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Systemic sclerosis (SSc) is a heterogeneous autoimmune disease, where a significant proportion of patients develop interstitial lung disease (ILD), which is the major cause of mortality. In recent years, the diagnosis of SSc-ILD has improved a lot, and caring rheumatologists, together with pulmonologists, regularly screen and follow the development and course of ILD. Considerable progress has also been made in the treatment of SSc-ILD based on several clinical trials. The recommendations for immunosuppressive treatment have been modified and supplemented with targeted agents (tocilizumab, rituximab), and antifibrotic drugs such as nintedanib registered as a new treatment for SSc-ILD. However, there are no clear recommendations regarding the start and timing of nintedanib treatment. A debate on the early introduction of nintenadib or not took place on the 7th edition of the International Congress on Controversies in Rheumatology and Autoimmunity (CORA) in March/2023, and this review summarizes the main arguments that were discussed in this session., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paolo Spagnolo reports a relationship with Boehringer Ingelheim Pharmaceuticals Inc. that includes: board membership, consulting or advisory, funding grants, and speaking and lecture fees. Paolo Spagnolo reports a relationship with PPM Services SA that includes: consulting or advisory, funding grants, and travel reimbursement. Paolo Spagnolo reports a relationship with Novartis that includes: board membership and consulting or advisory. Paolo Spagnolo reports a relationship with Roche that includes: funding grants. Paolo Spagnolo reports a relationship with CSL Behring LLC that includes: board membership. Paolo Spagnolo reports a relationship with Pieris Pharmaceuticals Inc. that includes: consulting or advisory. Paolo Spagnolo reports a relationship with A Menarini International Pharmaceutics that includes: speaking and lecture fees. Paolo Spagnolo reports a relationship with Galapagos that includes: board membership and consulting or advisory. Paolo Spagnolo reports a relationship with Chiesi Pharmaceuticals Inc. that includes: speaking and lecture fees. Elisabetta Zanatta reports a relationship with Boehringer Ingelheim Pharmaceuticals Inc. that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Gabriella Szucs reports a relationship with Boehringer Ingelheim Pharmaceuticals Inc. that includes: speaking and lecture fees., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

To investigate corneal microstructure of systemic sclerosis (SSc) patients using in vivo confocal microscopy (IVCM). 33 patients with SSc and 30 age-matched healthy subjects were recruited. All participants underwent comprehensive ophthalmic examination including IVCM (Heidelberg Retina Tomograph III, Heidelberg Engineering GmbH, Heidelberg, Germany) and ocular surface evaluation. Subbasal nerve plexus morphology was investigated using automated software analysis (ACCMetrics V3; University of Manchester, Manchester, UK). Keratocyte cell densities in the anterior stroma were significantly lower in patients with SSc compared to controls (P < 0.0001). In 7 SSc patients no keratocyte nuclei were identified in the anterior stroma and in most patients scattered hyperreflective punctate material were observed in the anterior stroma. Significantly lower subbasal nerve fiber parameters were found in patients with SSc compared to healthy subjects (P < 0.05). There were no significant correlations between the duration of SSc and any of the corneal cell density values. Tear break-up time values (4.82 ± 3.15 s) and Ocular Surface Disease Index scores (33.27 ± 30.11) were abnormal, Schirmer values (6.78 ± 5.82 mm) were borderline in SSc patients. In SSc, corneal morphological changes and accumulation of punctate material in the stroma was detected with confocal microscopy. Severe ocular surface disease was observed in SSc patients with significant impairment in subbasal nerve plexus morphology resembling peripheral neuropathy.

Objectives : Systemic sclerosis (SSc) is a rare, chronic connective tissue disease involving multiple organ systems, including the eye. We evaluated the detailed clinical ocular manifestations of outpatients with SSc. Methods : Demographics, disease duration and subtype, nailfold capillaroscopy (NFC) patterns and laboratory parameters encompassing the autoantibody profile of 51 SSc patients were evaluated, and a general ocular examination was performed for each participant. Results : Twenty-nine patients (56.86%) had eyelid skin alterations, 26 (50.98%) had retinal abnormalities, 26 (50.98%) had cataracts, 8 (15.69%) had conjunctival changes, 7 (13.73%) had iris abnormalities, 33 (64.71%) suffered from dry eye disease (DED), and 11 (21.57%) suffered from glaucoma. Significant positive correlations were found between NFC data and both tear breakup time and Ocular Surface Disease Index test values. Conclusions : Eyelid skin abnormalities, DED and retinal abnormalities are among the most common SSc-related ocular involvements. Diverse ophthalmic findings are attributed to the heterogeneity of SSc.

