Éva Szekanecz

Occurrence of malignancies in Hungarian patients with systemic lupus erythematosus: results from a single center.

abstract:  As a result of increasing life expectancy of lupus patients, malignant disorders have become major determinants of morbidity and mortality. The objectives of this study were to analyze cancer‐associated morbidity and mortality, the type of malignancies in Hungarian lupus patients, and to analyze association with immune‐suppressive therapy, disease duration, and age of the patients. Data from 860 systemic lupus erythematosus (SLE) patients were retrospectively analyzed in a study period between 1970 and 2004. Results were compared to data from age‐ and sex‐matched population obtained from the Health for All database, and also to literature data. A total of 37 patients presented with cancer, reflecting 4.3% cancer‐associated morbidity. Patients were 47 (20–73) years old at the onset of malignancy, which appeared 13 (1–45) years later than SLE. Cancer prevalence was the highest in the first 5–10 years of lupus. Breast cancer was the most common malignancy (n= 11) followed by gastrointestinal tumors (n= 9), cervix cancer and hematologic malignancies (n= 5 for both), bronchial cancer (n= 4), bladder, skin, and ovarian cancer (n= 1 for each). Standardized incidence ratio was the highest for non‐Hodgkin lymphoma (standardized incidence ratio [SIR] 3.5, 95%CI 0.4–12.5) and cervix cancer (SIR 1.7, 95%CI 0.6–4.1). Although 76% of patients with cancer received immune‐suppressive therapy besides corticosteroids, no direct correlation could be confirmed between therapy and malignancy. Out of the 164 patients that expired during the study period, 18 were cancer‐related. As such the cancer‐associated mortality was 11% (18/164). This peaked during the last 4 years of the study period (8/24, 33%). Lupus patients are at high risk for particular types of malignant disorders, highlighting the importance of screening measures and focused patient examination.

Malignancies in autoimmune rheumatic diseases - a mini-review.

Paraneoplastic symptoms, caused by a malignancy, but not directly related to invasion by the tumor or its metastases, are the result of a wide variety of tumor-derived biologic mediators like hormones, peptides, antibodies, cytotoxic lymphocytes, autocrine and paracrine mediators. Systemic inflammatory rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma or dermatomyositis, may increase the risk for the development of malignancies, predominantly lymphoproliferative disorders. Immunosuppressive drugs and biological agents may also be carcinogenic. However, sustained inflammatory activity seems to be the primary risk factor for malignancies in autoimmune diseases. Tumor-associated antigens may be produced by inflammatory cells and their production may be increased in rheumatoid arthritis and other autoimmune diseases.

Malignancies associated with systemic sclerosis.

The outcome of systemic sclerosis (SSc) has become more favorable during the past years. Respiratory failure or renal crisis became less frequent, therefore more attention should be paid to long-term comorbidities, such as malignancies secondary to scleroderma. The incidence of malignant lymphoproliferative diseases, as well as that of solid tumors are higher in a number of rheumatic diseases including SSc. Some cytotoxic agents, primarily cyclophosphamide used in the treatment of SSc, as well as exposure to chemicals or smoking may further increase cancer risk. We also present malignancies in 218 scleroderma patients undergoing follow-up in our department were assessed for secondary malignancies. Although the number of SSc patients with tumor is relatively small, we compared our cohort to the Health for All Hungarian database and calculated standard incidence ratios (SIR). We identified 11 cases of malignancy in 10 SSc patients (4.6%). One patient had two types of tumor: breast cancer before the onset of SSc and later malignant lymphoma. Half of SSc patients with cancer belonged to the diffuse cutaneous (dcSSc) subtype. The mean age at onset of SSc was 54.6 years, while that at the diagnosis of malignancy was 61.5 years. The mean disease duration of scleroderma at the time of cancer diagnosis was 6.6 years. Five patients died, 4 due to the underlying malignancy. Among the five surviving patients, the mean survival time was 4.9 years. Altogether 3 patients had non-Hodgkins lymphoma, 2 had bronchial cancer, 2 had breast cancer, one had leiomyosarcoma of the leg, one had esophageal cancer, one had cervix cancer and one had skin cancer. In comparison to the Health for All database, the overall SIR of all malignancies in SSc was 1.07 (CI: 0.82-1.38) varying between 5.8 and 52.4 in different tumor types. Only one cancer patient received cyclophosphamide therapy. In conclusion, secondary tumors including lung, skin and breast cancer, as well as lymphomas are more common in SSc than in the general population. The adequate treatment and follow-up of scleroderma patients may help us to lower the risk of malignancies secondary to SSc.

