János Gaál

The complex role of vitamin D in autoimmune diseases.

Vitamin D, besides having well‐known control functions of calcium and phosphorus metabolism, bone formation and mineralization, also has a role in the maintenance of immune‐homeostasis. The immune‐regulatory role of vitamin D affects both the innate and adaptive immune system contributing to the immune‐tolerance of self‐structures. Impaired vitamin D supply/regulation, amongst other factors, leads to the development of autoimmune processes in animal models of various autoimmune diseases. The administration of vitamin D in these animals leads to improvement of immune‐mediated symptoms. Moreover, in human autoimmune diseases, such as multiple sclerosis, or rheumatoid arthritis the pathogenic role of vitamin D has been described. The review aims at describing the complex immune‐regulatory role of vitamin D from the cellular level through autoimmune animal models and depicting the known contribution of vitamin D in the pathogenesis of human autoimmune diseases.

Vitamin D deficiency in undifferentiated connective tissue disease

IntroductionBoth experimental and clinical data provide evidence that vitamin D is one of those important environmental factors that can increase the prevalence of certain autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, insulin-dependent diabetes mellitus, and inflammatory bowel disease. The aim of the present study was to investigate the prevalence of vitamin D insufficiency in patients with undifferentiated connective tissue disease (UCTD).MethodsPlasma 25(OH)D3 levels in 161 UCTD patients were measured in both summer and winter periods. Autoantibody profiles (antinuclear antibody, anti-U1-ribonucleoprotein, anti-SSA, anti-SSB, anti-Jo1, anti-Scl70, anti-double-stranded DNA, anti-centromere, anti-cardiolipin, rheumatoid factor, and anti-cyclic citrullinated peptide) and clinical symptoms of the patients were assessed.ResultsPlasma levels of 25(OH)D3 in UCTD patients were significantly lower compared with controls in both summer and winter periods (UCTD summer: 33 ± 13.4 ng/mL versus control: 39.9 ± 11.7 ng/mL, P = 0.01; UCTD winter: 27.8 ± 12.48 ng/mL versus control: 37.8 ± 12.3 ng/mL, P = 0.0001). The presence of dermatological symptoms (photosensitivity, erythema, and chronic discoid rash) and pleuritis was associated with low levels of vitamin D. During the average follow-up period of 2.3 years, 35 out of 161 patients (21.7%) with UCTD further developed into well-established connective tissue disease (CTD). Patients who progressed into CTDs had lower vitamin D levels than those who remained in the UCTD stage (vitamin D levels: CTD: 14.7 ± 6.45 ng/mL versus UCTD: 33.0 ± 13.4 ng/mL, P = 0.0001).ConclusionsIn patients with UCTD, a seasonal variance in levels of 25(OH)D3 was identified and showed that these levels were significantly lower than in controls during the corresponding seasons. Our results suggest that vitamin D deficiency in UCTD patients may play a role in the subsequent progression into well-defined CTDs.

Clinical course, prognosis, and causes of death in mixed connective tissue disease

Objective. To study the survival rate and prognostic indicators of mixed connective tissue disease (MCTD) in a Hungarian population. Methods. Two hundred eighty patients with MCTD diagnosed between 1979 and 2011 were followed prospectively. Clinical features, autoantibodies, and mortality data were assessed. Prognostic factors for survival were investigated and survival was calculated from the time of the diagnosis by Kaplan-Meier method. Results. A total of 22 of 280 patients died: the causes of death were pulmonary arterial hypertension (PAH) in 9 patients, thrombotic thrombocytopenic purpura in 3, infections in 3, and cardiovascular events in 7. The 5, 10, and 15-year survival rates after the diagnosis was established were 98%, 96%, and 88%, respectively. The deceased patients were younger at the diagnosis of MCTD compared to patients who survived (35.5 ± 10.4 vs 41.8 ± 10.7 yrs; p < 0.03), while there was no difference in the duration of the disease (p = 0.835). Our cohort study showed that the presence of cardiovascular events (p < 0.0001), esophageal hypomotility (p = 0.04), serositis (p < 0.001), secondary antiphospholipid syndrome (p = 0.039), and malignancy (p < 0.001) was significantly higher in the deceased patients with MCTD. The presence of anticardiolipin (p = 0.019), anti-β2-glycoprotein I (p = 0.002), and antiendothelial cell antibodies (p = 0.002) increased the risk of mortality. Conclusion. Overall, PAH remained the leading cause of death in patients with MCTD. The prevalence of cardiovascular morbidity and mortality, malignancy, and thrombotic events increased during the disease course of MCTD. The presence of antiphospholipid antibodies raised the risk of mortality.

