Immunogenicity of subcutaneous TNF inhibitors and its clinical significance in real-life setting in patients with spondyloarthritis.

KEY MESSAGES: Considerable proportion of patients with SpA have been immunized to the subcutaneous anti-TNF drug they are using. Concomitant use of MTX protects from immunization, whereas SASP does not. Patients with SpA using subcutaneous anti-TNF drugs can benefit from monitoring of the drug trough levels. Immunization to biological drugs can lead to decreased efficacy and increased risk of adverse effects. The objective of this cross-sectional study was to assess the extent and significance of immunization to subcutaneous tumor necrosis factor (TNF) inhibitors in axial spondyloarthritis (axSpA) patients in real-life setting. A serum sample was taken 1-2 days before the next drug injection. Drug trough concentrations, anti-drug antibodies (ADAb) and TNF-blocking capacity were measured in 273 patients with axSpA using subcutaneous anti-TNF drugs. The clinical activity of SpA was assessed using the Bath AS Disease Activity Index (BASDAI) and the Maastricht AS Entheses Score (MASES). ADAb were found in 11% of the 273 patients: in 21/99 (21%) of patients who used adalimumab, in 0/83 (0%) of those who used etanercept, in 2/79 (3%) of those who used golimumab and in 6/12 (50%) of those who used certolizumab pegol. Use of methotrexate reduced the risk of formation of ADAb, whereas sulfasalazine did not. Presence of ADAb resulted in decreased drug concentration and reduced TNF-blocking capacity. However, low levels of ADAb had no effect on TNF-blocking capacity and did not correlate with disease activity. The drug trough levels were below the consensus target level in 36% of the patients. High BMI correlated with low drug trough concentration. Patients with low drug trough levels had higher disease activity. The presence of anti-drug antibodies was associated with reduced drug trough levels, and the patients with low drug trough levels had higher disease activity. The drug trough levels were below target level in significant proportion of patients and, thus, measuring the drug concentration and ADAb could help to optimize the treatment in SpA patients.

Antibodies to malondialdehyde-acetaldehyde modified low-density lipoprotein in patients with newly diagnosed inflammatory joint disease.

Objective:To assess antibodies to malondialdehyde-acetaldehyde-modified low-density lipoprotein (MAA-LDL) in patients with newly diagnosed inflammatory joint disease.Method: Patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and undifferentiated arthritis (UA), participating in the Northern Savo 2010 Study, were evaluated for metabolic syndrome (MetS), metabolic and inflammatory markers, antibodies to MAA-LDL, Aggregatibacter actinomycetemcomitans, and Porphyromonas gingivalis.Results: Among 135 newly diagnosed untreated patients, of whom 53 (39%) were diagnosed to have RA, 44 (33%) SpA, and 38 (28%) UA, 49%, 30%, and 47%, respectively, had MetS. After adjusting for age and gender, anti-MAA-LDL immunoglobulin (Ig)A (p = 0.009), IgG (p = 0.031), and IgM (p = 0.001) levels differed between the diagnostic categories, but not in patients with MetS present or absent. All antibody classes to MAA-LDL correlated with erythrocyte sedimentation rate (ESR), and IgA and IgG antibodies with high-sensitivity C-reactive protein (hs-CRP). IgA antibodies to MAA-LDL correlated with rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs), fasting plasma glucose, IgA antibodies to A. actinomycetemcomitans, and in IgA and IgG antibodies to P. gingivalis.Conclusion: Among various arthritis groups, antibodies to MAA-LDL were most common in RA. Antibodies to modified lipoproteins were associated with inflammation measured by ESR and hs-CRP. IgA antibodies to MAA-LDL correlated with age, antibodies to periodontal bacteria, RF, ACPA, and fasting glucose. Associations between antibodies to MAA-LDL and antibodies to periodontal bacteria, RA-associated antibodies, inflammatory parameters, and plasma glucose already reflect cardiovascular burden in inflammatory joint diseases at diagnosis.

Incidence of inflammatory joint diseases in Finland: results from a population-based epidemiological study.