Increased production of the soluble tumor-associated antigens CA19-9, CA125, and CA15-3 in rheumatoid arthritis: Potential adhesion molecules in synovial inflammation?

Abstract:  Some tumor‐associated antigens (TAAs) are expressed on inflammatory cells. We previously detected carcinoembryonic antigen (CEA; CD66) in the rheumatoid (RA) synovium. The production of CEA, CA19‐9, CA125, and CA15.3, may be increased in patients with RA, scleroderma, lupus, and Sjögrens syndrome (SS). Some of these TAAs contain sialylated carbohydrate motifs and they are involved in tumor‐associated cell adhesion and metastasis. We assessed levels of TAAs in the sera of RA patients and healthy subjects. Serum TAA levels were correlated with disease markers including serum rheumatoid factor (RF), C‐reactive protein (CRP), and anti‐CCP antibody levels, DAS28, age disease duration. TAAs including CEA, CA15‐3, CA72‐4, CA125, and CA19‐9, and neuron‐specific enolase (NSE) were assessed by immunoassay in the sera of 75 patients with RA and 50 age‐ and sex‐matched healthy controls. Normal upper limits for these TAAs were 3.4 μg/L, 25 kU/L, 6.9 kU/L, 35 kU/L, 34 kU/L, and 16.3 μg/L, respectively. There were significantly more RA patients showing abnormally high levels of CA125 (10.8% versus 7.1%), CA19‐9 (8.1% versus 0%), and CA15‐3 (17.6% versus 14.3%) in comparison to controls (P < 0.05). The mean absolute serum levels of CA125 (23.9 ± 1.8 versus 16.8 ± 2.2 kU/L) and CA19‐9 (14.2 ± 1.2 versus 10.5 ± 1.6 kU/L) were also significantly higher in RA compared to controls (P < 0.05). Among RA patients, serum CEA showed significant correlation with RF (r= 0.270; P < 0.05). None of the assessed TAAs showed any correlation with CRP, anti‐CCP, DAS28, age or disease duration. The concentration of some TAAs may be elevated in the sera of patients with established RA in comparison to healthy subjects. CEA, CA19‐9, CA125, and CA15‐3 contain carbohydrate motifs and thus they may be involved in synovitis‐associated adhesive events. Furthermore, some TAAs, such as CEA, may also correlate with prognostic factors, such as serum RF levels.

Tumor-associated antigens in systemic sclerosis and systemic lupus erythematosus: Associations with organ manifestations, immunolaboratory markers and disease activity indices

