Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis.

Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2 and Chr2p14) in recent GWAS and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis (P = 1.02 × 10(-5)) in the German cohort with genotypic odds ratios of 3.56 (95% CI 1.29-9.77) for CG heterozygotes and 5.38 (95% CI 2.39-12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (P = 0.014; ORallelic = 1.82 (95% CI 1.12-2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology (N = 244, P = 0.00014, ORallelic = 2.84) and of males only (N = 431, P = 2.17 × 10(-5), ORallelic = 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation.

Idiopathic hand osteoarthritis vs haemochromatosis arthropathy--a clinical, functional and radiographic study.

OBJECTIVE: Haemochromatosis arthropathy is a secondary OA and the most frequent and earliest clinical presentation of hereditary haemochromatosis (HH). The aim of this study was to perform a direct clinical, functional and radiographic comparison with idiopathic hand OA (HOA) to unravel important differences between these clinical entities. METHODS: In total, 299 patients (141 with HH arthropathy of the hands and 158 patients with idiopathic HOA) were recruited. Structured clinical assessment including hand function tests, as well as hand radiographs with scoring according to Kellgren-Lawrence, were carried out in all patients. RESULTS: HH arthropathy and HOA differed significantly: patients with HH arthropathy were younger and predominantly male as compared with HOA. In males but not females, HH arthropathy led to an earlier start of symptoms than in HOA. Patients with HOA had more tender joints and worse hand function than patients with HH arthropathy, although subjective measures of joint pain and function were similar. MCP and wrist joint involvement was more frequent and severe in HH arthropathy, while HOA patients more frequently had degenerative changes in the first CMC as well as PIP and DIP joints. CONCLUSION: HH arthropathy and idiopathic HOA differ significantly in terms of epidemiology, localization, severity of symptoms and radiographic changes.

Musculoskeletal disease burden of hereditary hemochromatosis.

OBJECTIVE: To determine the prevalence, clinical picture, and disease burden of arthritis in patients with hereditary hemochromatosis. METHODS: In this cross-sectional observational study of 199 patients with hemochromatosis and iron overload, demographic and disease-specific variables, genotype, and organ involvement were recorded. The prevalence, intensity, and localization of joint pain were assessed, and a complete rheumatologic investigation was performed. Radiographs of the hands, knees, and ankles were scored for joint space narrowing, erosions, osteophytes, and chondrocalcinosis. In addition, the number and type of joint replacement surgeries were recorded. RESULTS: Joint pain was reported by 72.4% of the patients. Their mean ± SD age at the time of the initial joint symptoms was 45.8 ± 13.2 years. If joint pain was present, it preceded the diagnosis of hemochromatosis by a mean ± SD of 9.0 ± 10.7 years. Bony enlargement was observed in 65.8% of the patients, whereas synovitis was less common (13.6%). Joint space narrowing and osteophytes as well as chondrocalcinosis of the wrist and knee joints were frequent radiographic features of hemochromatosis. Joint replacement surgery was common, with 32 patients (16.1%) undergoing total joint replacement surgery due to severe OA. The mean ± SD age of these patients was 58.3 ± 10.4 years at time of joint replacement surgery. Female sex, metacarpophalangeal joint involvement, and the presence of chondrocalcinosis were associated with a higher risk of early joint failure (i.e., the need for joint replacement surgery). CONCLUSION: Arthritis is a frequent, early, and severe symptom of hemochromatosis. Disease is not confined to involvement of the metacarpophalangeal joints and often leads to severe damage requiring the replacement of joints.

Validation of a radiographic scoring system for haemochromatosis arthropathy.

BACKGROUND: Arthropathy is one of the earliest and most common manifestations of hereditary haemochromatosis with a significant impact on quality of life. Although its radiographic features are well known, there is no assessment tool for their evaluation. OBJECTIVE: To develop and validate a novel scoring system for the evaluation of radiographic features of haemochromatosis arthropathy. METHODS: A dichotomous scoring system assessing four radiographic features of haemochromatosis arthropathy and a 4-grade scale reflecting severity of radiographic change have been developed. Standard radiographs (hand, wrist, knee and ankle) of 170 subjects (116 male, 54 female) with genetically confirmed haemochromatosis and laboratory signs of iron overload were assessed by three readers and construct validity, feasibility and cross-sectional reliability (intrareader and inter-reader) were assessed. RESULTS: Intrareader and inter-reader reliability as assessed by percentage pairwise agreement and Cohen's weighed κ were good to excellent for most features and locations evaluated. Radiographic scores correlated well with clinical parameters (bony swollen joint count, hand function and physician's global health assessment; Pearson's correlation, r²=0.18-0.62, p<0.0001). A complete set of radiographs took 3.4 ± 1.2 (mean ± SD) min to be assessed. An atlas of characteristic radiographic features was compiled. CONCLUSION: A feasible and reliable radiological assessment tool for the evaluation of haemochromatosis arthropathy has been validated and an atlas of characteristic radiographic features provided.

