Follicular thyroid cancer in a patient with Pendred syndrome.

We present the clinical and molecular studies of a family with Pendred syndrome, in which one affected individual developed follicular thyroid cancer. Two siblings with classic Pendred syndrome triad were operated on because of enormous multinodular goiter. Histopathology showed a follicular thyroid cancer in the male and a multinodular goiter in the female. PDS gene analysis revealed G-to-A transition in the splice donor site of intron 8 (IVS8+1G>A/c.1001+1G>A). Careful surveillance is needed in all cases of thyroid nodules in patients with Pendred syndrome, due to the high risk of malignancy.

Interleukin 1 beta (IL1beta) gene polymorphisms (SNP-511 and SNP+3953) in Hashimoto's thyroiditis among the Polish population.

AIM: The association between the interleukin IL1 beta gene polymorphisms SNP-511 and SNP+3953 and susceptibility to the development of Hashimoto's thyroiditis among adult Caucasian-Polish population were analyzed. PATIENTS AND METHODS: The group studied comprised of 115 unrelated patients with Hashimoto's thyroiditis (112 women and 3 men, mean age 53.3 years). All patients were euthyroid on thyroid replacement therapy, had extremely high serum anti-TPO levels and in 53 patients anti-TG levels were also increased. The control group consisted of 103 healthy blood donors without raised anti-TPO antibodies, in whom a personal and familial history of thyroid, autoimmune and inflammatory diseases was excluded. No goiter or thyroid dysfunction was found.2 polymorphisms of the IL1 beta were studied by PCR-RFLP analysis. To confirm the accuracy of the method used, randomly selected patients were analyzed by direct sequencing. RESULTS: In both groups allele frequencies were in Hardy-Weinberg equilibrium. The significant statistical differences between the frequency of C and T allele for both SNPs (C-511T and C+3953T) in the group studied and in the controls were found (p=0.0081; OR=1.846; 95% CI: 1.183-2.878 and p=0.0099; OR=1.953; 95% CI: 1.183-3.224).The frequencies of the genotype C-511C compared to C-511T and T-511T as well as C+3953C compared to C+3953T and T+3953T also differed significantly (p=0.0057; OR=2.248; 95% CI: 1.292-3.912 and p=0.0043; OR=2.338; 95% CI: 1.305-4.191) between patients and controls. CONCLUSIONS: An association between the SNPs of the IL1 beta and susceptibility to Hashimoto's thyroiditis among the group of Caucasian-Polish population studied was found.

Bone tissue metabolism in men with ankylosing spondylitis.

PURPOSE: The aim of the study was the composite estimation of bone tissue metabolism in ankylosing spondylitis (AS) after having taken into account such factors as a high risk of incidence of osteoporosis in patients with AS and potential danger of permanent immobility. MATERIAL AND METHODS: Sixty-six patients with established diagnosis of AS and 63 healthy individuals in the control group were included into the study. To measure bone mineral density (BMD) the dual energy X-ray absorptiometry (DEXA) method was used. Additionally, biochemical markers of osteoporosis such as bone fraction of an alkaline phosphatase (BALP), osteocalcin (BGP) and deoxypyridinoline (Dpd) as well as many inflammatory markers of disease activity have been determined. RESULTS: In our study with AS had significantly diminished bone mineral density, as compared with health controls. The presence of osteopenia/osteoporosis was associated with longer duration of the disease and with higher age. In the overall group of AS patients bone degradation marker, Dpd, correlated with serum concentration of interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and C-reactive protein (CRP), and inversely with BMD measured in the forearm. However, no direct association could be revealed between lower bone density and markers of inflammation or inflammatory cytokines, except of IL-6 witch was significantly higher in AS patients with osteoporosis/osteopenia than those without. CONCLUSIONS: Our results indicate that disease duration and higher age are risk factors for osteoporosis in patients with AS. Inflammation might contribute to the accelerated bone loss in AS through stimulation of bone degradation.

Differential association of juvenile and adult systemic lupus erythematosus with genetic variants of oestrogen receptors alpha and beta.

