Efficacy and quality of life assessment in the use of subcutaneous immunoglobulin treatment for children with primary immunodeficiency disorder.

Summary: Introduction. Most patients with primary and secondary immunodeficiencies need regular Intravenous Immunoglobulin (IVIG) or Subcutaneous Immunoglobulin (SCIG) treatment. This study aimed to evaluate the serum IgG trough levels, frequency of mild and severe infections, frequency and duration of hospitalization, duration of absence of school, and quality of life in patients switching their IVIG therapy to SCIG administration. Materials. Twenty-nine patients with immunodeficiency on regular IVIG treatment and who agreed to receive SCIG treatment were included. Seven patients discontinued treatment after the first SCIG administration. We collected data regarding serum IgG levels, annual numbers of infections, hospital admissions, and adverse events prior to and following SCIG initiation. PedsQL tests such as Scale Total Score (STS), Physical Health Total Score (PHTS), Psychosocial Health Total Score (PsyHTS), emotional functionality, social functionality, school/work problems score were calculated separately for all patients and their parents. Results. In twenty-two cases who were diagnosed as primary immunodeficiency, the most common indication for initiation of SCIG treatment was the long transfusion period of IVIG treatments and the difficulty of access to the hospital. No systemic side effects were noted except local redness, pain, and swelling on the injection site. The median IgG value was 588.9 mg/dl during IVIG treatment and 872 mg/dl one year after SCIG treatment. Annual frequency of infections and absence to school/work decreased significantly in the SCIG group while the annual number of hospitalizations and hospital stay time did not change significantly. There was a significant increase in the "quality of life" scores of the patients and their families. Conclusions. SCIG treatment provides ideal and protective immunoglobulin levels and offers the comfort of treatment in their home environment, thus increasing the patient's satisfaction and quality of life.

Spectrum and management of complement immunodeficiencies (excluding hereditary angioedema) across Europe.

INTRODUCTION: Complement immunodeficiencies (excluding hereditary angioedema and mannose binding lectin deficiency) are rare. Published literature consists largely of case reports and small series. We collated data from 18 cities across Europe to provide an overview of primarily homozygous, rather than partial genotypes and their impact and management. METHODS: Patients were recruited through the ESID registry. Clinical and laboratory information was collected onto standardized forms and analyzed using SPSS software. RESULTS: Seventy-seven patients aged 1 to 68 years were identified. 44 % presented in their first decade of life. 29 % had C2 deficiency, defects in 11 other complement factors were found. 50 (65 %) had serious invasive infections. 61 % of Neisseria meningitidis infections occurred in patients with terminal pathway defects, while 74 % of Streptococcus pneumoniae infections occurred in patients with classical pathway defects (p < 0.001). Physicians in the UK were more likely to prescribe antibiotic prophylaxis than colleagues on the Continent for patients with classical pathway defects. After diagnosis, 16 % of patients suffered serious bacterial infections. Age of the patient and use of prophylactic antibiotics were not associated with subsequent infection risk. Inflammatory/autoimmune diseases were not seen in patients with terminal pathway, but in one third of patients classical and alternative pathway defects. CONCLUSION: The clinical phenotypes of specific complement immunodeficiencies vary considerably both in terms of the predominant bacterial pathogen, and the risk and type of auto-inflammatory disease. Appreciation of these phenotypic differences should help both immunologists and other specialists in their diagnosis and management of these rare and complex patients.

Do elevated serum IgM levels have to be included in probable diagnosis criteria of patients with ataxia-telangiectasia?