The aim of this study was to evaluate the association between clinical signs and symptoms of dry eye disease (DED) in patients with systemic sclerosis (SSc). This cross-sectional observational study included 19 SSc patients and 19 normal subjects with no ocular symptoms or ocular surface disorders. Clinical parameters included tear film break-up time (tBUT), Schirmer I, lissamine green (LG) dye, and tear film osmolarity tests, tear production, and tear secretion flow. For assessment of the dry eye symptoms, the Ocular Surface Disease Index (OSDI) questionnaire was administered to all patients. The following mean values were found in SSc patients: OSDI 33.6 ± 19.86; osmolarity of the tear fluid 310.8 mOsmol/l ± 14.47; tBUT time 5.158 ± 2.328 s; Schirmer I test 5.395 mm/5 min; LG grading score 2.026 ± 0.8893; collected tear fluid volume 6.397 ± 2.761 µl. The calculated average tear velocity was 4.654 ± 1.963 µl/min. A significant correlation was found between the OSDI as a subjective parameter and disease duration. Early recognition of dry eye symptoms, a possible extra-intestinal manifestation of SSc, should be included in the check up of the disease to reduce ocular complications. The objective tear functional tests were strongly influenced by individual factors like age and disease duration.

The human precorneal tear film is a special body fluid, since it is a complex mixture of proteins, lipids, small bioactive molecules, and their concentrations and relative distribution represent not only the metabolic state of the ocular surface but also the systemic and local homeostasis of the outer eye and the human body. This suggests that biochemical analysis of the precorneal tear film composition may provide a non-invasive tool for diagnosis and monitoring of disease progression or treatment efficacy in human medicine. However, collecting tears is demanding, and obtaining reproducible and unaltered samples is challenging because of the small sample volumes of tears. Several methods are available for tear collection as a preparatory step of precorneal tear film analysis, and the collection method used has to be assessed since it has a critical impact on the effectiveness of the assays and on the quality of the results. Each sampling method has advantages and disadvantages; therefore, it is not easy to choose the appropriate collecting method for tear collection. To overcome these limitations various methods have been recommended by different authors for special aspects of specific tests. The aim of our review was to evaluate tear sampling methods with regard to our ongoing biochemical analysis. *Contributed equally.

Although serious ocular manifestations of systemic sclerosis (SSc) have been described, tear analysis of patients with SSc has not been performed in previous studies. Our aim was to measure a wide panel of cytokines and chemokines in tears of patients with SSc and to assess the most significant molecules with a more sensitive and specific method. Unstimulated tear samples were collected from nine patients with SSc and 12 age- and gender-matched healthy controls. The relative levels of 102 different cytokines were determined by a cytokine array, and then absolute levels of four key cytokines were determined by a magnetic bead assay. Array results revealed shifted cytokine profile characterized by predominance of inflammatory mediators. Of the 102 analyzed molecules, nine were significantly increased in tears of patients with SSc. Based on the multiplex bead results, C-reactive protein, interferon-γ-inducible protein-10, and monocyte chemoattractant protein-1 levels were significantly higher in tears of patients with SSc. Our current data depict a group of inflammatory mediators, which play a significant role in ocular pathology of SSc; furthermore, they might function as excellent candidates for future therapeutic targets in SSc patients with ocular manifestations.

