Szilvia Szamosi

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.

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.

Rosuvastatin improves impaired endothelial function, lowers high sensitivity CRP, complement and immuncomplex production in patients with systemic sclerosis - a prospective case-series study

IntroductionWe studied the effect of rosuvastatin on endothelial and macrovascular function, cardiovascular risk factors and the complement pathway in patients with systemic sclerosis (SSc).MethodsAltogether 28 patients with SSc underwent laboratory and complex vascular assessments before and after six months of 20 mg rosuvastatin treatment. Flow-mediated dilation (FMD) of the brachial artery, as well as carotid artery intima-media thickness (ccIMT), carotid-femoral and aorto-femoral pulse wave-velocity (PWV) were analyzed by ECG-synchronized ultrasound. Ankle-brachial index (ABI) was determined by Doppler, and forearm skin microcirculation was assessed by Laser Doppler perfusion monitoring.ResultsBrachial artery FMD significantly improved upon rosuvastatin therapy (2.2% ± 3.3% before versus 5.7% ± 3.9% after treatment, P = 0.0002). With regard to patient subsets, FMD significantly improved in the 21 lcSSc patients (from 2.1% to 5.6%, P = 0.001). In the seven dcSSc patients, we observed a tendency of improvement in FMD (from 3% to 6%, P = 0.25). Changes in PWV, ccIMT and ABI were not significant. Mean triglyceride (1.7 ± 0.97 versus 1.3 ± 0.46 mmol/l, P = 0.0004), total cholesterol (5.3 ± 1.6 mmol/l versus 4.2 ± 1.3 mmol/l, P = 0.0003), low density lipoprotein cholesterol (3.0 ± 1.3 versus 2.2 ± 1.0 mmol/l, P = 0.005) and C-reactive protein levels (CRP) (5.1 ± 5.2 versus 3.4 ± 2.7, P = 0.01) levels significantly decreased after rosuvastatin treatment. Mean C3, C4 and IC levels also decreased significantly as compared to pretreatment values.ConclusionsSix-month rosuvastatin therapy improves endothelial function and lowers CRP, C3, C4 and IC levels indicating possible favourable effects of this statin on the cardiovascular and immune system in SSc.

Combined plasmapheresis and high-dose intravenous immunoglobulin treatment in systemic sclerosis for 12 months: follow-up of immunopathological and clinical effects

Systemic sclerosis (SSc) is an autoimmune disease which involves the skin, as well as several internal organs. Most therapies available in this disease are symptomatic. Authors present a case of diffuse SSc with progressive disease not responding to currently available treatments. Therefore a 12-month protocol of repeated plasmapheresis and high-dose intravenous immunoglobulin treatment was administered with good clinical efficacy. Apart from monitoring the clinical symptoms throughout the treatment, authors also assessed a number of humoral and cellular immunolaboratory markers in order to obtain information on the immunomodulatory effects of this combined treatment in SSc.

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.

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.

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.

Peripheral Blood Gene Expression and IgG Glycosylation Profiles as Markers of Tocilizumab Treatment in Rheumatoid Arthritis

Objective. Tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, has recently been approved as a biological therapy for rheumatoid arthritis (RA) and other diseases. It is not known if there are characteristic changes in gene expression and immunoglobulin G glycosylation during therapy or in response to treatment. Methods. Global gene expression profiles from peripheral blood mononuclear cells of 13 patients with RA and active disease at Week 0 (baseline) and Week 4 following treatment were obtained together with clinical measures, serum cytokine levels using ELISA, and the degree of galactosylation of the IgG N-glycan chains. Gene sets separating responders and nonresponders were tested using canonical variates analysis. This approach also revealed important gene groups and pathways that differentiate responders from nonresponders. Results. Fifty-nine genes showed significant differences between baseline and Week 4 and thus correlated with treatment. Significantly, 4 genes determined responders after correction for multiple testing. Ten of the 12 genes with the most significant changes were validated using real-time quantitative polymerase chain reaction. An increase in the terminal galactose content of N-linked glycans of IgG was observed in responders versus nonresponders, as well as in treated samples versus samples obtained at baseline. Conclusion. As a preliminary report, gene expression changes as a result of tocilizumab therapy in RA were examined, and gene sets discriminating between responders and nonresponders were found and validated. A significant increase in the degree of galactosylation of IgG N-glycans in patients with RA treated with tocilizumab was documented.

Plasma homocysteine levels, the prevalence of methylenetetrahydrofolate reductase gene C677T polymorphism and macrovascular disorders in systemic sclerosis: risk factors for accelerated macrovascular damage?

The purpose of this study was to investigate plasma homocysteine (Hcy) levels in patients with systemic sclerosis (SSc) and to study the association between plasma Hcy, C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR), and the clinical manifestations in SSc. Associations of Hcy level, C677T MTHFR polymorphism, and macrovascular diseases were investigated in 152 patients with SSc and 58 controls. No significant differences in Hcy levels and MTHFR genotypes were found in SSc patients compared to controls or in SSc patients with limited cutaneous compared to diffuse disease. Significantly higher Hcy concentration was observed in patients with macroangiopathy/thromboembolic events compared to patients without such clinical manifestations (p < 0.05). There was significant correlation between age and macrovascular disorders, between Hcy level and the disease duration (r = 0.164; p < 0.05). Seventy-one percent of patients with macrovascular disorders had MTHFR polymorphism. In addition, 45% of patients with hyperhomocysteinemia had pulmonary hypertension. The presence of MTHFR C677T mutation influences the incidence of macrovascular abnormalities in SSc patients. Elevated Hcy levels may be associated with disease duration and the evolution of macrovascular disorders and pulmonary hypertension in SSc.

Juvenile Systemic Sclerosis: A Follow‐up Study of Eight Patients

Abstract: Juvenile systemic sclerosis (jSSc) is a rare form of systemic sclerosis (also known as scleroderma). Fewer than 10% of SSc cases have their onset before age 20 and fewer than 2% before the age of 10. Few case reports and cohort studies on jSSc have been published. Our objective was to assess the clinical and laboratory characteristics of eight cases of juvenile‐onset SSc followed up at our institution. Clinical manifestations of SSc were recorded, and immunologic laboratory tests including antinuclear antibodies (ANAs), anti‐centromere antibodies (ACAs), and anti‐Scl‐70 antibodies were assessed. The female‐to‐male ratio was 7:1, and age at onset ranged from 3‐17 years. At the time of analysis, 2 of 8 patients were still under 18 years of age, and 6 of 8 patients were adults. The mean follow‐up period from the onset of disease was 19.1 years. Raynauds phenomenon was present in all cases. Only 2 of 8 patients had diffuse SSc. During follow‐up, pulmonary fibrosis developed in only 2 of 8 patients and cardiovascular manifestations in 3 of 8 patients. Secondary sicca syndrome was present in 2 of 8 cases. Regarding immunologic laboratory markers, 7 of 8 patients were ANA positive. However, none of these patients ever carried anti‐Scl‐70 antibodies, and only 2 of 8 patients had ever had ACA seropositivity. Our results suggest that in jSSc, Raynauds phenomenon is more severe, whereas internal organ manifestations and the frequency of autoantibodies are far less pronounced than in adult‐onset SSc. Also, the survival rate and final outcome of patients with jSSc appear to be better than those in patients with adult‐onset SSc.