Andrea Váncsa

Cancer-associated myositis: clinical features and prognostic signs.

Abstract: Idiopathic inflammatory myositis is characterized by progressive weakness of the proximal muscles. There is a higher risk of malignancy than in the normal population. The aim of this study was to evaluate the frequency of malignancy among 251 myositis patients. We also compared clinical and immunological characteristics of cancer‐associated myositis with primary myositis. There were no malignancies among polymyositis, overlap, or juvenile myositis patients. Twenty‐two of ninety dermatomyositis patients also had a malignant disease. Patients with cancer‐associated dermatomyositis were significantly older than primary myositis patients and had more severe cutaneous and muscle symptoms. Dysphagia and diaphragmatic involvement were more frequent among cancer‐associated patients, while extramuscular features were less frequent. After successful treatment of the malignancy, we were able to manage myositis symptoms. One‐year survival rate was significantly better in primary dermatomyositis patients. The subset of cancer‐associated myositis differs from primary myositis in many aspects of its clinical and immunological features. Prognosis and life expectancy in cancer‐associated myositis patients is determined by the underlying malignant disease. Therefore, age‐ and sex‐specific examinations for detection of an underlying malignancy are important in the management of patients with dermatomyositis.

Myositis-specific and myositis-associated antibodies in overlap myositis in comparison to primary dermatopolymyositis: Relevance for clinical classification: Retrospective study of 169 patients

OBJECTIVE The current study was performed in order to determine the prevalence of different myositis-specific and myositis-associated antibodies, as well as their association with clinical characteristics, disease course and response to therapy in 169 Hungarian patients with idiopathic inflammatory myopathy. METHODS Sera of 130 primary and 39 overlap myositis including systemic sclerosis (13), rheumatoid arthritis (12), systemic lupus erythematosus (5) and Sjögrens syndrome (9) cases were analyzed. Antinuclear antibody, scleroderma-associated antibodies (anti-centromere, anti-topoisomerase I), anti-Jo-1, anti-PL-7, anti-PL-12, anti-Mi-2, anti-SRP and anti-PM-Scl, anti-Ku, anti-SS-A, anti-SS-B, anti-U1snRNP were tested. Autoantibody results were compared with clinical characteristics, disease course of overlap versus primary myositis patients, as well as with response to therapy. RESULTS Associated connective tissue disease occurred in 23.1% of the patients. Myositis-associated antibodies were found in 8.5% of primary myositis patients, indicating that 11 additional primary myositis patients (23% vs. 29.6%) can be classified as overlap in all cohort according to the newly proposed diagnostic criteria. Polymyositis was found to be the most common myositis form in overlap myositis (87.2%), while scleroderma was the most common disease associated (33.3%). ANA was positive in 25.4% of primary and in 61.5% of overlap myositis cases. Altogether 39.6% of myositis patients (n=67) had autoantibodies, most commonly anti Jo-1 (18.3%) correlating with a polycyclic disease course. CONCLUSION Inclusion of myositis-specific and associated antibodies into the newly proposed diagnostic criteria for inflammatory myopathies is of great importance in order to determine subclasses and to introduce adequate therapy in time.

Pregnancy outcome in idiopathic inflammatory myopathy

The aim of our study was to assess the prevalence and outcome of pregnancy in idiopathic inflammatory myopathy patients who became pregnant after the onset of the disease. Female idiopathic inflammatory myopathy patients (173) were included in our study. The patients’ charts and clinical data were retrospectively analyzed. One hundred and four female idiopathic inflammatory myopathy patients had 186 pregnancies, but only nine of these patients (4 polymyositis-PM, 5 dermatomyositis-DM) became pregnant after the onset of the disease. Nine patients with pregnancies after the disease onset had 14 gravidities. Six pregnancies resulted in normal deliveries, two ended in prematurity, six ended in abortions (two induced abortions). Regarding the four patients (3 PM, 1 DM) with active disease at the time of pregnancy, two pregnancies ended in prematurity, four ended in spontaneous abortion and one healthy baby delivered. The other five patients (2 PM, 3 DM) with the disease in remission had uneventful pregnancies and healthy babies were delivered. Treatment was not required during pregnancy in case of two dermatomyositis patients with long lasting remission. New onset dermatomyositis developed in one patient in her pregnancy’s third trimester. The mean weight of newborns in the active myositis cases was 2,193 (1,680–2,700) g; while in patients with remission was 3,167 (2,800–3,800) g. The active maternal disease in idiopathic inflammatory myopathy (IIM) might result intrauterin retardation and death. Disease activity in active and new-onset cases could be controlled by increasing the dose of corticosteroid.