Objective: The aim of this study was to evaluate the efficacy, reasons for switching and drug survival of TNF-α inhibitors (TNFis) used as first- and second-line drugs in ankylosing spondylitis (AS)., Methods: Data on patients suffering from AS and treated with at least one TNFi between November 2005 and 2013 were extracted retrospectively from the database of a single clinical centre. Beside demographic data, the disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the response rates (BASDAI50), reasons for switching and survival curves of TNFis were analysed in general and in subgroups of patients treated with each of the available TNFis. The reasons for switching were defined as inefficacy, side effects of the given drug, patient's request and occurrence of extra-articular manifestations., Results: Altogether, 175 patients were on TNFis and 77 of them received at least two TNFis. The patients' age at the initiation of the first TNFi was higher among switchers compared to non-switchers (42.5 ± 12.6 vs. 38.8 ± 11.2 years, p = 0.049); otherwise, gender, disease duration and initial disease activity had no influence on the risk of switching. The decrease of the BASDAI was similar among non-switchers and switchers using either the first or second TNFi, but the response rates to the first and second TNFi were worse in switchers than in non-switchers. Following the failure of the first TNFi, the retention on therapy was unfavourable, especially in patients on infliximab after 1 year of treatment. The main reason for switching from the first drug was inefficacy. The frequency of side effects that led to switching was higher in the infliximab group than in patients treated with other agents., Conclusion: Although the retention rate to a second-line TNFi was somewhat worse than that to the first-line TNFi, the switching of TNFis is a good therapeutic option in AS patients who failed to respond to the first TNFi.

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.

Ferritin may play a direct role on the immune system. We sought to determine if elevated levels of ferritin in lupus patients correlate with disease activity and organ involvement in a large cohort. Ferritin levels (gender and age adjusted) were assessed in 274 lupus serum samples utilizing the LIASON Ferritin automated immunoassay method. Significant disease activity was determined if European Consensus Lupus Activity Index (ECLAM)>2 or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)>4. Utilizing an EXCEL database, we compared elevated ferritin levels to manifestations grouped by organ involvement, serology, and previous therapy. The patients were predominantly female (89%), median age was 37 years old, and disease duration was 10.6 ± 7.7 years. Hyperferritinemia was found in 18.6% of SLE patients. Compared to subjects with normal ferritin levels, a significantly greater proportion of patients with hyperferritinemia had thrombocytopenia (15.4% vs. 33.3%, p=0.003) and lupus anticoagulant (11.3% vs. 29.0%, p=0.01). Additionally, compared to normoferritinemic subjects, hyperferritinemic subjects had significantly higher total aCL (99.7 ± 369 vs. 30.9 ± 17.3 GPI, p=0.02) and aCL IgM antibody levels (75.3 ± 357.4 vs. 9.3 ± 10.3 GPI, p=0.02), and marginally lower aCL IgG antibody levels (9.2 ± 4.9 vs. 9.7 ± 3.9 GPI, p = 0.096). While the ECLAM score significantly correlated with hyperferritinemia (p=0.04), the SLEDAI score was marginally associated with hyperferritinemia (p = 0.1). Serositis was marginally associated with hyperferritinemia, but not with other manifestations. An association with serologic APS was encountered. Hyperferritinemia was associated with thrombocytopenia, lupus anticoagulant, and anti-cardiolipin antibodies suggest that it may be an early marker for secondary antiphospholipid syndrome in SLE patients.

Evidence points to an association of prolactin to autoimmune diseases. We examined the correlation between hyperprolactinemia and disease manifestations and activity in a large patient cohort. Age- and sex-adjusted prolactin concentration was assessed in 256 serum samples from lupus patients utilizing the LIASON prolactin automated immunoassay method (DiaSorin S.p.A, Saluggia, Italy). Disease activity was defined as present if European Consensus Lupus Activity Measurement (ECLAM) > 2 or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) > 4. Lupus manifestations were grouped by organ involvement, laboratory data, and prescribed medications. Hyperprolactinemia was presented in 46/256 (18%) of the cohort. Hyperprolactinemic patients had significantly more serositis (40% vs. 32.4%, p = 0.03) specifically, pleuritis (33% vs. 17%, p = 0.02), pericarditis (30% vs. 12%, p = 0.002), and peritonitis (15% vs. 0.8%, p = 0.003). Hyperprolactinemic subjects exhibited significantly more anemia (42% vs. 26%, p = 0.02) and marginally more proteinuria (65.5% vs. 46%, p = 0.06). Elevated levels of prolactin were not significantly associated with other clinical manifestations, serology, or therapy. Disease activity scores were not associated with hyperprolactinemia. Hyperprolactinemia in lupus patients is associated with all types of serositis and anemia but not with other clinical, serological therapeutic measures or with disease activity. These results suggest that dopamine agonists may be an optional therapy for lupus patients with hyperprolactinemia.