Ataxia-telangiectasia (AT) is a rare multisystem, neurodegenerative genetic disorder that is characterised by progressive neurological abnormalities, oculocutaneous telangiectasias and immunodeficiency. Delay in diagnosis or misdiagnosis is probable due to its wide clinical heterogeneity in infancy. Recurrent sinopulmonary infections are often the only presenting symptom and usually patients have decreased immunoglobulins. A total 10% of patients who present with decreased serum immunoglobulin G and A and with normal or elevated immunoglobulin M levels are often misdiagnosed as hyperimmunoglobulin M syndrome. Definitive diagnosis is made if a patient with progressive cerebellar ataxia has a disease causing mutation on the ATM gene. Ataxia-telangiectasia guideline of the European Society for Immunodeficiencies defines the probable diagnosis criteria. We evaluated twenty ataxia-telangiectasia patients (mean age 13.8±4.1 years) retrospectively who were followed-up for a mean of 38.6±27.0 months. Twelve patients had a family history of consanguinity. A total of 80% patients suffered from various infections. Neoplasms occurred in three of them. Patients showed immunological abnormalities as low IgG (45%), low IgA (65%) and elevated IgM (60%) levels. CD3+CD4+ T lymphocyte frequency was low in 45% patients. The mean AFP concentration at the diagnosis was 191.9±140.1 ng/mL and the raised IgM values did not show any statistically significant relationship with high AFP concentrations. Frequency of the elevated IgM concentrations in (60%) patients raises the concerns about thinking this finding has to be accepted as a probable diagnosis criterium.

Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients.

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re-examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long-term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post-splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second-line management of autoimmune cytopenia in CVID.

Hyper-immunoglobulin M syndrome type 3 with normal CD40 cell surface expression.

Mutations of the CD40 gene have been found in patients with autosomal recessive hyper-immunoglobulin M (HIGM) syndrome type 3. Five patients from four unrelated families with CD40 mutation have been reported so far. Clinical manifestations include recurrent sinopulmonary infections, Pneumocystis carinii pneumonia and Cryptosporidium parvum infection. Affected patients typically have very low levels of IgG and IgA and normal or high levels of IgM. Flow cytometry analysis of these five patients demonstrated that peripheral blood B lymphocytes lacked expression of surface CD40. Herein, we present two siblings from second-degree consanguineous Turkish parents with homozygous CD40 deletion of four nucleotides including the stop codon resulting presumably to a longer protein. Clinical and immunological profile of these patients is similar to the already reported HIGM3 patients except normal CD40 expression on B lymphocytes. This observation emphasizes the requirement of CD40 mutation analysis for definite diagnosis of HIGM3 despite normal flow cytometric expression of CD40, particularly if the immunological and clinical profile is suggestive for HIGM3.

IgG-anti-IgA antibodies: an autoimmune finding in patients with psoriasis vulgaris.

AIM: Psoriasis is thought to be an autoimmune disease caused by inappropriate activation of the cellular immune system. In this study, we aimed to search out IgG-anti-IgA antibody levels, serum immunoglobulins and antinuclear antibodies (ANA). METHODS: The study enrolled 38 psoriasis vulgaris patients and 40 healthy controls. RESULTS: Mean IgG-anti-IgA levels were significantly higher in psoriasis patients. The frequency of positive ANA testing was 21.1%; however, there was no correlation between IgG-anti-IgA antibody levels and ANA positivity. Only one patient had low IgA levels without high IgG-anti-IgA concentrations. CONCLUSION: The data about high IgG-anti-IgA antibody levels are noteworthy for a new evidence of autoimmune mechanism.

A novel Y331X nonsense mutation in TNFRSF1A gene in two unrelated Turkish families with periodic fever syndrome.

The autoinflammatory disorders differ in severity, as well as age of onset, duration, and manifestations, but they all share some common features: recurring fever peaks, inflammation of serosal membranes, musculoskeletal involvement, varying types of skin rash, amyloidosis as a sequel of the disease. TRAPS is very rare in Turkish population and we present two unrelated Turkish children with similar clinical phenotypes and laboratory findings related with autoinflammatory disorders and with novel p. Y331X mutation in TNFRSF1A gene. Both of the patients were male and they had recurrent fever without abdominal pain and arthralgia. Full cDNA and exon-intron binding regions of TNFRSF1A, MEFV, MVK, CIAS1 genes were analysed by direct DNA sequencing methods in order to differentiate TRAPS, FMF, HIDS, CINCA/MWS/FCAS respectively. We screened ten exons of TNFRSF1A gene, and detected a heterozygous c.1080C>G nucleotide substitution in exon 10 in both of the unrelated patients, resulting p.Y360X nonsense (protein truncated) mutation. According to classical TNFRSF1A gene nomenclature and the agreement of 30th amino acid as the first one, it is accepted as p.Y331X. It was interesting to determine same mutations in fathers of two patients. In one of the cases, E148Q heterozygous mutation, which is one of the disease-causing mutations of MEFV gene, was detected. No nucleotide substitution was identified in exon and exon-intron splicing regions encoding 396 amino acid of MVK gene in both of the patients. In CIAS1 gene, two different nucleotide substitutions resulting synonymous amino acid mutation were detected in exon 3: c.[732G>A] and c.[786A>G] nucleotide substitutions and compatible p.A242A (according to c.DNA p.A244A) and p.R260R (according to c.DNA p.R262R) synonymous amino acid mutations. These nucleotide substitutions were also detected in parents and were reported to be normal variations in Turkish population. In conclusion, in Turkish patients, with dominantly inherited recurrent fever, TRAPS is a diagnosis worthy of attention and novel mutations have to be reported with phenotype associations.