Biologics — beyond the joints

Biologics including tumor necrosis factor α (TNF-α), interleukin-6 receptor (IL-6R), T and B cell inhibitors are very effective therapeutic agents for the treatment of arthritides. These compounds effectively improve articular symptoms and inhibit joint damage. In this respect, there are no major differences in the efficacy of the available biologics. However, many arthritis patients also exert extra-articular features, systemic manifestations of the disease. These associated conditions include uveitis, inflammatory bowel disease, psoriasis, secondary bone loss and cardiovascular disease. There have been data suggesting that there may be differences in the effects of various TNF inhibitors, rituximab and tocilizumab on the systemic manifestations described above. At present, we do not always have sufficient evidence to confirm these differences, therefore, more information should be obtained from large trials and long-term observational studies.

Pharmacogenetics and pharmacogenomics in rheumatology

Pharmacogenetics and pharmacogenomics deal with possible associations of a single genetic polymorphism or those of multiple gene profiles with responses to drugs. In rheumatology, genes and gene signatures may be associated with altered efficacy and/or safety of anti-inflammatory drugs, disease-modifying antirheumatic drugs (DMARDs) and biologics. In brief, genes of cytochrome P450, other enzymes involved in drug metabolism, transporters and some cytokines have been associated with responses to and toxicity of non-steroidal anti-inflammatory drugs, corticosteroids and DMARDs. The efficacy of biologics may be related to alterations in cytokine, chemokine and FcγR genes. Numerous studies reported multiple genetic signatures in association with responses to biologics; however, data are inconclusive. More, focused studies carried out in larger patient cohorts, using pre-selected genes, may be needed in order to determine the future of pharmacogenetics and pharmacogenomics as tools for personalized medicine in rheumatology.

Peripheral blood derived gene panels predict response to infliximab in rheumatoid arthritis and Crohn's disease.

BackgroundBiological therapies have been introduced for the treatment of chronic inflammatory diseases including rheumatoid arthritis (RA) and Crohns disease (CD). The efficacy of biologics differs from patient to patient. Moreover these therapies are rather expensive, therefore treatment of primary non-responders should be avoided.MethodWe addressed this issue by combining gene expression profiling and biostatistical approaches. We performed peripheral blood global gene expression profiling in order to filter the genome for target genes in cohorts of 20 CD and 19 RA patients. Then RT-quantitative PCR validation was performed, followed by multivariate analyses of genes in independent cohorts of 20 CD and 15 RA patients, in order to identify sets ofinterrelated genes that can separate responders from non-responders to the humanized chimeric anti-TNFalpha antibody infliximab at baseline.ResultsGene panels separating responders from non-responders were identified using leave-one-out cross-validation test, and a pool of genes that should be tested on larger cohorts was created in both conditions.ConclusionsOur data show that peripheral blood gene expression profiles are suitable for determining gene panels with high discriminatory power to differentiate responders from non-responders in infliximab therapy at baseline in CD and RA, which could be cross-validated successfully. Biostatistical analysis of peripheral blood gene expression data leads to the identification of gene panels that can help predict responsiveness of therapy and support the clinical decision-making process.