A case of a young man with fever of unknown origin is presented. This diagnosis can be frustrating for both patients and physicians because the diagnostic workup often involves numerous noninvasive and invasive procedures that sometimes fail to explain the fever. In the presented case some of the imaging diagnostic findings suggested malignant hematological disorder. However, histopathological and microbiological investigation proved vertebral osteomyelitis caused by Staphylococcus haemolyticus. Diagnosis was established by positron emission tomography, magnetic resonance imaging, and culture and histopathological analysis of a spinal biopsy. 3 months of antibiotic therapy was curative. Biopsy and microbiological investigation may be necessary in patients with fever, back pain and evidence of a spinal lesion on imaging, even if neoplastic disease is suspected.

Background: Increased cardiovascular morbidity has become a leading cause of mortality in rheumatoid arthritis (RA). Tumor necrosis factor-alpha (TNFa) inhibitors may influence flow-mediated vasodilation (FMD) of the brachial artery, common carotid intima-media thickness (ccIMT) and arterial stiffness indicated by pulse-wave velocity (PWV) in RA., Objectives: To assess the effects of adalimumab treatment on FMD, ccIMT and PWV in early RA., Methods: Eight RA patients with a disease duration < or =1 year received 40 mg adalimumab subcutaneously every 2 weeks. Ultrasound was used to assess brachial FMD and ccIMT. PWV was determined by arteriograph. These parameters were correlated with C-reactive protein, vonWillebrand factor (vWF), immunoglobulin M (IgM)-rheumatoid factor (RF), anti-CCP levels and 28-joint disease activity score (DAS28)., Results: Adalimumab therapy successfully ameliorated arthritis as it decreased CRP levels (P = 0.04) and DAS28 (P < 0.0001). Endothelial function (FMD) improved in comparison to baseline (P < 0.05). ccIMT decreased after 24 weeks, indicating a mean 11.9% significant improvement (P = 0.002). Adalimumab relieved arterial stiffness (PWV) after 24 weeks. Although plasma vWF levels decreased only non-significantly after 12 weeks of treatment, an inverse correlation was found between FMD and vWF (R = -0.643, P = 0.007). FMD also inversely correlated with CRP (R = -0.596, P= 0.015). CRP and vWF also correlated with each other (R = 0.598, P = 0.014). PWV and ccIMT showed a positive correlation (R = 0.735, P = 0.038)., Conclusions: Treatment with adalimumab exerted favorable effects on disease activity and endothelial dysfunction. It also ameliorated carotid atherosclerosis and arterial stiffness in patients with early RA. Early adalimumab therapy may have an important role in the prevention and management of vascular comorbidity in RA.

Objectives: To determine the causes and predictors of mortality in systemic sclerosis (SSc)., Methods: Patients with SSc (n=5860) fulfilling the American College of Rheumatology criteria and prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. EUSTAR centres completed a structured questionnaire on cause of death and comorbidities. Kaplan-Meier and Cox proportional hazards models were used to analyse survival in SSc subgroups and to identify predictors of mortality., Results: Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fibrosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Of the non-SSc-related fatalities, 25% died of causes in which SSc-related complications may have participated (pneumonia, sepsis and gastrointestinal haemorrhage). Independent risk factors for mortality and their HR were: proteinuria (HR 3.34), the presence of PAH based on echocardiography (HR 2.02), pulmonary restriction (forced vital capacity below 80% of normal, HR 1.64), dyspnoea above New York Heart Association class II (HR 1.61), diffusing capacity of the lung (HR 1.20 per 10% decrease), patient age at onset of Raynaud's phenomenon (HR 1.30 per 10 years) and the modified Rodnan skin score (HR 1.20 per 10 score points)., Conclusion: Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.