Oestrogens acting via nuclear receptors (encoded by ESR1 or ESR2) are important for pathogenesis of systemic lupus erythematosus (SLE). rs2234693 and rs4986938 are two single nucleotide polymorphisms (SNPs) whose C and A variants increase transcription of ESR1 and ESR2, respectively. The T allele of rs2234693 was associated with early onset SLE, whereas the role of rs4986938 in SLE was not reported. Our aim was to examine the role of rs2234693 and rs4986938 in conferring susceptibility to juvenile and adult SLE (jSLE and aSLE). Genotype distribution of both SNPs was analysed in 84 jSLE, 112 aSLE patients and 1001 controls. Allele C of rs2234693 was associated with jSLE (OR = 1.87, p = 0.006, p(corrected) = 0.02), whereas allele A of rs4986938 showed an association with aSLE (OR = 1.46, p = 0.008, p(corrected) = 0.03). In jSLE, rs2234693 C had lower frequency in patients with central nervous system involvement (OR = 0.39, p = 0.005, p(corrected) = 0.04) and showed a trend for increase among males, patients with renal involvement and those without DR2/3 (p < 0.05, p(corrected) > 0.05). Whereas our results are consistent with a role of ESR1 variation in jSLE, more studies are needed since the direction of association was the opposite of that reported previously. The association between rs4986938 (ESR2) and aSLE is a novel finding, consistent with our recent report associating this variant with Graves' disease.

Target therapies in systemic lupus erythematosus: current state of the art.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology and limited available therapeutic options frustrating both clinicians and patients. However, recent advances in the understanding of disease mechanisms have given rise to numerous studies on specific approaches to SLE treatment. The purpose of this review is to explain the rationale for new treatments and results of the first clinical studies. We will focus on agents which deplete B cells (anti-CD20, anti-CD22), block cytokines (TNF α, Il 6), inhibit B/T cells interaction (CTLA-4Ig, anti-CD40L), or are even expected to reconstruct physiologic immunotolerance. Although preliminary results seemed promising, two randomized clinical trials with rituximab (EXPLORER and LUNAR study) failed to prove efficacy. Data analysis continues to explain the reasons. Trial design, subject population, limitations of the outcome measure instrument and site qualification have been questioned. Future studies are likely to focus on specific organ involvement or treatment combinations with other immunosuppressive agents.

Association between IL-17F gene polymorphisms and susceptibility to and severity of rheumatoid arthritis (RA).

Interleukin-17F (IL-17F) is a novel proinflammatory cytokine. IL-17F gene is an excellent candidate for chronic inflammatory disease. We investigated the association between rheumatoid arthritis (RA) and His161Arg (7488A/G; rs763780) and Glu126Gly (7383A/G; rs2397084) polymorphism of IL-17F gene. The gene polymorphisms in 220 Polish patients with RA and 106 healthy subjects were amplified by polymerase chain reaction with restriction endonuclease mapping. Overall, the polymorphisms of the IL-17F gene were not correlated with susceptibility to RA in Polish population. However, the IL-17F His161Arg variant was associated with parameters of disease activity, such as number of tender joints, HAQ score or DAS-28-CRP. Moreover, our findings have shown that Glu126Gly IL-17F gene polymorphism may be correlated with longer disease duration in patients with RA. Our results for the first time showed the relationship between IL-17F gene polymorphisms and severity of RA.

Interleukin-10 gene promoter polymorphism in Polish rheumatoid arthritis patients.

Interleukin (IL)-10 is an important multifunctional cytokine with both anti-inflammatory and immunoregulatory effects in rheumatoid arthritis (RA). In the present study, we evaluated the frequency and potential impact of IL-10 promoter polymorphisms on susceptibility to and severity of RA in Polish in - patients with a high disease activity (mean DAS 28 C-reactive protein 5.25). DNA was obtained from 244 RA patients and 106 healthy controls. The -592C/A and -1082G/A IL-10 gene polymorphisms were amplified by polymerase chain reaction with restriction endonuclease mapping. The frequency of the IL-10-592CA, -592AA genotypes (respectively: 30% vs 5% and 7% vs 0%) and allele -592A (37% vs 5%) were significantly higher in RA patients as compared with a control group. We did not find any association of the IL-10-592C/A genotype distribution with disease parameters, except for an increased ESR (erythrocyte sedimentation rate) in patients with the -592CC genotype as compared with those with -592CA or -592AA genotypes (P = 0.01). The frequency of the IL-10-1082GG genotype was lower (P = 0.0001), and that of the IL-10-1082GA genotype was higher (P = 0.009) in RA patients comparing with the control group. In RA patients with -1082GA or -1082AA genotypes the time duration of the disease (P = 0.03), Health Assessment Questionnaire (HAQ) Score (P = 0.04) and PLT count (P = 0.001) were significantly increased as compared with subjects with -1082GG genotype. Presented findings indicate that IL-10-592C/A and IL-10-1082G/A polymorphisms may be considered genetic risk factors for RA susceptibility and severity.