Longterm effects of rituximab on B cell counts and autoantibody production in rheumatoid arthritis: Use of high-sensitivity flow cytometry for more sensitive assessment of B cell depletion

Objective. To assess the efficacy and safety of longterm rituximab (RTX) therapy for rheumatoid arthritis (RA) and study correlations among B cell depletion, clinical response, and autoantibody production. Methods. Seventy-seven patients with moderate or high RA activity received RTX and were re-treated every 6 months regardless of clinical response. All patients received at least 5 cycles. We assessed 28-joint Disease Activity Score (DAS28), IgM rheumatoid factor (RF), and anticitrullinated protein antibody (ACPA) levels at baseline, after 15 days, and then every 6 months for 24 months. Absolute CD19+ B lymphocyte counts were determined in 50 patients using high-sensitivity flow cytometry (hsFACS) by reading 100,000 events. Results. After 6, 12, 18, and 24 months, 51.6%, 51.9%, 73.3%, and 83.8% of patients, respectively, showed good European League Against Rheumatism responses. Significant and sustained decreases in IgM RF and ACPA levels were observed as early as 6 months and 12 months, respectively. The baseline mean absolute B cell number was 0.234 g/l. B cell numbers diminished significantly after the very first infusion by Day 15 (0.104 g/l; p = 0.007); they further decreased until 24 months (0.0013 g/l; p < 0.001). One RTX infusion resulted in incomplete depletion in 76.7% of patients. Upon RTX treatment, changes in CD19+ B cell numbers positively correlated with changes in DAS28 (r = 0.963, p = 0.008) and IgM RF (r = 0.859, p = 0.028), but not with changes in ACPA production (r = 0.726, p = 0.102). The correlations between B cell numbers and DAS28 were observed in both ACPA-seropositive (r = 0.999, p < 0.0001) and ACPA-negative patient subpopulations (r = 0.962, p = 0.009). The correlation between CD19+ cell numbers and IgM RF was observed only in the ACPA-positive population (r = 0.944, p = 0.005) but not in seronegative patients (r = 0.398, p = 0.435). No safety issues arose. Conclusion. In RA, clinical response to RTX is associated with the extent of B cell depletion and with autoantibody production. Changes in CD19+ B cell numbers correlate with those in disease activity and, in seropositive patients, also with IgM RF, but not with ACPA production. We found that hsFACS may be a useful method to more accurately assess incomplete B cell depletion.

Combination of IgG N-glycomics and corresponding transcriptomics data to identify anti-TNF-α treatment responders in inflammatory diseases

Prediction of responsiveness in biological therapies is an important and challenging issue in different diseases. Analyzing glycosylation pattern changes of key serum glycoproteins is one of the possible avenues to follow disease remission. The aim of this study was to investigate the changes of serum IgG glycoforms in Crohns disease (CD) and rheumatoid arthritis patients in response to antitumor necrosis factor alpha (anti‐TNF‐α) treatment. IgG was isolated from patient serum samples using Protein A affinity pull‐down, followed by the release of N‐glycans with peptide‐N‐glycosidase F. The released glycans were fluorescently tagged with 8‐aminopyrene‐1,3,6‐trisulfonate and analyzed by CGE with laser‐induced fluorescent detection. Significant alterations were detected between responders and nonresponders in both disease groups. In CD patients, disease‐specific alteration was found in response to anti‐TNF‐α therapy, which was also confirmed by transcriptomics data analysis of the corresponding glycosyltransferases and glycosidases.