Synovial immunopathology in haemochromatosis arthropathy.

BACKGROUND: Hereditary haemochromatosis (HH) is a common autosomal recessive inherited disorder that frequently causes arthritis. The pathophysiology of musculoskeletal involvement is, however, unclear. OBJECTIVE: To analyse synovial tissue obtained at surgery from patients with HH arthropathy and compare it qualitatively and quantitatively with specimens from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Synovial tissue from 15 patients with HH, 20 with RA and 39 with OA was obtained during surgery. A synovitis grading system was used to determine the severity of synovial inflammation. Using immunohistochemistry, synovial neovascularisation and infiltration of macrophages, neutrophils and lymphocytes were quantitatively assessed. RESULTS: Synovitis in HH arthropathy largely resembles OA with mild infiltration of mononuclear cells and lymphocytes, formation of synovial microvessels and a low degree of synovial hyperplasia. While many features of HH arthropathy are reminiscent of OA, macrophage and especially neutrophil invasion is clearly more prominent in HH arthropathy than in primary OA and mimics features of RA. This finding was observed particularly in synovial tissue of HH samples with marked haemosiderin deposition. DISCUSSION: The histological picture of the synovium in HH arthropathy largely resembles a process reminiscent of OA. Neutrophil invasion is, however, markedly increased in HH arthropathy, especially in joints with iron deposition. Accumulation of neutrophils may be crucial for the production of matrix enzymes, which enables cartilage degradation and more rapidly progressive articular damage.

Inflammatory bone spur formation in psoriatic arthritis is different from bone spur formation in hand osteoarthritis.

OBJECTIVE: To investigate the different patterns of bone spur formation in psoriatic arthritis (PsA) and hand osteoarthritis (OA), using high-resolution peripheral quantitative computed tomography (QCT). METHODS: The study group comprised 70 subjects (25 patients with PsA, 25 patients with hand OA, and 20 healthy controls). The 2 patient groups were similar with regard to age and sex distribution and clinical involvement of the metacarpophalangeal (MCP) joints. All patients underwent high-resolution peripheral QCT scanning of the second, third, and fourth MCP joints of the dominantly affected hand. Demographic and disease-specific data were recorded, and the number, size, and distribution of bone spurs were assessed and compared between patients with PsA and patients with hand OA. RESULTS: The overall number and size of bone spurs were similar in patients with PsA and patients with hand OA. However, localization of lesions within individual joints was substantially different between patients with PsA and those with hand OA. In PsA, bone spurs dominated the radial sides of the joints (for the metacarpal head of the second joint, P < 0.001 versus hand OA; for the base of the second phalangeal joint, P < 0.001 versus hand OA), whereas the palmar and dorsal quadrants were the predilection sites in hand OA. Detailed anatomic analysis showed that bone spurs in the entheseal regions were prominent in patients with PsA but rare in patients with hand OA, and that bone spurs in patients with hand OA typically emerged at the cartilage-bone interphase and the joint margins. CONCLUSION: Our findings show that the overall number and size of bone spurs are similar in patients with PsA and patients with hand OA. Nonetheless, the anatomic sites of bone proliferation are different between these 2 groups of patients.

A typically atypical tenosynovitis.

A 68-year-old woman developed tenosynovitis of the right second digit without a history of injury or animal bites. Apart from high titer anti-nuclear antibodies, serological studies were unremarkable. Tuberculin test and interferon gamma release assay were both negative. Several immunosuppressive therapies led only to partial relief of symptoms. Of note, clinical symptoms worsened significantly after introduction of adalimumab therapy. Tenosynovectomy was performed revealing a granulomatous inflammatory process. Seven weeks later, Mycobacterium malmoense could be cultured from the surgical specimen. A four drug antibiotic regimen was started and immunosuppressive therapy discontinued resulting in complete clinical remission. Our case highlights non-tuberculous mycobacterial (NTM) tenosynovitis as an important differential diagnosis of atypical arthritis. A negative tuberculin skin test as well as negative Ziehl-Neelsen stain does not argue against NTM infection. In fact, mycobacterial culture for extended periods remains the gold standard for diagnosis.

Diabetes is an independent predictor for severe osteoarthritis: results from a longitudinal cohort study.