Alfacalcidol treatment restores derailed immune-regulation in patients with undifferentiated connective tissue disease

Vitamin D deficiency may contribute to pathological changes in the number and function of CD4+ T helper cell subsets (CD4+Th1, CD4+Th17, CD4+CD25(bright)Foxp3-natural regulatory T cells-nTreg) in patients with undifferentiated connective tissue disease (UCTD). The aim of the present study was to evaluate, whether alfacalcidol could restore immune-regulatory changes in patients with UCTD. We assessed the optimal dose of alfacalcidol that could normalize the elevated levels of IFN-γ expressed by the CD4+Th1 cells and the IL-17 expressed by Th17 cells. Furthermore alfacalcidol decreased the Th1 and Th17 related cytokine levels, repaired the nTreg/Th7 balance, and restored the functional activity of nTreg cells. Twenty one UCTD patients with Vitamin D deficiency (<30 ng/ml) were administered with three different daily doses of alfacalcidol. Seven patients were supplemented with 0.5 μg/day, 7 patients with 1.0 μg/day, and 7 patients with 1.5 μg/day alfacalcidol treatment during 5 weeks. Our results indicated that 1.0 μg/day alfacalcidol during 5 weeks was the optimal therapeutic regime to increase the vitamin D levels, repair the nTreg/Th17 balance and raise the capacity of nTreg cells to suppress the proliferation of autologous CD4+CD25- cells. 1.5 μg daily dose alfacalcidol was not more effective than the 1.0 μg/day treatment. In this study we described that vitamin D deficiency can contribute to the complex immune-regulatory abnormalities in patients with UCTD and vitamin D substitution therapy can improve the fine balance of pro- and anti-inflammatory processes in the disease.

Immunological and Clinical Effects of Alphacalcidol in Patients with Psoriatic Arthropathy: Results of an Open, Follow-up Pilot Study

The aim of this study was to describe the effect of systemic alphacalcidol (1 OH vitamin D3) treatment on clinical and immunological parameters in patients with psoriatic arthropathy. Among the 19 patients investigated, 10 were treated with 0.25 microg oral alphacalcidol twice daily for 6 months, while 9 other patients served as controls. In the peripheral blood of the treated group but not in the controls, a statistically significant decrease was observed in the percentage of CD3/CD69-positive activated and CD8-positive interferon-gamma-producing T cells and in the serum level of interferon-gamma during the first 3 months and also in the clinical activity of the disease during the whole 6-month follow-up period. Our results show that systemic alphacalcidol treatment has an immunomodulatory effect on patients with psoriatic arthropathy. This effect is manifested by a short-term temporary decrease in type 1 immune responses and a continuous decrease in disease activity.

Impaired regulatory T-cell homeostasis due to vitamin D deficiency in undifferentiated connective tissue disease.

Objective: The aim of this study was to perform a quantitative and functional analysis of natural CD4+CD25highFoxp3+ regulatory T cells (nTregs) and CD4+IL-17+ T cells, and to assess the serum levels of proinflammatory cytokines in patients with undifferentiated connective tissue disease (UCTD) before and after 5 weeks of 0.5 μg/day alfacalcidol supplementation. Methods: Twenty-five patients with UCTD were enrolled in an open-label trial of alfacalcidol. Plasma levels of 25-hydroxyvitamin D [25(OH)D] were assessed by a high-performance liquid chromatography (HPLC) method. Flow cytometry was used for the quantification of nTregs and the IL-17 expression of T-helper (Th)17 cells. The serum concentrations of cytokines interleukin (IL)-12, interferon (IFN)-γ, IL-23, IL-17, IL-6, and IL-10 were measured by an enzyme-linked immunosorbent assay (ELISA). Results: Treatment with alfacalcidol raised 25(OH)D levels from a mean of 23.5 ± 5.6 to 34.5 ± 7.4 ng/mL (p = 0.059; NS). Alfacalcidol treatment decreased both Th1- (IL-12 and IFN-γ) and Th17-related (IL-23, IL-17, IL-6) cytokine levels in UCTD patients, while the soluble IL-10 level increased (IL-12: 156.7 ± 75.2 vs. 87.5 ± 42.1 pg/mL, p < 0.001; IFN-γ: 41.5 ± 12.0 vs. 21.7 ± 9.9 pg/mL, p < 0.001; IL-23: 385.2 ± 82.2 vs. 210.0 ± 69.3 pg/mL, p < 0.001; IL-17: 37.8 ± 9.6 vs. 17.8 ± 4.5 pg/mL, p = 0.009; IL-6: 39.4 ± 11.3 vs. 23.5 ± 6.3 pg/mL, p < 0.001, IL-10: 8.4 ± 3.0 vs. 21.4 ± 9.7 pg/mL, p < 0.001). Alfacalcidol improved the Th17/nTreg imbalance, as it inhibited the IL-17 expression of Th17 cells, and increased the number of nTregs. The alfacalcidol might increase the capacity of nTreg cells to suppress the proliferation of autologous CD4+CD25– cells. Conclusion: Our findings support the idea that vitamin D influences the Th17/nTreg imbalance in vitamin D-insufficient patients with UCTD and could be beneficial in the management of the disease.

