARD (n = 10). The primary endpoint was achievement of remission. Results. At 8 and 24 weeks, 7/12 and 6/12 receiving anakinra and 5/10 and 2/10 receiving DMARD achieved remission. Anakinra induced greater improvement in physical health measured by Medical Outcomes Study Short-Form 36 (SF-36; p < 0.011). During an open-label extension (OLE) of 28 weeks, 7/14 patients taking anakinra and 2/3 taking DMARD were in remission. Conclusion. Anakinra induced more beneficial responses than DMARD in patients with AOSD and was favored in the OLE phase. (ClinicalTrials.gov Protocol Registration NCT01033656).

Risks and relative risks of Wegener's granulomatosis among close relatives of patients with the disease

OBJECTIVE The etiology of Wegeners granulomatosis (WG) supposedly involves interplay between genetic susceptibility and environmental triggers. However, little is known about whether WG actually clusters in families. Information on the degree of familial aggregation in WG is of clinical relevance, because patients with WG often want to know whether their diagnosis puts their closest relatives at increased risk of the disease. The aim of this study was to investigate the risk of WG in relatives of patients with WG. METHODS Using Swedish nationwide registers on morbidity, family structure, and vital status, we compared the occurrence of WG (register-based plus chart review) among 6,670 first-degree relatives and 428 spouses of 1,944 Swedish patients with WG with the occurrence among 68,994 first-degree relatives and 4,812 spouses of 19,655 control subjects from the general population. Relative risks were estimated using the Cox proportional hazards regression model. RESULTS Two of the 6,670 first-degree relatives of patients with WG and 13 of the 68,994 first-degree relatives of their population controls had WG, resulting in a relative risk of 1.56 (95% confidence interval 0.35-6.90). None of the 428 spouses of patients had WG. CONCLUSION In absolute terms, the occurrence of WG among close biologic and nonbiologic relatives of patients with WG is low. In terms of relative risk, our results provide strong evidence against a pronounced increase in familial risk such as that noted for systemic lupus erythematosus, irritable bowel disease, and multiple sclerosis but are compatible with familial aggregation of a magnitude similar to that for rheumatoid arthritis.

Injection-site reactions upon Kineret (anakinra) administration: experiences and explanations

Anakinra (Kineret), a recombinant form of human interleukin-1 (IL-1) receptor antagonist, is approved for the treatment of rheumatoid arthritis (RA) in combination with methotrexate. Kineret is self-administered by daily subcutaneous injections in patients with active RA. The mechanism of action of anakinra is to competitively inhibit the local inflammatory effects of IL-1. Kineret is generally safe and well tolerated and the only major treatment-related side effects that appear are skin reactions at the injection site. Due to the relatively short half-life of anakinra, daily injection of the drug is required. This, in combination with the comparably high rates of injection-site reactions (ISRs) associated with the drug, can become a problem for the patient. The present review summarises published data concerning ISRs associated with Kineret and provides some explanations as to their cause. The objective is also to present some clinical experiences of how the ISRs can be managed.

Increased Risk of Autoimmune Disease in Families with Wegener's Granulomatosis

Objective. The etiology of Wegener’s granulomatosis (WG) is unknown. Susceptibility genes for WG that also affect the risks of other autoimmune/inflammatory diseases have been identified, indicating the existence of shared interdisease genetic susceptibilities. To determine the effect, on a population level, of shared susceptibility on disease risk, we assessed the occurrence of autoimmune/inflammatory disease in first-degree relatives of patients with WG. Methods. In the Swedish Hospital Discharge Register we identified 2288 individuals discharged with the diagnosis of WG between 1970 and 2003. Through linkage to the Swedish Multi-generation Register we identified 787 parents, 1212 siblings, and 3650 children of these patients. From the Register of Total Population we identified 10 controls for each patient with WG, and 65,000 of their first-degree relatives. Through linkage to the nationwide Outpatients Register, we identified autoimmune/inflammatory disease among all relatives. Relative risks were estimated as hazard ratio (HR) using Cox regression. The study period was 2001–2006. Results. Biological first-degree relatives of patients with WG were at a moderately increased risk of any autoimmune/inflammatory disease (HR 1.32, 95% CI 1.18–1.49), including specific associations with, for example, multiple sclerosis (HR 1.92, 95% CI 1.16–3.16), Sjögren’s syndrome (HR 2.00, 95% CI 1.07–3.73), and seropositive rheumatoid arthritis (HR 1.54, 95% CI 1.09–2.19). Conclusion. Relatives of patients with WG are at increased risk of being diagnosed with other autoimmune/inflammatory diseases, indicating shared susceptibility between WG and other auto-immune/inflammatory disease.

Occupational risk factors for Wegener's granulomatosis- a case control study

Background Wegeners granulomatosis is a systemic vasculitis of unknown aetiology. Previous studies have presented environmental exposures such as silica and farming as potential risk factors. Objective To investigate the potential risk for Wegeners granulomatosis associated with occupations involving contact with animals and various airway exposures, using a population-based approach. Methods In the Swedish Register of inpatient care 2288 cases with Wegeners granulomatosis were identified. Ten matched controls for every case were selected from the Swedish Population Register. By linking the cases and controls to the Swedish population censuses, information on employments before the diagnosis of Wegeners granulomatosis was collected. Relative risks were assessed as odds ratios using conditional logistic regression. Results Odds ratios for specific occupations ranged from 0.6 to 1.9, and centred symmetrically around 1. No statistically significant increased risk was noted for the investigated occupations.

A multicentre, randomised, controlled, open-label pilot study on the feasibility of discontinuation of adalimumab in established patients with rheumatoid arthritis in stable clinical remission.

