Halil Yazici

Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism Systemic Vasculitis Task Force

Objectives: We undertook a systematic literature review as a background to the European League Against Rheumatism (EULAR) recommendations for conducting clinical trials in anti-neutrophil cytoplasm antibody associated vasculitis (AAV), and to assess the quality of evidence for outcome measures in AAV. Methods: Using a systematic Medline search, we categorised the identified studies according to diagnoses. Factors affecting remission, relapse, renal function and overall survival were identified. Results: A total of 44 papers were reviewed from 502 identified by our search criteria. There was considerable inconsistency in definitions of end points. Remission rates varied from 30% to 93% in Wegener granulomatosis (WG), 75% to 89% in microscopic polyangiitis (MPA) and 81% to 91% in Churg–Strauss syndrome (CSS). The 5-year survival for WG, MPA and CSS was 74–91%, 45–76% and 60–97%. Relapse (variably defined) was common in the first 2 years but the frequency varied: 18% to 60% in WG, 8% in MPA, and 35% in CSS. The rate of renal survival in WG varied from 23% at 15 months to 23% at 120 months. Methods used to assess morbidity varied between studies. Ignoring the variations in definitions of the stage of disease, factors influencing remission, relapse, renal and overall survival included immunosuppressive therapy used, type of organ involvement, presence of ANCA, older age and male gender. Conclusions: Factors influencing remission, relapse, renal and overall survival include the type of immunosuppressive therapy used, pattern of organ involvement, presence of ANCA, older age and male gender. Methodological variations between studies highlight the need for a consensus on terminology and definitions for future conduct of clinical studies in AAV.

Acute phase response in familial Mediterranean fever

Objective: To test the hypothesis that not all acute phase reactants respond in the same way during attacks of familial Mediterranean fever (FMF) and that there is a subclinical acute phase response (APR) in a proportion of patients during the interval between attacks. Methods: Blood and urine samples were obtained from 49 patients with FMF during an attack and the attack-free period that followed, to test for erythrocyte sedimentation rate, C reactive protein (CRP), fibrinogen, white blood cell count, platelet count, factor VIII related antigen, haptoglobin, protein electrophoresis, ferritin, proteinuria, and haematuria. Control groups comprised 29 patients with juvenile idiopathic arthritis, 10 patients with various infectious diseases, and 19 healthy subjects. Results: A marked APR was seen during the FMF attacks which was comparable with that obtained in the diseased control groups. CRP was the only acute phase protein that was raised during all attacks. Neither thrombocytosis nor an increase in ferritin levels (except one) was noted in any attack. Serum albumin levels remained unchanged. In two thirds of the patients with FMF a continuing APR was seen in between the attacks. Conclusion: Platelet, ferritin, and albumin responses are not part of the significant APR seen during short lived attacks of FMF, and inflammation continues in about two thirds of the patients during an attack-free period.

Gastrointestinal involvement in Behçet's syndrome: a controlled study.

OBJECTIVE: To make a retrospective and prospective analysis of the frequency of symptomatic inflammatory bowel disease in patients with Behçets syndrome (BS). METHODS: The medical records of the first 1000 patients with BS were reviewed retrospectively for past or present history of diarrhoea. The past and present history of diarrhoea was also elicited prospectively among 147 consecutive patients with BS and 78 diseased controls (42 with rheumatoid arthritis, 17 with systemic lupus erythematosus, seven with seronegative spondylarthropathy, and 12 with miscellaneous rheumatic diseases). Inflammatory mucosal changes were sought in rectal biopsy specimens from 75 patients with BS, 47 diseased controls (29 with nephrotic syndrome, eight with rheumatoid arthritis, six with familial Mediterranean fever, and four with ankylosing spondylitis), and 14 patients with ulcerative colitis. RESULTS: In chart review there were only seven Behçets patients with diarrhoea; none of them had inflammatory bowel disease. In the prospective survey there were no significant differences between the BS and control groups in the past and present history of diarrhoea. There were no significant differences in the rectal mucosal histology between patients with BS and controls, while patients with ulcerative colitis showed pronounced differences. CONCLUSION: Symptomatic inflammatory bowel disease is not common in BS patients from Turkey.

EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis

Objectives The systemic vasculitides are multiorgan diseases where early diagnosis and treatment can significantly improve outcomes. Robust nomenclature reduces diagnostic delay. However, key aspects of current nomenclature are widely perceived to be out of date, these include disease definitions, classification and diagnostic criteria. Therefore, the aim of the present work was to identify deficiencies and provide contemporary points to consider for the development of future definitions and criteria in systemic vasculitis. Methods The expert panel identified areas of concern within existing definitions/criteria. Consequently, a systematic literature review was undertaken looking to address these deficiencies and produce ‘points to consider’ in accordance with standardised European League Against Rheumatism (EULAR) operating procedures. In the absence of evidence, expert consensus was used. Results There was unanimous consensus for re-evaluating existing definitions and developing new criteria. A total of 17 points to consider were proposed, covering 6 main areas: biopsy, laboratory testing, diagnostic radiology, nosology, definitions and research agenda. Suggestions to improve and expand current definitions were described including the incorporation of anti-neutrophil cytoplasm antibody and aetiological factors, where known. The importance of biopsy in diagnosis and exclusion of mimics was highlighted, while equally emphasising its problems. Thus, the role of alternative diagnostic tools such as MRI, ultrasound and surrogate markers were also discussed. Finally, structures to develop future criteria were considered. Conclusions Limitations in current classification criteria and definitions for vasculitis have been identified and suggestions provided for improvement. Additionally it is proposed that, in combination with the updated evidence, these should form the basis of future attempts to develop and validate revised criteria and definitions of vasculitis.

Genetic anticipation in Behçet’s syndrome

OBJECTIVE To examine the presence of genetic anticipation in families with Behçet’s syndrome (BS). METHODS A total of 18 families with 40 affected members in two successive generations were evaluated by interviewing them for their ages at the onset of the first symptom of BS and for their ages at the time they fulfilled the diagnostic criteria. RESULTS It was noted that the age of onset of the first symptom was lower in the second generation in 14 families (p=0.01) with a mean (SD) age of 20.57 (7.47) years in the children compared with 33.29 (9.92) years in the parents (t=7.79, p<0.0001), whereas the diagnostic criteria were fulfilled at an earlier age in the children in 15 families (p=0.01) with a mean age of 21.2 (6.74) years in the children compared with 36.4 (9.55) years in the parents (t=7.41, p<0.0001). CONCLUSION Genetic anticipation was present in 15 of 18 (84%) of the families with BS in the form of earlier disease onset in the children compared with their parents.

Papulopustular skin lesions are seen more frequently in patients with Behçet's syndrome who have arthritis: a controlled and masked study

OBJECTIVE To determine the prevalence of acneiform skin lesions (comedones, papules, and pustules) in patients with Behçets syndrome (BS) with arthritis. METHODS Study groups included 44 patients with BS with arthritis (32 men, 12 women, mean (SD) age 37.8 (8.9)), 42 patients with BS without arthritis (31 men, 11 women, mean age 35.5 (6.4)), 21 patients with active rheumatoid arthritis (five men, 16 women, mean age 48.8 (14)), and 33 healthy volunteers (28 men, five women, mean age 40.1 (8.1)). All probands and controls were examined by a rheumatologist and a dermatologist, in a prospective and masked protocol. An ophthalmological evaluation was performed if necessary. Skin lesions, including comedones, papules, and pustules, were counted and scored as 0: absent, 1: 1–5, 2: 6–10, 3: 11–15, 4: 16–20, and 5: >20. RESULTS Although there was no significant difference between the four groups in the prevalence of comedones, the number of papules and pustules was significantly higher in patients with BS with arthritis (p=0.0037 for papules and p<0.0001 for pustules) than in the remaining three groups. CONCLUSION Acneiform skin lesions (papules and pustules) seem to be more frequent in patients with BS with arthritis. This suggest that the arthritis seen in BS may possibly be related to acne associated arthritis.

Efficacy of anakinra treatment in a patient with colchicine-resistant familial Mediterranean fever

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by self-limited recurrent attacks of fever and serositis. The serious complication of FMF is AA-type amyloidosis, which can result in end-stage renal disease. Although colchicine is effective in the majority of patients, there is no established treatment for those who are resistant or intolerant to colchicine. We herein report the efficacy of anakinra in a 52-year-old Turkish patient with FMF, secondary amyloidosis and renal transplant, who was resistant to colchicine treatment.

Reduction of uric acid levels with allopurinol treatment improves endothelial function in patients with chronic kidney disease.