Objective: Systemic sclerosis (SSc) is a connective tissue disease that is characterized by microvascular disease and tissue fibrosis. Progressive loss and irregular architecture of the small blood vessels are well characterized, but the potential involvement of the lymphatic vessel system has not been analyzed directly in SSc. This study was undertaken to assess whether the lymphatic vascular system is affected in SSc, and whether changes to the lymphatic vessels are associated with dystrophic changes and tissue damage in patients with SSc., Methods: Lymphatic endothelial cells in skin biopsy samples from patients with SSc and age- and sex-matched healthy volunteers were identified by staining for podoplanin and prox-1, both of which are specifically expressed in lymphatic endothelial cells but not in blood vascular endothelial cells. CD31 was used as a pan-endothelial cell marker. Statistical analyses were performed using Kruskal-Wallis, Mann-Whitney U, and Spearman's rank correlation tests., Results: The numbers of podoplanin- and prox-1-positive lymphatic vessels were significantly reduced in patients with SSc as compared with healthy individuals. The number of podoplanin-positive lymphatic precollector vessels was significantly lower in SSc patients with fingertip ulcers than in SSc patients without ulcers. Moreover, the number of lymphatic vessels correlated inversely with the number of fingertip ulcers at the time of biopsy and with the number of fingertip ulcers per year. The inverse correlation between lymphatic precollector vessel counts and fingertip ulcers remained significant after statistical adjustment for the blood vessel count, age, and modified Rodnan skin thickness score., Conclusion: These results demonstrate a severe reduction in the number of lymphatic capillaries and lymphatic precollector vessels in patients with SSc. Patients with decreased lymphatic vessel counts may be at particularly high risk of developing fingertip ulcers.

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.

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.

Recent results suggest that B cells may have multiple pathogenic roles in systemic sclerosis (SSc) and there may be increased incidence of B cell lymphomas in SSc. Here, we assessed the prevalence of lymphomas in a large SSc cohort. We analyzed data of 218 Hungarian patients undergoing follow-ups in our institutions between 1995 and 2007. During this follow-up period, there were three SSc patients, who eventually developed B cell lymphoma. The first case is a woman with diffuse cutaneous form of SSc (dcSSc) including pulmonary, cardiac, gastrointestinal, and renal manifestations and anti-topoisomerase I antibody positivity. B cell chronic lymphocytic leukemia (B-CLL) with Zap70 expression (Rai I stage) developed 2 years after the onset of SSc. The second case is a woman with dcSSc presenting with pulmonary, cardiac, and gastroesophageal manifestations. Twenty-one months after disease onset, a chronic small lymphocytic B cell non-Hodgkin's lymphoma was diagnosed from retroperitoneal lymph nodes. Our third case is a woman with dcSSc and no internal organ manifestations. She also developed Zap70-positive B-CLL, stage Rai I 9 months after the onset of SSc. Thus, there were three cases of B cell lymphoma among our 218 SSc patients (1.38%). The association of scleroderma and non-Hodgkin's lymphoma may be a rather uncommon feature; however, the incidence of lymphoma among Hungarian SSc patients may be 1.9-2.5 times higher than that in the general population. In our three patients, B cell lymphoma developed within 2 years after the onset of SSc. Altered B cell function implicated in the pathogenesis of SSc may lead to the development of lymphoid malignancies.

Objective: Rho-associated kinases (Rock) are the major cellular mediators of Rho GTPases and play an important role in the organization of the actin cytoskeleton. Inhibitors of Rock are currently being evaluated for the treatment of pulmonary arterial hypertension. This study was undertaken to analyze the role of Rock in the activation of fibroblasts in systemic sclerosis (SSc)., Methods: Rock signaling was inhibited using chemical inhibitors and small interfering RNA. The expression of extracellular matrix (ECM) proteins and alpha-smooth muscle actin was analyzed by real-time polymerase chain reaction, Western blotting, and SirCol assay. Metabolic activity was quantified by MTT assay. Cell viability was assessed by staining with annexin V and propidium iodide. The role of MAP kinases was investigated using selective inhibitors and Western blotting., Results: Inhibition of Rock strongly reduced the synthesis of the major ECM proteins at the messenger RNA level as well as the protein level. Counterregulatory changes in the expression of tissue inhibitors of metalloproteinases and matrix metalloproteinases were not observed. Inhibition of Rock prevented myofibroblast differentiation. Transforming growth factor beta activated ERK in a Rock-dependent manner, and ERK mediated in part the stimulatory effects of Rock on myofibroblast differentiation. Toxic adverse effects of the inhibition of Rock were not observed., Conclusion: Our findings demonstrate that Rock potently stimulates the differentiation of resting fibroblasts into myofibroblasts and the production of ECM at biologically relevant concentrations without cell toxicity. These findings, along with the beneficial effects of Rock inhibition on vascular disease, indicate that inhibition of Rock might be an interesting novel therapeutic approach for the treatment of SSc.