CD24 Ala57Val gene polymorphism and the risk of systemic lupus erythematosus.

It was recently shown that the CD24 Ala57Val (rs 52812045) polymorphism plays a significant role in susceptibility to systemic lupus erythematosus (SLE) in a Spanish population, which has not been confirmed in other ethnic groups. We investigated the distribution of the CD24 Ala57Val polymorphism in patients with SLE (n = 250) and controls (n = 350) in Poland. The odds ratio (OR) for patients with SLE with the Ala/Val genotype compared with Ala/Ala genotype was 1.490 [95% confidence interval (CI) = 1.052-2.111, P = 0.0275], and OR for the Val/Val genotype compared with Ala/Ala genotypes was 2.001 (95% CI = 1.154-3.467, P = 0.0154). Moreover, we observed a significant association between the CD24 Val allele and the presence of anti-Scl-70 antibody (Ab) OR = 2.155 (1.438-3.229, P = 0.0002). There was also an association of Val allele with the presence of anti-snRNP Ab OR = 1.984 (1.266-3.110, P = 0.0034) in patients with SLE. We also found that the CD24 Val/Val and Ala/Val genotypes contribute to immunologic manifestations OR = 2.244 (1.323-3.806, P = 0.0037). Our observations indicate that the CD24 Ala57Val polymorphism may predispose to SLE incidence and can be linked to immunologic manifestations and production of autoantibodies in this disease.

The CD3Z 844 T>A polymorphism within the 3'-UTR of CD3Z confers increased risk of incidence of systemic lupus erythematosus.

Recently, a family-based association analysis showed that the haplotype carrying a low expression of the variant CD3Z 844 T>A (rs1052231) polymorphism located in the 3'-untranslated region of CD3Z predisposes to systemic lupus erythematosus (SLE) incidence. We analyzed the prevalence of the CD3Z 844 T>A polymorphism in SLE patients (n = 152) and controls (n = 304) in Poland. We observed that women with the CD3Z AA and CD3Z AT genotypes exhibited a 1.845-fold increased risk of SLE [95% confidence intervals (95% CI) = 1.222-2.787, P = 0.0038]. However, we did not find an increased risk for the homozygous CD3Z AA genotype (odds ratio = 1.204, 95% CI = 0.2838-5.108, P = 1.0000). This observation confers that genetic factors causing a decreased level of CD3-zeta in T cells may predispose to SLE incidence.

Decreased expression of integrins by hematopoietic cells in patients with rheumatoid arthritis and anemia: relationship with bone marrow cytokine levels.

BACKGROUND AND OBJECTIVES: In order to gain a better insight into the pathogenesis of the anemia of chronic disease (ACD) accompanying rheumatoid arthritis, we analyzed the density of the integrins very late antigen (VLA) 4 and VLA-5 on the surface of erythroblasts from bone marrow in patients with rheumatoid arthritis. We also measured the concentration of interleukin (IL) 3 and tumor necrosis factor (TNF) alpha in bone marrow. Finally, we analyzed the relationship between integrin expression on hematopoietic cells and the degree of anemia and concentration of cytokines in bone marrow in patients with rheumatoid arthritis. RESULTS: Patients with rheumatoid arthritis who also had ACD were found to have lower hemoglobin levels and higher C-reactive protein and erythrocyte sedimentation rate compared to patients who had rheumatoid arthritis without ACD or osteoarthritis of the hip. The mean bone marrow concentration of IL-3 was elevated in patients with rheumatoid arthritis and ACD compared to those without ACD or patients with osteoarthritis. IL-3 concentration in bone marrow showed a significant negative correlation with VLA-4 and VLA-5 expression on erythroblasts, but only in patients with rheumatoid arthritis and ACD. CONCLUSION: Patients with rheumatoid arthritis and ACD have abnormal erythroblasts (decreased VLA density), possibly through an effect on early stages of erythroblast development. Increased levels of IL-3 and the negative correlation between IL-3 concentration in bone marrow and expression of the integrins VLA-4 and VLA-5 may suggest positive feedback between erythroblasts and IL-3, probably associated with decreased sensitivity of bone marrow erythroblasts to IL-3.

Contribution of the R620W polymorphism of protein tyrosine phosphatase non-receptor 22 to systemic lupus erythematosus in Poland.