Inclusion body myositis pathomechanism and therapy

Inclusion body myositis is an acquired inflammatory muscle disease belonging to the family of idiopathic inflammatory myopathy with vacuole formation. Approximately 15-28% of idiopathic inflammatory myopathy patients suffer from inclusion body myositis. Early diagnosis is very important due to the slowly progressive disease course and consecutive muscle atrophy. Inclusion body myositis is the most common chronic progressive muscle disease over the age of 50 years. Both degenerative processes including beta-amyloid accumulation and inflammatory processes, such as CD8 positive T-lymphocytes mediated cellular cytotoxicity take part in the pathomechanism of the inclusion body myositis. These findings are well demonstrated by the parallel presence of vacuolized muscle fibers rarely invaded by T cells and intact muscle fibers invaded by inflammatory T-cells in biopsy specimens. MHC-I/CD8 complex was introduced into the newly revised diagnostic criteria as a specific immune marker which helps to differentiate inclusion body myositis from aspecific inflammation present in other muscle dystrophies. Clinically both proximal and distal muscle weakness, respiratory muscle weakness and dysphagia are present. Interstitial lung disease is infrequent. Inclusion body myositis responds poorly to antiinflammatory treatment due to the predominant degenerative processes and it often results in only biochemical response instead of clinical. Diagnosis and differential diagnosis of inclusion body myositis are a very special challenge for the physician due to the diagnostic procedures which need immunohistochemical background. New therapeutic targets, monoclonal antibodies against the costimulatory molecules, anticytokine therapy may provide further improvement in the quality of life of inclusion body myositis patients.

A4.3 Effects of anti-TNF therapy on markers of bone homeostasis in rheumatoid arthritis and ankylosing spondylitis

Background and objectives Uncoupling of bone resorption and formation has been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Generalised bone loss and erosions are characteristic for RA, while in AS, bone formation overrides resorption. The RANKL/OPG and the Wnt/DKK-1/sclerostin systems have been implicated in disturben bone homeostasis in arthritides. Anti-TNF biologics may beneficially influence erosions and bone loss in RA, however, they have little effect on bone formation in AS. In the present study, we assessed the effects of 1-year anti-TNF treatment on various bone biomarkers. Patients and methods Altogether 43 arthritis patients including 30 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 13 AS patients treated with ETN were included in a 12-month follow-up study. Disease activity (DAS28 or BASDAI), CRP, IgM rheumatoid factor, anti-CCP, calcium (Ca), phosphate (P), osteocalcin (OC), P1NP, CTX, BNP, sclerostin (SOST), DKK-1, soluble RANKL (sRANKL), cathepsin K (cathK) and vitamin D3 (vitD) levels were assessed at baseline, as well as 6 and 12 months after treatment initiation. Results Anti-TNF treatment was highly effective in both diseases, as the mean DAS28 decreased from 6.32 to 3.16 (p = 0.02) in RA, mean BASDAI decreased from 5.87 to 1.84 (p < 0.001) in AS. In RA, anti-TNF treatment significantly decreased DKK-1 (60.5 ± 28.9 pM and 54.7 ± 20.8 pM, p = 0.036) and CathK (28.7 ± 6.2 pm and 26.8 ± 4.0 pm, p = 0.014) but increased SOST (107.0 ± 47.5 pM and 131.2 ± 85.2 pM, p = 0.04) levels from baseline to 12 months, respectively. In RA, ETN and CZP treatment also increased OPG/sRANKL ratio after 6 months (51.9) vs. baseline (43.9) (p = 0.01). In AS, ETN therapy significantly increased the bone formation marker P1NP (49.4 ± 19.0 pM and 56.9 ± 28.7 pM, p = 0.03) and SOST (70.6 ± 29.0 pM and 82.4 ± 48.3 pM, p = 0.022) levels from baseline to 12 months, respectively. ETN therapy also increased OPG/sRANKL ratio after 6 months (44.5) and 12 months (46.9) compared to baseline (34.5) in AS (p < 0.01). Both baseline and 12-month SOST levels were significantly lower in AS compared to RA (p < 0.001). When RA and AS data were pooled, TNF inhibition resulted in significantly decreased DKK-1 (p = 0.035) and cathK (p = 0.008) but increased P1NP (p = 0.04) and SOST (p = 0.04) after 12 months. In this study, biologics did not affect Ca, P, OC, CTX, BNP, vitD levels. Conclusions In a mixed cohort of RA and AS patients, anti-TNF therapy resulted in a restoration of bone homeostasis by decreasing DKK-1 and CathK, increasing P1NP, SOST and OPG/sRANKL ratio. Lower SOST levels in AS compared to RA, as well as the induction of bone formation over resorption may account for the inefficacy of TNF inhibitors on syndesmophyte formation in AS.