Skin vasculitis may be associated with infections and autoimmune diseases. Furthermore, vasculitis may appear as a paraneoplastic symptom. A 19-year-old male patient was examined with swollen joints and papules presented on lower extremitis. Laboratory results showed high erythrocyte sedimentation ratio, positive C reactive protein, increased number of leukocytes and high circulating immune complex level. Histopatology of skin biopsy specimen proved vasculitis. ANCA was not present. No other changes could be observed besides skin involvement. Symptoms disappeared on 0.5-mg/bwkg methylprednisolon therapy. Few weeks later, enlarged cervical lymph nodes developed besides fever and weight loss. Biopsy indicated the presence of mixed cell type Hodgkin lymphoma. Appropriate examinations revealed clinical stage III/B with favorable prognosis (IPS=2). After eight cycles of ABVD therapy complete remission was achieved as confirmed by FDG-PET. As a consequence of the treatment of Hodgkin lymphoma, vasculitis also disappeared. The present case report calls to attention the importance of careful examinations to exclude other diseases, especially malignancies that may remain at the background of cutaneous vasculitis. Treatment of the primary disease also results in the improvement of secondary skin vasculitis.

The development of autoimmune diseases may be influenced by hormonal, immunomodulatory, and metabolic pathways. Prolactin (PRL), ferritin, vitamin D, and the tumor marker tissue polypeptide antigen (TPA) were measured in autoimmune diseases: systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), polymyositis (PM), dermatomyositis (DM), multiple sclerosis (MS), autoimmune thyroid diseases, and antiphospholipid syndrome. Hyperprolactinemia (HPRL) was detected in 24% of PM patients, in 21% of SLE patients, in 6.7% of MS patients, 6% of RA patients, and in 3% of SSc patients. Hyperferritinemia was detected in 23% of SLE patients, 15% of DM patients, 8% of MS patients, and 4% of RA patients. The patients had relatively low levels of 25 OH Vitamin D: the average results (mean +/- SD) were between 9.3 +/- 4.4 to 13.7 +/- 7.1 ng/mL in the different diseases, while the 25 OH Vitamin D concentrations less than 20 ng/mL are regarded as deficient. TPA levels were in the same range of the controls, elevated only in SLE. HPRL, hyperferritinemia, hypovitaminosis D, and TPA levels did not correlate with SLE activity elevated levels of rheumatoid factor or anti-CCP antibodies in RA. HPRL, hyperferritinemia, and hypovitaminosis D have different immunological implications in the pathogenesis of the autoimmune diseases. Preventive treatment with vitamin D or therapy for HPRL with dopamine agonists, may be considered in certain cases. Hyperferritinemia may be used as an acute-phase reactant marker in autoimmune diseases mainly SLE. TPA may be used to indicate the tendency for malignancies.

Background: Soluble, human low affinity Fcgamma receptors, such as sFcgammaRII and sFcgammaRIII, are known to play a pathologic role in different diseases. Sandwich ELISAs had previously been applied for the specific detection and determination of these soluble receptors. In these ELISAs, commercial monoclonal antibodies (Ab) were used as capture antibodies with monoclonal or polyclonal antibodies serving as detector Abs. Increased levels of cell-free FcgammaRIII have been detected in patients with lupus but the functions and levels of sFcgammaRII have not been fully characterized yet., Objectives: The aim of this work was to determine the ligand binding capacities and levels of soluble FcgammaRII and FcgammaRIII in sera of patients with systemic lupus erythematosus (SLE). Moreover, correlation between the levels of sFcgammaRII and sFcgammaRIII and the clinical activity of the disease were investigated., Methods: Sera of 47 patients with SLE, and 51 healthy subjects were analyzed. In the newly developed indirect sandwich ELISAs commercial monoclonal anti-FcgammaRs are used as capture antibodies, and the ligand of FcgammaRII and FcgammaRIII, an artificial immune complex (IC), serves as a detection component replacing the second antibodies used in previous methods., Results: The ligand binding capacity of both soluble FcgammaRII and sFcgammaRIII were elevated in the sera of SLE patients compared to control samples. This increase was significant in patients with the active disease (n = 30; p < 0.01). It was also revealed that a substantial part of the soluble Fcgamma receptors in these patients was bound in vivo to circulating IC., Conclusion: These newly developed ELISAs are probably more phisiologically relevant than other previous assays because they detect the circulating receptors on the basis their in vitro ligan binding capacities. Therefore this method can separately measure the levels of the soluble, free FcgammaRs and those bound circulating IC in vivo.