Progressive divergent shifts in natural and induced T-regulatory cells signify the transition from undifferentiated to definitive connective tissue disease

The objectives of the study is to determine clinical signs and distribution of peripheral T-cell subsets, B cells and T regulatory cells in patients with undifferentiated connective tissue disease (UCTD) and during the development toward well-established connective tissue diseases (CTD). The methods include 46 patients with UCTD were followed and investigated for differentiation into defined CTDs for 2 years. Cell subsets were determined on the basis of cell surface markers, intracellular cytokine production by flow cytometry and serum cytokine levels by ELISA. The results are as follows: 45.6% of UCTD patients developed into a defined CTD. The number and percentage of activated T cells, memory T cells and NKT cells were increased in patients compared with controls. In addition, in patients with UCTD, the percentage of CD4+/IFN gamma+ T(h)1 was significantly higher compared with controls and further increased in patients that developed CTDs. The percentage and absolute number of CD4+CD25+Foxp3+ regulatory T cells (Tregs) were diminished in UCTD patients compared with healthy controls, while the number of CD4+/IL-10+ Tregs increased. The conclusions are Overproduction of IFN gamma and the decrease of natural (Foxp3+) Tregs seem to be characteristic features of UCTD patients. The increased IL-10 production of CD4+ T cells might be a compensatory suppressive mechanism; however, it is probably not able to balance the overproduction of IFN gamma and the observed decrease of Foxp3+ Tregs. The shift toward T(h)1 with increased IFN gamma production in patients with UCTD combined with the degree of immunoregulatory disturbances characterized by the progressive divergent shifts in natural and induced T-regulatory cell populations signify the transition from undifferentiated to definitive CTD.

99mTc-HMPAO labelled leukocyte scintigraphy in patients with rheumatoid arthritis: A comparison with disease activity

The aim of this study was to test the applicability of 99mTc-hexamethylpropylene amine oxime (99mTc-HMPAO) labelled leukocyte joint scintigraphy in the assessment of disease activity in 21 patients with rheumatoid arthritis, and to compare leukocyte scintigraphy with the Disease Activity Score (DAS), a validated activity index developed by the European League Against Rheumatism (EULAR). Twenty-one patients with rheumatoid arthritis were investigated by using 99mTc-HMPAO labelled leukocyte joint scintigraphy. The clinical and laboratory data were recorded, and the DAS was calculated and compared with the scintigraphic results in each case. A relatively high DAS score (4.71±1.07) was found in the majority of patients. The degree of accumulation of 99mTc-HMPAO leukocytes showed no correlation with a patients age, gender, duration of disease, use of disease modifying anti-rheumatic drugs (DMARDs), visual analogue scale (VAS), Richie index, DAS, or any laboratory parameters. In contrast, a significant correlation was found between the global regional accumulation of the labelled leukocytes of the hands and feet, and the swollen-joint count. It is concluded that radiolabelled leukocyte scintigraphy could become one of the promising methods in the assessment of disease activity in patients with rheumatoid arthritis.

The prevalence of obesity is increased in patients with late compared with early onset psoriasis

PURPOSE We compared the clinical and epidemiologic characteristics of early and late onset psoriasis with an emphasis on potential differences in the comorbidities associated with each subtype. METHODS An observational, multicenter study was performed, and associations between the age at the time of diagnosis and binary comorbidity outcomes were evaluated using multiple logistic regression analysis adjusted for age and other relevant confounders. RESULTS An increased prevalence of positive family history, psoriatic arthritis, and depression was observed in patients with early onset psoriasis. On the other hand, late onset psoriasis was more frequently associated with obesity and elevated waist circumference compared with early onset form. Elderly psoriatic patients (at the age of 75 years) with late onset psoriasis are at an especially high risk for obesity compared with individuals at the same age with an early onset disease. CONCLUSIONS The increased frequency of psoriasis in the family of early onset patients may suggest that manifestation of psoriasis at younger age is driven by strong genetic influence. However, such a remarkable association of abdominal obesity with late onset psoriasis may suggest that obesity can be one of the acquired factors that may predispose for the development of psoriasis in the elderly.

Vitamin D3 levels and bone mineral density in patients with psoriasis and/or psoriatic arthritis.

Limited data are available on the vitamin D3 status and bone mineral density (BMD) of patients with psoriasis or with psoriatic arthritis. Our study intended to explore possible correlations between vitamin D status and BMD, as well as among these parameters and the features of the underlying disorder. Seventy‐two patients with psoriasis/or psoriatic arthritis (female : male ratio, 40:32; mean age, 58.5 ± 11.6 years; mean duration of follow up, 142.7 ± 147.7 months) participated in the study. We evaluated the characteristic clinical features of the underlying disease, performed bone densitometry of the lumbar spine and the hip region, measured the serum vitamin 25(OH)D3 levels of the patients, and undertook the statistical analysis of the relationships between the clinical and the laboratory parameters. The proportion of patients with a low BMD value did not exceed that seen in the general population. We found an inverse correlation between the serum level of vitamin 25(OH)D3 and body mass index, as well as between the former and the severity of skin involvement. Furthermore, the activity of psoriatic arthritis was significantly higher in patients with inadequate vitamin D3 status. In patients with psoriatic arthritis, BMD significantly exceeded the values measured in patients suffering from psoriatic skin lesions only. Our findings suggest the importance of evaluating the vitamin D3 status and screening for comorbid conditions in patients with psoriasis or psoriatic arthritis. This appears justified, in particular, due to the possible role of hypovitaminosis D3 in provoking the development of skin lesions and joint symptoms.