The protein tyrosine phosphatase non-receptor 22 (PTPN22) 1858 C>T poly-morphic variant gene (rs2476601) displays an association with systemic lupus erythematosus (SLE) and other autoimmune diseases. However, its contribution to SLE has been found to be disputable. We therefore examined the association of PTPN22 1858 C>T polymorphism with susceptibility to SLE in the Polish population, among patients with SLE (n=150) and controls (n=300). We found a contribution of the PTPN22 1858 C>T polymorphism to the incidence of SLE. Women with the PTPN22 TT and PTPN22 CT genotypes displayed a 2.016-fold increased risk of SLE (95% CI=1.324 - 3.070, P=0.0014). However, we did not observe an increased risk for the homozygous PTPN22 TT genotype OR= 2.552 (95% CI=0.6748-9.64, p=0.1675). Our results confirm an association of the 1858 C>T polymorphism of the PTPN22 gene with SLE, which was previously observed in other populations.

The effect of methylprednisolone on proliferation of PBMCs obtained from steroid-sensitive and steroid-resistant rheumatoid arthritis patients.

OBJECTIVE: Glucocorticoids (GCs) are among the most frequently used drugs for the treatment of rheumatoid arthritis (RA). Unfortunately, up to 30% of patients with RA fail to respond to the treatment. We investigated the hypothesis that patients with RA who did not respond to GC treatment have steroid-resistant peripheral blood mononuclear cells (PBMCs). METHODS: Forty-four patients with RA were enrolled in the study. PBMCs were isolated from blood samples. The effect of methylprednisolone (MP) on the proliferation of stimulated cells was measured. After taking the blood samples, 10 days of MP therapy (20 mg i.v.) was started, in order to classify the patients into either a GC-sensitive (RA/GCS) or a GC-resistant (RA/GCR) group. RESULTS: A quarter of our patients did not show any improvement after short-term GC therapy and were assigned to the RA/GCR group. The inhibition of PBMC proliferation after MP treatment was significantly lower in the RA/GCR as compared to the RA/GCS group. CONCLUSION: Based on the close relationship between clinically observed GC resistance and a diminished response of PBMCs to MP treatment, we conclude that measurement of the steroid sensitivity of PBMCs may be a useful tool in predicting the therapeutic effect of GC in patients with RA.

Antibodies to ubiquitin in relation to Yersinia infection status in patients with ankylosing spondylitis.

The aim of this study was to investigate IgG and IgM antibodies to ubiquitin in relation to Yersinia enterocolitica infection status in patients with AS. Twenty-eight AS patients (M:F 24:4, mean age 43.9 yrs, range 22-70 yrs, mean disease duration 15.9 yrs) and 35 healthy controls (M:F 31:4, mean age 52.1 yrs, range 22-80 yrs) were included. The levels of antibodies to ubiquitin and Yersinia O:3 and O:9 antigens were measured using specific ELISA. The results were expressed as optical density (OD) ratio. Antibody levels were assumed increased when the OD ratio was higher than mean OD ratio + 3SD in the control group. IgM antibodies to ubiquitin were found in five patients and one control ( P < 0.05, Fisher's exact test). Anti-ubiquitin antibodies of IgG class were found in two cases, one AS patient and one control (NS). IgG antibodies to Yersinia serotypes O:3 and O:9 were present in eight and five AS patients, respectively ( P < 0.001 and P < 0.05 vs. controls, Fisher's exact test). No IgM antibodies to Yersinia were found. High levels of IgG antibodies to Y. enterocolitica serotype O:3 were found in three out of five patients with high levels of IgM antibodies to ubiquitin, compared with five out of 23 patients with low levels of anti-ubiquitin antibodies ( P=0.1231, NS). Antibodies to Yersinia serotype O:9 were found in three out of five patients with IgM antibodies to ubiquitin, compared to two out of 23 patients with low serum levels of IgM antibodies to ubiquitin ( P < 0.05). The results suggest that Y. enterocolitica infection may induce antibodies to ubiquitin in a subset of patients with AS. This may be explained by the involvement of a newly discovered ubiquitin-dependent mechanism related to Y. enterocolitica virulence.

[Bone tissue metabolism in systematic lupus erythematosus patients treated with glucocorticosteroids]. / Metabolizm tkanki kostnej u chorych na toczen rumieniowaty ukladowy leczonych glikokortykosteroidami.