The objective of the study was to assess the incidence of inflammatory joint diseases and possible environmental factors contributing to their occurrence in a defined population in Finland. All rheumatologists practising in the Northern Savo rheumatological outpatient departments collected data on their newly diagnosed patients with an inflammatory joint disease in 2010. Antibodies to Aggregatibacter actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg) were determined from patients with various arthritides. The incidence of all arthritis cases was 141.8/100,000 (95% CI 126.1-159.1). Eighty-six patients, 43 men and 43 women, satisfied the ACR/Eular 2010 classification criteria for rheumatoid arthritis (RA) yielding an annual incidence of 41.6/100,000 (33.3-51.4), 42.5 (30.8-57.3) for men and 40.8 (29.9-56.1) for women. The incidence of chronic spondyloarthritides was 36.3 (28.6-45.5), reactive arthritis 7.8 (4.4-12.6), undifferentiated arthritis 38.7 (30.7-48.2), and crystalline arthritis 15.0 (10.2-21.3). Immunoglobulin A (IgA) antibody levels to Pg were higher among men, patients with anti-cyclic citrullinated peptide antibodies (ACPA) or missing teeth and AaIgA antibody levels in patients with missing teeth. In RA, 67 % of men and 35% of women had a smoking history, p = 0.012. There was no difference between the genders in the incidence of RA, which might be explained by a higher carriage of periodontal bacteria and a higher smoking rate among men. In other disease categories, the incidences were comparable to those earlier reported. By influencing behavioral and environmental factors, it might be possible to reduce the burden of ACPA-positive RA.

Estimating the incidence of connective tissue diseases and vasculitides in a defined population in Northern Savo area in 2010.

Objective of the study was to evaluate the annual incidence and distribution of autoimmune connective tissue diseases and vasculitides during 2010. All units practicing rheumatology in the Northern Savo area, Finland, participated in the study by collecting data on newly diagnosed adult patients with autoimmune connective tissue disease or vasculitis over 1-year period. Seventy-two cases with autoimmune connective tissue disease were identified. The annual incidence rates were as follows: systemic lupus erythematosus 3.4/100,000 (95 % CI 1.4-7.0), idiopathic inflammatory myopathies 1.9 (0.5-5.0), systemic sclerosis 4.4 (2.0-8.3), mixed connective tissue disease 1.0 (0.1-3.5), Sjögren's syndrome 10.7 (6.7-16.1) and undifferentiated connective tissue disease 13.6 (9.0-19.6). The annual incidence rates among vasculitis category were as follows: antineutrophil cytoplasmic antibody-associated vasculitis 1.5/100,000 (95 % CI 0.3-4.3), central nervous system vasculitis 0.5 (0-2.7) and Henoch-Schönlein purpura 1.5 (0.3-4.3). The annual incidence of giant cell arteritis in the age group of 50 years or older was 7.5/100,000 (95 % CI 3.2-14.8). The longest delay from symptom onset to diagnosis occurred in systemic sclerosis. The incidences of autoimmune connective tissue diseases and vasculitides were comparable with those in published literature. The present study showed female predominance in all connective tissue diseases, excluding idiopathic inflammatory muscle diseases and mean age at onset of disease around 50 years of age. Despite improved diagnostic tools, diagnostic delay is long especially among patients with systemic sclerosis.

Drugs used in incident systemic lupus erythematosus - results from the Finnish nationwide register 2000-2007.

The objectives of the study were to examine the initial, first-year anti-rheumatic outpatient therapy in patients with incident SLE, as well as the concomitant use of drugs for certain comorbidities, compared to the use in the general population. The Finnish nationwide register data on special reimbursements for medication costs was screened to identify the inception cohort of 566 adult SLE patients (87% females, mean age 46.5 ± 15.9 years) over the years 2000-2007. The patients were linked to the national Drug Purchase Register. Of those, 90% had purchased at least once some disease-modifying anti-rheumatic drugs (DMARDs) during the first year. Hydroxychloroquine was the most common (76%), followed by azathioprine (15%) and methotrexate (13%). With the exception of increase in mycophenolate mofetil, the proportions remained stable over the whole study period 2000-2007. Drugs for cardiovascular diseases, dyslipidemia, diabetes mellitus, hypothyroidism and obstructive pulmonary disease were more frequently purchased than in the sex- and age-adjusted population, with rate ratios ranging from 1.6 to 7.8. Over the years 2000-2007, almost all the patients with incident SLE in Finland started with a DMARD. Higher percentages of SLE patients were on medication for several common chronic diseases than in the population as a whole.