Determination of cut-off titers and agreement between immunofluorescence and immunoblotting methods for detecting antinuclear antibodies in children.

Detection of antinuclear antibodies (ANA) is a diagnostic adjunct in patients with suspected autoimmune connective tissue diseases, and various detection methods are in use. The aim of this study was to analyze the agreement between the ANA immunoflourescence (IF) and immunoblotting (IB) methods and determine cut-off for children subjects in a laboratory setting. We evaluated 729 serum samples that were analyzed by both ANA IF and IB. The results were evaluated by chi(2) test and, for agreement, kappa index was used. Frequencies determined for both 1:40-1:100 cut-off titers of ANA IF in relation to IB testing supported the idea that 1:100 starting dilution should be recommended in children subjects for ANA IF method and antigen specific immunoblot testing was needed, especially for some of the ANA IF negative samples. Agreement between the two methods, especially with homogenous, granular, and nucleolar ANA IF patterns, was statistically significant.

The effect of adjunctive chlorhexidine mouthrinse on clinical parameters and gingival crevicular fluid cytokine levels in untreated plaque-associated gingivitis.

OBJECTIVE AND DESIGN: To examine the effectiveness of chlorhexidine mouthrinse (CHX) in addition to daily plaque control on gingival inflammation. METHODS: Fifty gingivitis patients were randomized to CHX or placebo groups. In addition to proper plaque control, CHX group rinsed with CHX, while placebo group rinsed with placebo mouthrinse for 4 weeks. Gingival crevicular fluid (GCF) samples were collected and clinical parameters including plaque index (PI), papillary bleeding index (PBI), calculus index and probing depth (PD) were recorded at baseline and repeated at 4 week. GCF IL-1alpha, IL-1beta, IL-1Ra, and IL-8 levels were determined by ELISA. RESULTS: Whole mouth clinical parameters were significantly improved in both groups at 4 weeks. CHX group showed greater reduction in the mean PI scores than placebo at 4 weeks (p < 0.05). GCF IL-8 levels of anterior sites significantly reduced in CHX and placebo group at 4 weeks (p < 0.05). GCF IL-1alpha, IL-1beta, IL-1Ra levels remained unchanged at 4 weeks in both groups. GCF cytokine levels of CHX group were similar to those of placebo at 4 weeks. CONCLUSIONS: Within the limitations of this study, CHX mouthrinse as adjuncts to daily plaque control could be useful in management of plaque-associated gingivitis, although ineffective on GCF cytokine levels.

Renal involvement as a rare complication of Dorfman-Chanarin syndrome: a case report.

Dorfman-Chanarin syndrome is a rare, autosomal recessive inherited lipid storage disease with congenital ichthyotic erythroderma due to an acylglycerol recycling defect. It is characterized by accumulation of neutral lipids in different tissues. Liver, muscle, ear, eye, and central nervous system are generally involved, so we presented a patient with severe ichthyosis, lipid vacuoles in neutrophils, and multiorgan involvement including a very rare complication, renal involvement. A 7-month-old girl was presented with frequent respiratory infection, congenital ichthyotic erithroderma and suspicion for immune deficiency. On her physical examination hepatomegaly, developmental delay, palmar and plantar hyperkeratosis and increased deep tendon reflexes with clonus and high tonus were found. Laboratory investigations revealed elevation at transaminases levels, hypoalbuminemia, hypergammaglobulinemia, presence of autoantibodies and eosinophilia. Vacuolization in leukocytes confirmed Dorfman-Chanarin syndrome, whereas no mutation at RAG1-2 and ARTEMIS genes ruled-out immune deficient status of the patient. At the age of eight months the patient died from severe renal failure. Her necropsies demonstrated microvesicular lipid accumulation not only at the liver but also at the renal species. The variability of involvement of different systems in Dorfman-Chanarin syndrome is well described, however the renal findings has not been reported previously at the literature.