BACKGROUND Endothelial dysfunction (ED) is a key event in the development of atherosclerotic cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Association of hyperuricemia with CVD has been previously reported in the nonuremic population. In this prospective study, we aimed to evaluate the effects of treatment of hyperuricemia with allopurinol on ED and changes in the serum reactive oxygen species in patients with CKD. METHODS In this study, 19 (13 male) hyperuricemic (UA > 7 mg/dl) nondiabetic CKD patients without any comorbidity, aged < 60 years with creatinine clearance (CrCl) between 20 and 60 ml/min were evaluated. Endothelial functions were assessed by ischemia-induced forearm vasodilatation method (EDD). Oxidative stress was evaluated by measuring the serum oxidized LDL (ox-LDL), advanced oxidation protein products (AOPP) and nitrotyrosine (NT) levels. After measuring all these tests at baseline, allopurinol therapy was commenced for 8 weeks. After 8 weeks of allopurinol treatment, all measurements were repeated. Then, allopurinol treatment was ceased and same measurements were also repeated 8 weeks after ceasing of the treatment. RESULTS Serum creatinine, total cholesterol, albumin, hs-CRP, CrCl and proteinuria levels of the patients were similar among three study periods. After allopurinol therapy, the mean serum UA and NT levels significantly reduced as compared to baseline. At the 8th week after cessation of allopurinol treatment, serum UA levels were significantly increased. After allopurinol therapy, EDD value increased from 5.42 ± 8.3% at baseline to 11.37 ± 9% (p < 0.001). At the 8th week after ceasing allopurinol treatment, EDD returned to baseline values (5.96 ± 8%, p < 0.001). CONCLUSION Treatment of hyperuricemia with allopurinol improve ED in patients with CKD. However, mechanism responsible for this beneficial effect seems to be apart from antioxidant effects of allopurinol.

Autoimmune thyroiditis and anti-thyroid antibodies in primary Sjögren’s syndrome: a case–control study

Objective: To determine the frequency of antithyroid antibodies and the presence of autoimmune thyroiditis among patients with primary Sjögren’s syndrome. Design: A case–control study. Methods: 53 consecutive patients with primary Sjögren’s syndrome, 30 with rheumatoid arthritis, 12 with secondary Sjögren’s syndrome associated with rheumatoid arthritis, 17 with autoimmune thyroiditis, and 53 apparently healthy controls were studied for anti-TG and anti-TPO antibodies as well as serum thyroid hormones and TSH levels. Results: The overall frequencies of thyroid antibodies were 6/53 (11%) in primary Sjögren’s syndrome, 2/30 (7%) in rheumatoid arthritis, 2/12 (17%) in secondary Sjögren’s syndrome, 4/53 (8%) in healthy controls, and 16/17 (94%) in autoimmune thyroiditis. There was no difference in the frequency of the thyroid antibodies among the groups if patients with autoimmune thyroiditis were excluded (p = 0.415 for anti-TPO; p = 0.275 for anti-TG; p = 0.696 for either anti-TG and/or anti-TPO). Only two patients with primary Sjogren’s syndrome had clinical hypothyroidism associated with autoimmune thyroiditis. Conclusions: In this Turkish population, no association between primary Sjögren’s syndrome and autoimmune thyroiditis was found.

Intestinal permeability in Behçet's syndrome

OBJECTIVE To measure the intestinal permeability in patients with Behçets syndrome (BS) and to compare the results with those obtained from healthy and diseased controls. METHOD The study group comprised 34 patients with BS without known gastrointestinal disease. Ten patients with ankylosing spondylitis (AS), 6 with inflammatory bowel diseases (IBD), 17 with systemic lupus erythematosus (SLE), and 15 healthy subjects (HC) constituted the controls. All patients received 100 μCi (3.7 MBq) of chromium-51 EDTA (51Cr-EDTA) as a radioactive tracer after a 72 hour abstinence from all drugs. The percentage of the isotope excreted in a 24 hour urinary specimen was the measure of permeability. RESULTS The percentage (SD) rate of excretion of 51Cr-EDTA was 4.6 (2.6) in BS, 6 (2.4) in AS, 5.2 (1.9) in IBD, 5.56 (1.78) in SLE, and 2.3 (1) in healthy controls. (Analysis of variance: f=6.4, p=0.0002. BSv HC, AS vHC, SLE v HC significant.) CONCLUSION The intestinal permeability in BS was significantly more than that seen among the healthy controls. Similar results in all the diseased controls cast doubt on its specificity.