Mortality and causes of death among incident cases of systemic lupus erythematosus in Finland 2000-2008.

The objectives of the study were to investigate mortality and causes of death in patients with recent-onset systemic lupus erythematosus (SLE) in Finland. Data for patients with SLE for the study were collected (2000-2007) from the nationwide register on decisions of special reimbursements for drugs, maintained by the Social Insurance Institution (SII) in Finland. Data on deaths of the patients were obtained from the official death certificate statistics of Statistics Finland until the end of 2008. Of the 566 incident SLE patients, median follow-up time was 5.4 (IQR 3.3, 7.1) years, and 30 patients (23 females, seven males) died in the years 2000 through 2008. Mean age at death was 67.8 ± 17.2 years for females and 62.3 ± 15.2 years for males. The 5-year survival rates were 94.8% (95%CI 92.0-96.6%) and 88.2% (95%CI 76.5-94.3%), respectively. The age- and sex-adjusted standardized mortality ratio was 1.48 (95%CI 1.01-2.12). Primary causes of death were cardiovascular diseases, malignancy and SLE itself. In conclusion, survival of the patients with SLE was inferior to that of the general population. Cardiovascular diseases were responsible for 37% of deaths.

Telomere shortening and mitotic dysfunction generate cytogenetic heterogeneity in a subgroup of renal cell carcinomas.

Most renal cell carcinomas (RCC) show only simple chromosomal changes. However, a more complex cytogenetic pattern has been found in a subgroup of aggressive RCC, indicating that further accumulation of chromosome changes could play a role in tumour progression. To explore the possible mechanisms behind cytogenetic evolution in RCC, a parallel assessment of chromosome mutations and mitotic segregation pattern in eight tumours was performed. In the majority of cases, no abnormalities in the cell division machinery were found and the rate of alterations in chromosome copy number, as measured by interphase FISH, was similar to that in non-neoplastic cells. This was reflected by relatively simple karyotypes, with little cytogenetic intratumour heterogeneity. In contrast, another group of tumours exhibited several cytogenetically related clones with additional structural chromosomal changes at two or more ploidy levels and a frequency of copy number alterations that was higher than in normal cells. In these cases, the telomere repeat sequences were abnormally short and chromosomal breakage-fusion-bridge events were observed at cell division, as well as multipolar configurations and supernumerary centrosomes. Abnormalities of the cell division machinery may thus contribute to the evolution of complex karyotypes and genetic intratumour heterogeneity in a subgroup of RCC.

Karyotypic characterization of urinary bladder transitional cell carcinomas.

Samples from 34 primary transitional cell carcinomas (TCCs) of the bladder were short-term-cultured and processed for cytogenetic analysis after G-banding of the chromosomes. Clonal chromosome abnormalities were detected in 27 tumors and normal karyotypes in 3, and the cultures from 4 tumors failed to grow. Losses of genetic material were more common than gains, indicating that loss of tumor suppressor genes may be of major importance in TCC pathogenesis. There was no clonal heterogeneity within individual tumors, consonant with the view that TCCs are monoclonal in origin. The most striking finding was the involvement of chromosome 9 in 92% of the informative cases, as numerical loss of one chromosome copy in 15 cases, but as structural rearrangement in 8. The changes in chromosome 9 always led to loss of material; from 9p, from 9q, or of the entire chromosome. A total of 16 recurrent, unbalanced structural rearrangements were seen, of which del(1)(p11), add(3)(q21), add(5)(q11), del(6)(q13), add(7)(q11), add(11)(p11), i(13)(q10), del(14)(q24), and i(17)(q10) are described here for the first time. The karyotypic imbalances were dominated by losses of the entire or parts of chromosome arms 1p, 9p, 9q, 11p, 13p, and 17p, loss of an entire copy of chromosomes 9, 14, 16, 18, and the Y chromosome, and gains of chromosome arms 1q and 13q and of chromosomes 7 and 20. The chromosome bands and centomeric breakpoints preferentially involved in structural rearrangements were 1q12, 2q11, 5q11, 8q24, 9p13, 9q13, 9q22, 11p11, and 13p10. Rearrangements of 17p and the formation of an i(5)(p10) were associated with more aggressive tumor phenotypes. There was also a general correlation between the tumors' grade/stage and karyotypic complexity, indicating that progressive accumulation of acquired genetic alterations is the driving force behind multistep bladder TCC carcinogenesis.