Fc gamma RIIa, IIIa and IIIb polymorphisms in Turkish children susceptible to recurrent infectious diseases.

The efficacy of IgG-induced Fc gamma receptor (FcgammaR) function displays interindividual heterogeneity due to genetic polymorphisms of three FcgammaR subclasses: FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb. FcgammaR polymorphisms may contribute to disease susceptibility or may alter disease course. The aim of this study is to examine FcgammaR gene polymorphisms in Turkish children with recurrent respiratory tract infections and without well known humoral immunodeficiencies. For the patients in the study group (n=52), recurrent infection was defined as the presence of at least six infection episodes a year. Seventy-one healthy children with a maximum of two infections in a year were enrolled as the control group. Subjects in both groups had no abnormalities in serum immunoglobulins, IgG subsets and specific antibody levels. For FcgammaRIIa: H131H, H131R, R131R genotypes and 131R, 131H alleles; for FcgammaRIIIa: F158F, F158V, V158V genotypes and 158F, 158V alleles; and for FcgammaRIIIb: -NA1/NA1, NA1/NA2, NA2/NA2 genotypes and NA1, NA2 alleles were determined by using amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Compared with the control group, the FcgammaRIIa-R131R genotype and 131R allele were found to be significantly elevated in the study group, and FcgammaRIIa-H131H genotype and 131H allele in the study group were significantly lower than in the control group. Genotypes and alleles related with FcgammaRIIIa and FcgammaRIIIb gene polymorphisms did not show any significant difference between the study and control groups. FcgammaRIIa gene polymorphism (R131R) may increase the risk and susceptibility for recurrent infectious diseases in children.

The value of posttransplant monitoring of interleukin (IL)-2, IL-3, IL-4, IL-6, IL-8, and soluble CD23 in the plasma of renal allograft recipients.

Over the past few years, the central role of cytokines in the amplification of the immune response has been reported and several studies have examined the relationship between the plasma level of individual lymphokines during renal allograft rejection. The aim of the present investigation was to study simultaneously IL-2, IL-3, IL-4, IL-6, IL-8, and soluble CD23. Analysis of results has allowed both the prognostic value and any possible interrelationships between the measured cytokines to be determined. We studied 16 renal transplant recipients for the first 14 days after transplantation. Seven patients showed clinical evidence of acute allograft rejection and 5 showed excellent stable graft function with no signs of rejection. Primary nonfunction was seen in 4 patients. The plasma levels of each cytokine were measured by commercially available ELISA and immunoradiometric assay kits. As reported in previous studies, plasma IL-2 levels, whenever found at detectable levels, were predictive of impending graft rejection. Serial monitoring of IL-4 and IL-6 was more reliable for the differential diagnosis of rejection, particularly toward the end of the first week after transplantation. IL-3, IL-8, and soluble CD23 were not diagnostic or predictive of rejection, due to the occurrence of significantly high levels in transplant patients who showed no evidence of clinical rejection. While the value of cytokine monitoring has been shown in this study, it should be remembered that infection, although not seen in these studies, may have a profound affect on the results obtained.

Plasma and synovial fluid soluble CD23 concentrations in children with juvenile chronic arthritis.

Since increased levels of sCD23 were demonstrated in patients with autoimmune diseases, plasma and synovial fluid sCD23 levels were examined in 22 patients with juvenile chronic arthritis (JCA) and in 10 children undergoing arthrocentesis for orthopedic disorders. There was no significant difference in plasma sCD23 concentrations between patients with pauciarticular and polyarticular onset. Plasma and synovial fluid sCD23 concentrations were found to be significantly increased in JCA patients as compared to controls. However, plasma sCD23 levels were not positively correlated with laboratory parameters showing disease activity such as erythrocyte sedimentation rate, C-reactive protein, serum IgG and IgA. It was concluded that increased production of sCD23 in peripheral blood and synovial fluid might be important in the pathogenesis of JCA. However, determination of this immunological parameter provides no useful clinical information about disease activity and management.