BACKGROUND Some tumor-associated antigens (TAAs) are expressed on inflammatory cells. We previously detected increased production of CA15-3, CA19-9 and CA125 in rheumatoid arthritis (RA). The production of some TAAs may also be increased in patients with systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and other connective tissue diseases. Some of these TAAs contain sialylated carbohydrate motifs and they are involved in tumor-associated cell adhesion and metastasis. OBJECTIVES We assessed levels of TAAs in the sera of SSc, SLE patients, patients with infectious diseases and healthy subjects. Serum TAA levels were correlated with each other, as well as with disease activity markers and organ involvement. METHODS TAAs including CEA, CA15-3, CA72-4, CA125 and CA19-9 were assessed by immunoassay in the sera of 92 patients with SSc, 40 patients with SLE, 50 age- and sex-matched healthy controls, as well as with 40 patients with current bacterial or viral infections. Normal upper limits for these TAAs were 3.4 mg/l, 25 kU/l, 6.9 kU/l, 35 kU/l and 34 kU/l, respectively. RESULTS There were significantly more SSc patients showing abnormally high levels of CA19-9 (8.8% vs 2.0%), CA125 (11.0% vs 6.0%) and CA15-3 (28.4% vs 14.0%) in comparison to controls (p < 0.05). In SLE, significantly more patients had elevated levels of CEA (32.5% vs 20.0%), CA19-9 (7.5% vs 2.0%), CA125 (15.0% vs 6.0%) and CA72-4 (15.0% vs 8.0%) than did controls (p < 0.05). The mean absolute serum levels of CEA (6.6+/-1.7 vs 1.8+/-1.4 mg/l) and CA15-3 (22.9 +/- 1.8 vs 18.6 +/- 2.2 kU/l) were also significantly higher in SSc compared to controls (p < 0.05). We found numerous correlations between the serum levels of different TAAs within the SSc and SLE population. Among SSc patients, serum CEA (R = 0.290; p = 0.005), CA15-3 (R = 0.260; p = 0.020) and CA19-9 (R = 0.257; p = 0.013) correlated with renal involvement. Serum CA15-3 also correlated with joint involvement (R = 0.329; p = 0.003), ANA positivity (R = 0.288; p = 0.010) and CRP levels (R = 0.407; p < 0.001). Within the SLE population, serum CA72-4 correlated with central nervous involvement (R = 0.624; p = 0.004) and CA125 correlated with the SLEDAI composite activity index (R = 0.666; p = 0.002). Patients with infections exerted serum TAA patterns similar to healthy controls. CONCLUSION The concentration of some TAAs may be elevated in the sera of patients with SSc or SLE in comparison to healthy subjects. Pathogenically, most of these TAAs contain carbohydrate motifs and thus they may be involved in inflammation-associated adhesive events. Furthermore, the production of some TAAs may correlate with organ involvement or disease activity in scleroderma or lupus.

Recurrent laryngeal nerve paralysis due to subclinical Lyme borreliosis

OBJECTIVE We report an extremely rare case of recurrent laryngeal nerve paralysis due to subclinical Lyme borreliosis. METHOD Case report presenting a 15-year-old girl referred with hoarseness and soft voice. RESULTS Right-sided recurrent laryngeal nerve paralysis was observed using videolaryngoscopy. Imaging was used to exclude intracranial, cervical and intrathoracic embryological lesions, vascular malformations and tumours. Laboratory and electrophysiological investigations were used to exclude inflammatory and paraneoplastic processes, endocrinopathy and metabolic disorders. Serological testing was positive for Lyme disease. Parenteral ceftriaxone therapy was commenced. The patients nerve paralysis showed complete recovery on the seventh day of antibiotic treatment; this was confirmed by videolaryngoscopy. CONCLUSION Recurrent laryngeal nerve paralysis is an extremely rare complication of neuroborreliosis associated with Lyme disease. In patients with recurrent laryngeal nerve paralysis in whom the clinical history is uncertain and the usual diagnostic methods give negative results, screening with anti-borrelia immunoglobulin M is suggested.

First Line Sorafenib Treatment for Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis

BACKGROUND Medullary thyroid cancer (MTC) is a rare disease, the prognosis of advanced and metastatic disease is poor and few therapeutic options are available in this setting. Based on the results of phase II and III studies with sorafenib in differentiated thyroid cancer and the lack of availability of registered tyrosine kinase inhibitors, vandetabin and cabozantinib in Hungary, we designed a uncontrolled, prospective efficacy and safety study of patients with metastatic MTC treated with first-line sorafenib in five Hungarian oncology centers. METHODS Ten consecutive patients with progressive or symptomatic metastatic MTC were included and started sorafenib 400  mg twice a day between June 2012 and March 2016. The primary end point was median progression-free survival (mPFS). Secondary endpoints included disease control rate, biochemical response, symptomatic response and toxicity. RESULTS Four patients achieved partial remission (40%) according to RECIST 1.1 evaluation. Five patients had stable disease beyond 12 months (50%) and one patient had progressive disease (10%). Median PFS was 19.1 months. The disease control rate was 90%. Association between radiologic response and biochemical or symptomatic response was inconsistent. Most common side effects were Grade 1-2 fatigue (60%), palmar-plantar erythrodysesthesia, rash/dermatitis 50-50%, alopecia 40%. CONCLUSIONS In our prospective case series in patients with MTC first-line sorafenib showed at least similar efficacy as in other small phase II trials and case reports. Based on comparable efficacy with registered tyrosine kinase inhibitors and its manageable toxicity profile, we believe that sorafenib has role in the sequential treatment of MTC.