The effect of isoniazid on BCG-induced toxicity in patients with superficial bladder cancer.

The use of bacillus Calmette-Guérin in the treatment of transitional cell cancer of the bladder has caused concern because of its associated adverse effects. We conducted a randomized prospective, double-blind, multicentre study to determine whether isoniazid prophylaxis could reduce BCG-induced toxicity without compromising its immunotherapeutic effects. Patients (n = 160) with histologically documented urothelial cancer (pTa-T1, pTis, G1-3) were treated with 6 weekly instillations of BCG Connaught strain, 81 mg, administered concomitantly with a 3-day course of isoniazid (300 mg o.d.) or placebo. Side-effects were recorded with each treatment and at follow-up. Of the patients treated with isoniazid, 19% remained free from side-effects, compared with 16% of the placebo group. Local side-effects confined to the bladder were significantly lower among those receiving isoniazid (35% vs. 48%, p < 0.01). Local side-effects together with systemic adverse effects such as fever, nausea or skin rash were experienced by 30% of patients in each arm. There were no differences in tumour recurrence between the two patient groups. Concomitant isoniazid reduces the local, but not the systemic side-effects of topically applied BCG without compromising the antitumour effect on superficial, transitional cell cancer of the bladder during a follow-up period that now exceeds 2 years.

Cytogenetic analysis of upper urinary tract transitional cell carcinomas.

Ten primary (nine regular and one post-radiation) upper urinary tract transitional cell carcinomas (TCC), i.e., tumors of the renal pelvis and ureter, were obtained from 10 patients following nephroureterectomy and processed for cytogenetic analysis after short-term culturing. Clonal chromosomal aberrations were found in eight tumors. While 10 karyotypically related and/or unrelated clones were detected in the post-radiation tumor, cytogenetic monoclonality was seen in all other tumors. With the exception of two tumors with loss of the Y chromosome as the only change, chromosome 9 was invariably involved, either with loss of the entire chromosome or with partial loss from the short arm. Our findings indicate that the karyotypic profile of upper urinary tract TCC is identical to that of bladder TCC, an indication that the same pathogenetic mechanisms are at work in both regions.

Cytogenetic monoclonality in multifocal uroepithelial carcinomas: evidence of intraluminal tumour seeding.

Twenty-one multifocal urinary tract transitional cell carcinomas, mostly bladder tumours, from a total of six patients were processed for cytogenetic analysis after short-term culturing of the tumour cells. Karyotypically related, often identical, cytogenetically complex clones were found in all informative tumours from each case, including the recurrent tumours. Rearrangement of chromosome 9, leading to loss of material from the short and/or the long arm, was seen in all cases, indicating that this is an early, pathogenetically important event in transitional cell carcinogenesis. The presence of related clones with great karyotypic similarity in anatomically distinct tumours from the same bladder indicates that multifocal uroepithelial tumours have a monoclonal origin and arise via intraluminal seeding of viable cancer cells shed from the original tumour. Later lesions may develop also from cells shed from the so called second primary tumours. The relatively complex karyotypes seen in all lesions from most cases argue that the seeding of tumour cells is a late event that succeeds the acquisition by them of multiple secondary genetic abnormalities.

Cytogenetic heterogeneity in a second primary radiation-induced bladder carcinoma: ten karyotypically unrelated clones.