Mycobacterium fortuitum-chelonae complex infection in a child with complete interleukin-12 receptor beta 1 deficiency.

A 10-year-old boy had chronic diarrhea, abdominal pain, severe weight loss and hepatomegaly; multiple enlarged para-aortic and mesenteric lymph nodes. Mycobacterium fortuitum-chelonae complex was identified in the culture of the lymph nodes. Interleukin-12 receptor beta 1 expression could not be observed in phytohemagglutinin-driven T cell blasts. A homozygous missense interleukin-12 receptor beta 1 mutation was found (R173P).

Anticardiolipin antibodies in acute rheumatic fever and chronic rheumatic heart disease: is there a significant association?

OBJECTIVE: The incidence and significance of IgG and IgM anticardiolipin antibodies (aCLa) in patients with acute rheumatic fever (ARF), chronic rheumatic heart disease (CRHD) and streptococcal pharyngitis have been investigated in order to determine whether these antibodies play an important role in the pathogenesis and if they are markers that can be used to confirm disease activity. METHODS: An enzyme-linked immunosorbent assay was used to measure the IgG and IgM aCLa levels. aCLa levels of patients were considered positive if they were greater than 3.0 standard deviations above the mean for healthy children. RESULTS: No significant difference in aCLa levels was found between patients with rheumatic fever or streptococcal pharyngitis and healthy controls, and aCLa concentrations did not correlate with the acute phase reactant levels. CONCLUSIONS: aCLa in patients with ARF and CRHD do not appear to be markers of disease activity, and our data suggest that aCLa do not play an important role in the pathogenesis of rheumatic fever.

Immune status and autoantibody formation in children with chronic hepatitis B infection.

BACKGROUND: The hepatitis B virus (HBV) causes a wide spectrum of disease which ranges from acute hepatitis to liver cirrhosis. Patients who fail to mount a vigorous immune response in acute HBV develop chronic infection. Therefore, the aim of the study was to determine the cellular and humoral immune parameters of the patients with chronic HBV and to evaluate the prevalence of autoantibodies before the beginning of immunomodulator and antiviral therapy. METHODS: In this comparative study, serum immunoglobulins, IgG subclasses, secretory IgA, serum complement components, lymphocyte subsets and CD11a, CD18, CD54 molecules on lymphocytes were determined in 44 hospitalized patients of chronic HBV infection and 20 cases of healthy control subjects. RESULTS: Significant increase in IgG and significant decrease in the complement C4 were observed. The mean percentage of CD3+ lymphocytes, reflecting the percentage of total T cells was significantly higher in the patient group due to the increase of CD8+ lymphocytes. The mean percentage of CD19+ B lymphocytes was lower in the patient group secondary to the increase of their total T cells. No significant difference was found in cell surface adhesion molecules between patient and control groups. The percentage of antinuclear antibody positivity was 18.2%. CONCLUSIONS: Our data show that ANA formation is part of the natural course of chronic HBV infection and this value may reflect the tendency to autoimmune diseases and the importance of clinical follow-up. The abnormalities observed in immunological parameters may reflect the role of the cellular and humoral immune system in pathogenesis.

Idiopathic CD4+ T cell lymphocytopenia with the absence of B cells and CD8+28+ cells in peripheral blood.

The absence of B cells and a severe decrease in CD8+28+ cells were observed in two female children with CD4+ T cell lymphocytopenia. Idiopathic (primary) CD4+ lymphocytopenia is a rare entity and its pathogenesis and genetics are not yet known. The literature was reviewed, in particular for severe alterations in B and CD8+28+ cells and for the role of NF-kappa B and p56 (lck) in the immunopathogenesis. Whether the underlying mechanism in idiopathic CD4+ lymphocytopenia is found or not, these patients who present with severe symptoms of a combined immunodeficiency must be treated with intravenous immunoglobin regularly until they have a compatible donor for bone marrow transplantation.