Objectives Treatment with tumour necrosis factor (TNF) blockers, once started as therapy for rheumatoid arthritis (RA), is usually continued indefinitely. The aim of this trial was to assess the possibility of discontinuing treatment with adalimumab (ADA) while maintaining remission in patients with RA with established disease in stable remission on combination therapy with ADA and methotrexate (MTX). Methods In a randomised, controlled, open-label pilot study of patients with RA in stable remission treated with ADA+MTX, patients were randomised in a 1:1 ratio to continue with ADA plus MTX (arm AM) or MTX monotherapy (arm M) for 52 weeks. Flare was defined as Disease Activity Score (DAS28) ≥2.6 or a change in DAS28 (ΔDAS28) of >1.2 from baseline at any time. Patients in arm M with a flare restarted ADA. The primary end point was the proportion of patients in remission at week 28. Results 31 patients were enrolled in the study and randomised to arm AM (n=16) or arm M (n=15). At 28 weeks, 15/16 patients (94%) and 5/15 patients (33%) in arms AM and M, respectively, were in remission (p=0.001). During the first 28 weeks, 50% (8/16) in the AM arm and 80% (12/15) in the M arm had a flare (p=0.08). The number of patients in the AM and M arms with ≥1 ΔDAS28 >1.2 during the first 28 weeks was 1/16 (6%) and 8/15 (53%), respectively (p=0.005). Conclusions In this study, remission was rarely maintained in patients with long-standing disease who discontinued ADA. Discontinuation may be feasible in only a minority of patients with established RA in stable clinical remission. Trial registration number NCT00808509.

Late-onset neutropenia after rituximab in ANCA-associated vasculitis.

Background: Rituximab (RTX) is being used increasingly in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV). Late-onset neutropenia (LON) and risks of infections have been observed following RTX therapy in rheumatological diseases including granulomatosis with polyangiitis (GPA) but data on microscopic polyangiitis (MPA) are lacking. Method: We studied the occurrence of LON in 59 AAV (47 GPA/12 MPA) patients treated with RTX. Patient charts were retrospectively reviewed for the occurrence of LON and clinical data were extracted and included in the analysis. Results: Seven of the total 59 patients (11.9%) developed LON after a median time of 86 days (range 56–168 days) since their latest RTX treatment. Of these seven LON patients, 5/47 (10.6%) had a diagnosis of GPA and 2/12 (16.7%) of MPA. Three of the patients developed LON after the first RTX treatment and four had received repeated courses. Five LON patients developed infectious symptoms. Six of the patients were hospitalized. Retreatment with RTX was given in three cases without further LON episodes. Conclusions: LON is a potentially severe side-effect of RTX occurring in both GPA and MPA and may develop after both single and repeated treatment courses. As infections are commonly seen, the condition requires an increased awareness. No predisposing factors for LON were identified.

Cathepsin S and cathepsin L in serum and synovial fluid in rheumatoid arthritis with and without autoantibodies

OBJECTIVES Cathepsin S and cathepsin L are endosomal proteolytic enzymes involved in the degradation of extracellular matrixes, angiogenesis and antigen presentation. Cathepsins could thus play several roles in the disease process of RA. The aim of this study was to examine differences in cathepsin S and cathepsin L levels in serum and SF of RA patients with and without ACPA and RF. METHODS In this study 121 patients with RA and clinical signs of knee synovitis were recruited. Patient characteristics were collected and matched samples of serum and SF were analysed for cathepsin S, cathepsin L, ACPA, IgA and IgM RF, CRP and MMP3. RESULTS SF levels of cathepsin L, cathepsin S and MMP3 were significantly higher than in serum. Serum levels of both cathepsins were significantly higher in patients with ACPA, IgM-RF and IgA-RF compared with patients without these antibodies. SF levels of both cathepsins correlated with DAS28 and CRP in ACPA- and RF-positive but not in seronegative patients. CONCLUSION The differences in cathepsin S and cathepsin L between RA patients with and without autoantibodies indicate that these cathepsins have a specific role in the disease process of seropositive RA. In this phenotype, cathepsin serum levels may reflect the autoimmune activity, whereas the levels in SF may reflect the local inflammatory and matrix degrading process in the joint.

Tick-borne encephalitis (TBE) vaccine to medically immunosuppressed patients with rheumatoid arthritis: A prospective, open-label, multi-centre study

BACKGROUND Tick-borne Encephalitis (TBE) is endemic in south-eastern Sweden as well as in the Baltic regions, Central Europe and Russia. Ageing and immunosuppressed individuals are more prone to severe disease and neurological complications. We assessed the immunogenicity of TBE-vaccine in rheumatoid arthritis (RA) patients treated with tumor necrosis factor-inhibitors (TNFi) and/or methotrexate (MTX). METHODS TBE vaccine, FSME-Immune(®) or Encepur(®), was administered to non-immune RA patients as well as age and gender matched healthy controls. Individuals <60 years of age were given three doses at month 0, 1, 12. Individuals ≥ 60 years old were given an additional priming dose at month 3, i.e. a total of four doses. Tick-borne encephalitis neutralizing antibodies were assessed by a rapid fluorescent focus inhibition test. RESULTS The study population consisted of 66 patients and 56 age and gender matched healthy controls. Median age was 58.5 years. The patients were either treated with TNFi (n=16), TNFi+MTX (n=36) or MTX (n=14). After the last TBE-vaccine dose, given one year after the first, 39% of the patients compared to 79% of the healthy controls had seroprotective levels (p=<0.05). CONCLUSIONS Standard TBE-vaccine schedule does not confer enough immunogenicity in this group of immunosuppressed patients, who should be carefully informed about a higher risk for vaccination failure and risk of infection when exposed in high-endemic areas.