Cytogenetic analysis of a transitional cell carcinoma (TCC) of the bladder, the tumor having developed 32 years after the patient received pelvic irradiation and interstitial radium implantation for an endometrial carcinoma, revealed the presence of 10 cytogenetically abnormal, unrelated clones. Although the tumor was poorly differentiated, all clones were pseudo- or near-diploid with rather simple balanced or unbalanced structural rearrangements or both. The chromosomes involved in structural changes more than once were chromosomes 8, 9, and 11, which were rearranged in three clones, and chromosomes 3 and 17, both rearranged in two clones. No previous TCC of the bladder with cytogenetically unrelated clones has been reported, nor has any such radiation-induced tumor with chromosomal abnormalities been described. The distinct karyotypic and clonal pattern of the case presented here is probably indicative of a carcinogenic field effect due to the previous pelvic irradiation. Postradiation bladder carcinomas thus seem to be distinct cytogenetically in addition to their known unique etiological and clinical features.

Chromosome abnormalities in squamous cell carcinoma of the urethra.

Cytogenetic analysis of short-term cultured cells from a urethral squamous cell carcinoma showed the tumor to have an abnormal, karyotypically complex near-diploid clone as well as its near-tetraploid duplicate. This is the first urethral carcinoma with chromosomal abnormalities to be reported. Chromosomes Y, 2, 3, 4, 6, 7, 8, 11, and 20 were all involved in numerical and/or structural rearrangements. Of particular interest was the fact that no rearrangements of chromosomes 9 and 17, both almost ubiquitously involved in transitional cell carcinoma of the urinary tract, were seen.

Prognostic implications of cytogenetic findings in kidney cancer.

OBJECTIVE: To evaluate the prognostic impact of cytogenetic findings in renal cell carcinoma (RCC). PATIENTS AND METHODS: Tumour cytogenetics, histomorphology, DNA ploidy and S-phase fraction, stage, size, and grade were related to survival in 50 consecutive patients with RCC. The mean follow-up was 3.9 years (median 4.2, range 0-8.8). RESULTS: The predictive probability for recurrence-free survival at 5 years (5-year RFS) for all 50 patients was 0.54. There was a significant association between the degree of cytogenetic complexity and survival, in that patients with five or less aberrations had a better prognosis than those with more than five changes (5-year RFS 0.71 and 0.43, respectively; P < 0.05). Patients with del(8p)/-8, +12, and +20 had a significantly worse prognosis compared with those without these aberrations. Of the well-known prognostic variables grade and stage, the former was far better for predicting prognosis. A Spearman correlation test showed a significant covariation of grade with the S-phase fraction, T-stage, and cytogenetic complexity. CONCLUSION: The degree of cytogenetic complexity and recurrent cytogenetic abnormalities affect the prognosis in RCC, although grade was the most reliable independent prognostic factor predicting disease recurrence.

Trisomy 7 in non-neoplastic tubular epithelial cells of the kidney.

The cellular origin of trisomy 7 in non-neoplastic kidney tissue specimens from 10 patients, seven with malignant tumors and three with non-neoplastic kidney diseases, was studied by the MAC (morphology antibody chromosomes) technique, which allows analysis of cellular morphology/histology, immunophenotype, and chromosomal aneuploidy by conventional cytogenetics, and/or fluorescent in situ hybridization in both interphase and mitotic cells. In primary cultures, trisomy 7 was detected primarily in cytokeratin-positive cells. Among freshly isolated renal cells, the trisomy was mainly observed in proximal tubular cells positive to brush-border antigen, and, to a lesser extent, in distal tubular cells positive to Tamm-Horsfall glycoprotein. The frequency of trisomy 7 in lymphocytes expressing CD3 or CD22 antigens isolated from non-neoplastic and tumor tissues was substantially lower than in the epithelial cells and was not increased compared with that in control lymphocytes from peripheral blood. The results thus demonstrate that the non-neoplastic kidney cells with trisomy 7 are mainly normal epithelial cells, preferentially those of the proximal tubule.

Trisomy 7 in nonneoplastic epithelial kidney cells.