The present study has been undertaken to evaluate bone turn-over in patients with systemic lupus erythematosus (SLE) treated with glucocorticosteroids. Thirty-eight patients with definite SLE has been investigated. The following parameters have been determinated. Some proinflammatory cytokine: interleukin-IL-1 alpha (IL-1 alpha), interleukin-IL-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony stimulating factor (GM-CSF) and some biochemical markers of osteoporosis: osteocalcin (BGP), alkaline phosphatase-bone formation (AP-B), procollagen type I carboxyterminal propeptide (PICP), carboxyterminal telopeptides of type I collagen (CTx) deoxypyridinoline (Dpd) and calcium/creatinin ratio have been determined. The forearm densitometry measurement was performed in all patients. We did not notice statistically significant decrease in bone mineral content and bone mineral density in spite of long term glucocorticosteroids treatment. Based on statistically significant correlation between carboxyterminal telopeptides of type I collagen (CTx) and calcium/creatinin ratio we observed increased bone resorption in analysed group of patients.

The presence of HLA-DR B1 shared motif does not influence cyclophosphamide and methotrexate cytotoxicity in rheumatoid arthritis patients.

In the present study we investigated the relation between cyclophosphamide and methotrexate toxicity and the presence of HLA- DR B1 alleles in rheumatoid arthritis patients. Seventy-eight such patients (67 women and 11 men) were observed for 12 months. Eighteen were treated with intravenous cyclophosphamide, 28 with oral methotrexate, and 32 with intramuscular gold salts. The prevalence of this shared motif was higher in the study population than in the healthy controls. However, detailed observations did not demonstrate a relation between particular genotype and drug intolerance. Based on the obtained findings we concluded that HLA-DR B1 typing cannot affect cyclophosphamide or methotrexate tolerance in rheumatoid arthritis patients. However, taking into account the relatively small number of patients expressing single genotype, further studies are recommended.

[Quantitative ultrasound densitometry (QUS) and dual X-ray densitometry (DXA) in patients with rheumatoid arthritis]. / Densytometria ultradzwiekowa (QUS) oraz densytometria klasyczna (DXA) u chorych na reumatoidalne zapalenie stawów.

UNLABELLED: The aim of this study was to assess of bone mineral content (BMC) and bone mineral density (BMD) of the forearm using DXA technique (DTX-200) and to evaluate broadband ultrasound attenuation (BUA) and speed of sound (SOS) of the heel using QUS technique (DTU-ONE). We examined 83 RA patients: 73 women and 10 men, at average age (55.0 +/- 12.2 yrs), ranging from 29 to 85 yrs. Average disease duration was 112.6 +/- 98.1 months. Disease activity was assessed according to Mallya and Mace index and radiological stage of the disease according to Steinbrocker index. We found significant correlation between BMC, BMD and BUA (r = 0.6572, r = 0.6081, respectively) and between BMC, BMD and SOS (r = 0.4704, r = 0.4723, respectively). IN CONCLUSION: quantitative ultrasound parameters (BUA and SOS) significant correlate with BMC and BMD values of the forearm assessed by DXA technique in rheumatoid arthritis patients.

[Glucocorticosteroid induced osteoporosis in patients with rheumatoid arthritis]. / Osteoporoza posteroidowa u chorych na reumatoidalne zapalenie stawów.

Glucocorticosteroids have been recognized as a well known risk factor for drug induced osteoporosis. Many studies have shown a decrease in bone mass, bone quality disorders and an increase in the risk of fractures in patients with long-term corticosteroid therapy. Rheumatic patients, particular with rheumatoid arthritis, who are usually chronic steroid users are at the highest risk. On the other hand uncontrolled active inflammatory process is also a main factor for rapid bone loss. Some studies suggest that patients with low dose corticosteroid therapy (prednisone 5 to 7.5 mg per day) are not at increased risk of osteoporosis. Our study of 36 rheumatoid arthritis women treated with daily prednisone doses between 5 to 7.5 mg in comparison with non-steroid control group confirmed the above suggestion.

TNF-alpha gene polymorphism does not affect the clinical and radiological outcome of rheumatoid arthritis.

The present study was undertaken in order to investigate the relationship between tumor necrosis factor-alpha (TNF-alpha) gene polymorphism and the radiological progression of rheumatoid arthritis (RA) within the first 3-years of the disease. Sixty-eight RA patients (59 women and nine men) were observed for 3-years. TNF-alpha polymorphism analysis was performed in all patients. Radiographs of the hands were taken at the onset of study and after 3-years of follow-up. Radiographs were assessed according to the Larsen index (damage score and progression of damage score). We did not observe any correlation between TNF gene polymorphism and damage score or progression of damage score. The obtained data suggests that TNF-308 polymorphism cannot serve as an indicator of the disease course in RA patients.