OBJECTIVE: To evaluate if type 2 diabetes is an independent risk predictor for severe osteoarthritis (OA). RESEARCH DESIGN AND METHODS: Population-based cohort study with an age- and sex-stratified random sample of 927 men and women aged 40-80 years and followed over 20 years (1990-2010). RESULTS: Rates of arthroplasty (95% CI) were 17.7 (9.4-30.2) per 1,000 person-years in patients with type 2 diabetes and 5.3 (4.1-6.6) per 1,000 person-years in those without (P < 0.001). Type 2 diabetes emerged as an independent risk predictor for arthroplasty: hazard ratios (95% CI), 3.8 (2.1-6.8) (P < 0.001) in an unadjusted analysis and 2.1 (1.1-3.8) (P = 0.023) after adjustment for age, BMI, and other risk factors for OA. The probability of arthroplasty increased with disease duration of type 2 diabetes and applied to men and women, as well as subgroups according to age and BMI. Our findings were corroborated in cross-sectional evaluation by more severe clinical symptoms of OA and structural joint changes in subjects with type 2 diabetes compared with those without type 2 diabetes. CONCLUSIONS: Type 2 diabetes predicts the development of severe OA independent of age and BMI. Our findings strengthen the concept of a strong metabolic component in the pathogenesis of OA.

Daily functioning and health status in patients with hand osteoarthritis: Fewer differences between women and men than expected.

OBJECTIVE: To explore and describe potential differences between women and men in functioning, health status and socio-economic variables in hand OA. METHODS: Unselected patients of an Austrian outpatient clinic meeting the ACR criteria for hand OA were consecutively included and assessed once. Descriptive statistics and subgroup analyses were performed for differences between women and men. By regression analysis, we explored whether the variables sex, practice of sports, manual activities, aesthetic changes and functioning in daily life predict the levels of pain and vitality. RESULTS: 223 (88.1%) women and 30 (11.9%) men were included in the study. Significant differences between women and men were found in involvement in housework, aesthetic changes and own net income. Sex did not contribute significantly to any of the regression models, while e.g. involvement in sports was a strong individual contributor to self-reported vitality - irrespective of sex. Total X-ray scores of both hands as well as the involvement of CMCI joints did not show significant differences. CONCLUSION: Our study showed significant differences between women and men with hand OA in socio-economic variables and aesthetic changes. In contrast to our expectations, no other differences between women and men were found in functioning and health status.

Hereditary hemochromatosis as a risk factor for joint replacement surgery.

OBJECTIVE: Hemochromatosis is an inherited disease with iron overload and joint involvement resembling osteoarthritis. To determine the rate of joint replacement surgery in patients with hemochromatosis, we performed a cross-sectional cohort study. METHODS: A total of 199 individuals with hereditary hemochromatosis were included. The prevalence of joint replacement surgery in hip, knee, and ankle joints because of secondary osteoarthritis was assessed. Data were compared with 917 healthy subjects from the population-based Bruneck study. RESULTS: A total of 32 of 199 individuals with hemochromatosis received joint replacement surgery with a total number of 52 joints replaced. Compared with expected rates in healthy individuals, patients with hemochromatosis had a significantly higher risk for joint replacement surgery (odds ratio 9.0; confidence interval, 4.6-17.4). Joint replacement occurred significantly earlier in life in patients with hemochromatosis; 21.9% of the patients with hemochromatosis and 1.7% of healthy individuals required joint replacement before the age of 50 years (P=.0027). Moreover, patients with hemochromatosis were more likely to require multiple joint replacements (8.5%) than the control group (expected rate 0.3%; P=.0001). CONCLUSION: Hemochromatosis is a risk factor for joint replacement surgery because of severe secondary osteoarthritis.

Pathogenesis of Churg-Strauss syndrome: recent insights.

Churg-Strauss syndrome (CSS) is a rare systemic necrotizing vasculitis associated with granuloma formation and severe blood and tissue eosinophilia. CSS occurs almost exclusively in patients with asthma. Its pathogenesis remains largely unknown, as triggering factors for CSS development have not been identified so far. AAb, such as anti-neutrophil cytoplasmic autoantibodies, are found in less than half of patients and possibly constitute a subtype of CSS with different clinical behaviour. On a cellular level, CSS is characterized by a strong Th2-type immune response. Th2-associated cytokines such as IL-4, IL-13 and IL-5 may precipitate the severe eosinophilia in CSS, while migration of Eos to inflammatory sites is possibly mediated by eotaxin-3. This review summarizes recent advances in the knowledge on epidemiology, clinical features, and pathogenesis of CSS.