Trisomy 7 has been found as the sole clonal chromosome aberration in a number of tumor types, including renal cell carcinomas (RCC), and also in non-neoplastic kidney tissue. It has recently been proposed that the cells harboring trisomy 7 in RCC and in the surrounding tissue may be tumor infiltrating T-helper lymphocytes. We performed cytogenetic analysis of metaphase cells and FISH of interphase nuclei in uncultured and cultured non-neoplastic kidney tissues from 13 patients with renal or urothelial carcinomas, and 4 patients with inflammatory kidney diseases. FISH analysis showed that the frequency of +7 varied between 1.0-8.9% (mean 3.3%) in uncultured cells and between 0.4-8.6% (mean 4.4%) after one week of cell culture. The frequency of +7 after one week of culture was 1.0-19.0% (mean 6.1%) as determined by cytogenetic analysis. Immunoenzymatic staining of both uncultured and cultured cells with the alkaline phosphatase reaction and monoclonal antibodies for CD3 showed that the frequency of T-cells in uncultured cells and in primary cultures varied between 2.9-10%. The number of T-cells decreased with time and number of in vitro passages to less than 1% after 7-8 weeks, but the frequency of +7 remained fairly constant. Combination of FISH with immunostaining using CD3 for T-lymphocytes and cytokeratins for epithelial cells showed that the cells with +7 were mainly epithelial cells whereas only 0-5% were T-lymphocytes. The results have obvious implications for the interpretation of the significance of trisomy 7 in neoplasia.

Morbidity of pelvic lymphadenectomy, radical retropubic prostatectomy and external radiotherapy in patients with localised prostatic cancer.

Staging pelvic lymphadenectomy (PLND) was performed in 210 prostatic cancer patients (mean age 67 years, clinical stage T0-T3 M0). A radical retropubic prostatectomy was subsequently performed in 54 men, ten of whom also received postoperative radiotherapy due to positive surgical margins. Ninety-eight patients were treated with external beam radiation alone (70 Gy in 35 fractions) and the remaining 58 received endocrine therapy. The complications of PLND alone (156 patients), consisted of wound infection in eight patients, hematoma or lymphocele in seven, venous thrombosis in three, and cardiac infarction in one patient. Early side-effects of radiotherapy included mild to moderate proctitis and/or cystitis in 57 patients. One year after completion of therapy, 48 of the irradiated men had proctitis, but only six had severe symptoms. Four patients developed radiation cystitis and two urethral stricture. Following prostatectomy (54 patients), two patients died in pulmonary embolism and another one developed a deep venous thrombosis. Hematoma occurred in five patients. Of the 42 surviving patients who did not receive postoperative radiotherapy, eight developed anastomotic strictures and four had severe stress incontinence. Only five were fully potent one year after surgery. Eight of the ten patients receiving radiotherapy after prostatectomy developed side-effects from the intestine and/or the urinary bladder. Two of them became totally incontinent. One developed a severe hemorrhagic cystitis necessitating urinary diversion. All ten were impotent after treatment.

[A study on prostatic cancer. The patient can decide himself: medical or surgical treatment]. / Studie om prostatacancer. Patienten kan få bestämma själv: medicinsk eller kirurgisk behandling.

In a multicentre study, 101 consecutive patients with advanced prostate cancer were offered the choice of orchiectomy or treatment with an LHRH analogue. Together with the cancer diagnosis the patients were given verbal information about the treatment alternatives, and detailed written information to peruse at home. One week later the patients informed the attending physicians of their choice. Information as to the reasons for the patients' choice, and their views on their choice after the start of treatment were elicited by questionnaire. Of the 101 patients, 48 chose orchiectomy, and 48 treatment with an LHRH analogue, five patients being excluded owing to their inability to decide. Mean age was about 73 years in both treatment groups, and about two thirds of each group lived with a partner. The level of education was higher among those who chose medical treatment. The predominant reasons for the choice of treatment were as follows: Orchiectomy, simpler (31 per cent), troublesome having to have monthly injections (19 per cent), simple to perform (15 per cent); medical treatment, possibility of change in treatment (27 per cent), simpler (17 per cent), fear of surgery (15 per cent). Most patients in both groups had no difficulty deciding, chose quickly, felt sure about their choice, appreciated the opportunity of choosing, and had discussed their choice with their partners or intimates. Three months after the start of treatment, almost all patients were still satisfied with their choice, and had no wish to change their choice even if that were possible.(ABSTRACT TRUNCATED AT 250 WORDS)