Lymphocyte subsets and inflammatory mediators in patients with subacute sclerosing panencephalitis.

A defective cell-mediated immunity and inflammatory cytokines are suggested in the pathogenesis of subacute sclerosing panencephalitis. In this study we analyzed lymphocyte subsets in peripheral blood and concentrations of interleukin-1alpha (IL-1alpha), interleukin-2 (IL-2alpha), tumor necrosis factor-alpha (TNF-alpha), and platelet activating factor in plasma and cerebrospinal fluid before and after immunomodulatory therapy (interferon-alpha plus isoprinosine) in three patients with subacute sclerosing panencephalitis. Increased percentage of CD8+cells (T-suppressor/cytotoxic cell) and CD16+CD56+cells (NK cell) and reduced percentage of CD3+/HLA-DR+ (active T-cell) and CD3+ (total T-cell) cells were found before therapy. After immunomodulatory therapy, CD3+/HLA-DR+ (active T-cell) cells were markedly increased and there was a slight increase in the percentages of all lymphocyte subsets in the patients. The concentrations of platelet activating factor in plasma and cerebrospinal fluid were higher than the mean value in controls. Cerebrospinal fluid and plasma TNF-alpha and IL-2 levels were nondetectable in two patients who had a stationary course of disease and were markedly elevated in patient 3, who displayed a rapidly progressive course.

Crevicular fluid interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6 levels in renal transplant patients receiving cyclosporine A.

Cyclosporine A(CsA) is successfully used to prevent graft rejection in organ transplantation and in the treatment of various systemic diseases. CsA-induced gingival overgrowth (CsA GO) is one of the most important side effects of this drug. However, the pathogenesis of this side effect is still unclear. It has been postulated that CsA-induced alterations of cytokine levels in gingival tissues might play a role in the drug-induced gingival overgrowth. The purpose of the present study was to determine the levels of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and IL-6 in gingival crevicular fluid (GCF) samples from renal transplant patients receiving CsA therapy and exhibiting CsA GO. Sixteen renal transplant patients receiving CsA, 12 patients with gingivitis, and 11 periodontally healthy subjects were included in this study. Data were obtained on plaque index, papilla bleeding index (PBI), and hyperplastic index from each study site. GCF samples and clinical data were obtained from: 1) 2 sites exhibiting CsA GO (CsA GO+) and 2 sites not exhibiting CsA GO (CsA GO-) in each CsA-treated patient; 2) diseased sites in each patient with gingivitis; and 3) 2 healthy sites in each subject with clinically healthy periodontium. CsA GO+ and CsA GO- sites were also divided into 2 subgroups as clinically uninflamed (PBI = 0) and inflamed (PBI > or = 1). The total amounts of cytokines in GCF were assayed by enzyme-linked immunosorbent assay. GCF IL-1beta levels were significantly higher in CsA GO+ sites compared to CsA GO-sites. Higher GCF levels of IL-1beta and IL-6 were detected in diseased sites compared to healthy sites. Although GCF IL-1beta levels in CsA GO+ sites were significantly higher than in the diseased sites, IL-6 levels of these sites were lower than in the diseased sites, whereas clinical degrees of gingival inflammation were similar in CsA GO+ and diseased sites. Additionally, while IL-1beta and IL-6 levels were similar in uninflamed CsA GO- sites and healthy sites, IL-1beta levels were significantly higher in uninflamed CsA GO+ sites compared to healthy sites and uninflamed CsA GO- sites. However, IL-1beta and IL-6 levels were significantly higher in inflamed CsA GO- sites compared to uninflamed CsA GO+ sites. No significant changes in GCF TNF-alpha levels were found between the groups. These data indicate that CsA therapy does not increase IL-1beta and IL-6 levels in GCF directly and that gingival inflammation plays a significant role in the elevation of GCF IL-1beta and IL-6 levels. For this reason, it is suggested that the alterations of GCF IL-1beta and IL-6 levels in CsA-treated patients might be responsible for the CsA-induced gingival overgrowth not by itself but also in combination with other factors associated with inflammation. To our knowledge, this is the first report describing the levels of cytokines in GCF of CsA-treated patients. We believe that further studies will contribute to the description of the pathogenesis of CsA-induced gingival overgrowth.