Systemic sclerosis (SSc) is a chronic connective tissue disease characterized by fibrosis and destruction of the microvasculature. Increased deposition of collagen and other extracellular matrix components affects not only the skin but most of the internal organs including lungs, heart, kidneys and the gastrointestinal (GI) tract. Within the GI tract, esophageal involvements are most frequently seen features. However, abnormalities in the small intestine, colon and anorectum may also occur. A retrospective study was performed to investigate the frequency and clinical relevances of GI involvement in patients with SSc. Charts of altogether 246 SSc patients were reviewed. This patient population included 40 males and 206 females, with a mean age of 54.2 years. In general, 176 of 246 patients (71.5%) had GI symptoms. Esophageal involvement including gastro-esophageal reflux disease (GERD), aperistalsis, pseudodiverticuli, etc. was the most common (62.6%). In addition, diseases of the stomach (31.7%), dysfunctions of the colon and anorectum (11.4%), as well as sclerosis of the biliary tract and other pancreato-biliary disorders (9.8%) also occurred. Diarrhea and malabsorption resulted in cachexia and other secondary complications leading to death in two cases. Our results support that GI manifestations are rather common in SSc. Apart from the esophagus, other GI complications in SSc are usually mild, however, early recognition is necessary to improve quality of life.

Objective: There are few large cohort studies available on the association of systemic and thyroid autoimmune diseases. In this study, we wished to determine the association of Hashimoto's thyroiditis (HT) and Graves' disease (GD) with systemic autoimmune diseases., Methods: One thousand five hundred and seventeen patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögren's syndrome (SS) and polymyositis/dermatomyositis (PM/DM) were included in the study. The HT and GD were diagnosed based on thorough clinical evaluation, imaging and fine-needle aspiration cytology (FNAC). The frequency of HT and GD in these diseases was assessed. In addition, 426 patients with HT or GD were assessed and the incidence of SLE, RA, SSc, MCTD, SS and PM/DM among these patients was determined. Prevalence ratios indicating the prevalences of GD or HT among our autoimmune patients in comparison to prevalences of GD or HT in the general population were calculated., Results: Altogether 8.2% of systemic autoimmune patients had either HT or GD. MCTD and SS most frequently overlapped with autoimmune thyroid diseases (24 and 10%, respectively). HT was more common among MCTD, SS and RA patients (21, 7 and 6%, respectively) than GD (2.5, 3 and 1.6%, respectively). The prevalences of HT in SLE, RA, SSc, MCTD, SS and PM/DM were 90-, 160-, 220-, 556-, 176- and 69-fold higher than in the general population, respectively. The prevalences of GD in the same systemic diseases were 68-, 50-, 102-, 76-, 74- and 37-fold higher than in the general population, respectively. Among all thyroid patients, 30% had associated systemic disease. In particular, 51% of HT and only 16% of GD subjects had any of the systemic disorders. MCTD, SS, SLE, RA, SSc and PM/DM were all more common among HT patients (20, 17, 7, 4, 2 and 2%, respectively) than in GD individuals (2, 5, 5, 1, 2 and 1%, respectively)., Conclusion: Systemic and thyroid autoimmune diseases often overlap with each other. HT and GD may be most common among MCTD, SSc and SS patients. On the other hand, these systemic diseases are often present in HT subjects. Therefore it is clinically important to screen patients with systemic autoimmune diseases for the co-existence of thyroid disorders.