Inflammasomes and autoimmune and rheumatic diseases: A comprehensive review.
Shin Jae Il,Lee Keum Hwa,Joo Yo Han,Lee Jiwon M,Jeon Jaewook,Jung Hee Jae,Shin Minkyue,Cho Seobum,Kim Tae Hwan,Park Seonghyuk,Jeon Bong Yeol,Jeong Hyunwoo,Lee Kangto,Kang Kyutae,Oh Myungsuk,Lee Hansang,Lee Seungchul,Kwon Yeji,Oh Geun Ho,Kronbichler Andreas
Journal of autoimmunity
Inflammasomes are a multi-protein platform forming a part of the innate immune system. Inflammasomes are at standby status and can be activated when needed. Inflammasome activation is an important mechanism for the production of active interleukin (IL)-1β and IL-18, which have important roles to instruct adaptive immunity. Active forms of inflammasomes trigger a series of inflammatory cascades and lead to the differentiation and polarization of naïve T cells and secretion of various cytokines, which can induce various kinds of autoimmune and rheumatic diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), gout, Sjögren's syndrome, Behçet's disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and IgA vasculitis (former Henoch-Schönlein purpura ). In this review, we summarize studies published on inflammasomes and review their roles in various autoimmune diseases. Understanding of the role of inflammasomes may facilitate the diagnosis of autoimmune diseases and the development of tailored therapies in the future.
Clinical significance of the serum biomarker index detection in children with Henoch-Schonlein purpura.
Purevdorj Narangerel,Mu Yun,Gu Yajun,Zheng Fang,Wang Ran,Yu Jinwei,Sun Xuguo
OBJECTIVE:To explore a panel of serum biomarkers for laboratory diagnosis of pediatric Henoch-Schönlein purpura (HSP). METHODS:The blood white blood cells (WBC) and serum levels of serum amyloid A (SAA), interleukin 6 (IL-6), immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin E (IgE), C-reactive protein (CRP), complement component 3 (C3), complement component 4 (C4), and ASO (anti-streptolysin O) were detected in 127 patients with Henoch-Schonlein purpura (HSP), 110 cases of septicemia patients, and 121 healthy volunteers. The diagnostic ability of biomarkers selected from HSP and septicemia patients was analyzed by ROC curve. By designing the calculation model, the biomarker index was calculated for laboratory diagnosis of HSP and differential diagnosis between HSP and septicemia. RESULTS:The levels of serum WBC, CRP, IL-6 and SAA in the septicemia patients were significantly higher than those in the control group (p<0.05). Compared with the healthy individuals, serum levels of WBC, CRP, IL-6, SAA, IgA and IgM were significantly increased in patients with HSP (p<0.05). The area under the curve (AUC) of SAA, IgA, IgM, WBC, IL-6, and CRP in the patients with HSP was 0.964, 0.855, 0.849, 0.787, 0.765, and 0.622, respectively. The values of SAA, IgA, IgM, WBC, IL-6, and CRP in septicemia patients were 0.700, 0.428, 0.689, 0.682, 0.891, and 0.853, respectively. Biomarker index=SAA+IgA/4000+IgM/4000×0.4CRPmean valueCRPi The biomarker index in HSP patients was significantly higher than that of the healthy controls. However, the biomarker index in septicemia patients was significantly lower than the control. CONCLUSION:The biomarker index of HSP patients is higher than that of the control group. While in the infectious disease represented by septicemia, it is decreased. The detection of biomarker index could exclude the interference of infection as the auxiliary examination to HSP patients.
Factor XIII deficiency in Henoch-Schönlein purpura - report on two cases and literature review.
Hogendorf Anna,Młynarski Wojciech
Developmental period medicine
Factor XIII (FXIII) deficiency is a rare, inherited or acquired coagulation disorder that potentially precipitates fatal haemorrhage. We report two consecutive pediatric patients with Henoch-Schönlein purpura (HSP) and symptomatic decrease in FXIII. The possible FXIII deficiency should be kept in mind by every doctor taking care of patients with HSP, in spite of normal value of routine coagulation tests.
Acute renal insufficiency and pancreatitis in a child with atypical Henoch-Schönlein purpura: efficacy of a single dose of cyclophosphamide.
Cristina Maggio Maria,Maringhini Silvio,Sabrina Ragusa Saveria,Corsello Giovanni
The Journal of international medical research
A 9-year-old boy with petechiae on the legs and abdominal pain was unsuccessfully treated with steroids. He was admitted to our hospital for the onset of fever, ecchymosis, and arthralgia. Skin lesions suggested vasculitis, but they were not typical of Henoch-Schönlein purpura. He showed ecchymosis of the scrotal bursa, diffusion of petechiae to the trunk and arms, vomiting, severe abdominal pain, oliguria with hyponatremia, hypoalbuminemia, low C3 levels, high levels of creatinine, blood urea nitrogen, and tubular enzymes, proteinuria, and glycosuria. The urinary sediment showed macrohaematuria, and hyaline and cellular casts. Ultrasound showed polyserositis. He was treated with intravenous furosemide, albumin, and methylprednisolone. He underwent colonoscopy and gastroscopy because of development of acute pancreatitis and severe anaemia. Typical lesions of Henoch-Schönlein purpura were observed in the small intestine and colon mucosa. He received three high doses of methylprednisolone, followed by intravenous cyclophosphamide. A dramatic and persistent response was observed after these doses. A single high dose of cyclophosphamide is appropriate in Henoch-Schönlein purpura with acute renal failure and severe pancreatitis that are non-responsive to high-dose steroids.
Therapeutic advances in the treatment of vasculitis.
Eleftheriou Despina,Brogan Paul A
Pediatric rheumatology online journal
Considerable therapeutic advances for the treatment of vasculitis of the young have been made in the past 10 years, including the development of outcome measures that facilitate clinical trial design. Notably, these include: a recognition that some patients with Kawasaki Disease require corticosteroids as primary treatment combined with IVIG; implementation of rare disease trial design for polyarteritis nodosa to deliver the first randomised controlled trial for children; first clinical trials involving children for anti-neutrophil cytoplasmic antibody (ANCA) vasculitis; and identification of monogenic forms of vasculitis that provide an understanding of pathogenesis, thus facilitating more targeted treatment. Robust randomised controlled trials for Henoch Schönlein Purpura nephritis and Takayasu arteritis are needed; there is also an over-arching need for trials examining new agents that facilitate corticosteroid sparing, of particular importance in the paediatric population since glucocorticoid toxicity is a major concern.
Vasculitis in childhood – a dermatological approach.
Sandrine Benoit,Goebeler Matthias
Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG
Vasculitis, an inflammatory condition affecting the blood vessels, may be restricted to a single organ or involve several organ systems. The size of the involved vessels is an important criterion for categorization of vasculitides, which is a prerequisite for rapid diagnosis and initiation of treatment. In pediatric patients, this particularly applies to Kawasaki disease. However, making the diagnosis can be challenging for dermatologists as skin involvement may be variable and non-specific. In contrast, Henoch-Schönlein purpura (IgA vasculitis) presents with the classic picture of palpable purpura. It predominantly affects postcapillary venules frequently following upper respiratory tract infections. Severe organ involvement is relatively rare in children and the prognosis is good. As renal involvement may occur during the course of disease, continuous monitoring is required. Acute hemorrhagic edema of infancy is considered as a distinct type of immune complex vasculitis and is characterized by a triad of fever, edema and rosette-shaped purpura. The clinical course of this rare disease is usually benign and self-limited. Due to the variability of clinical symptoms and manifestations, management of childhood vasculitides represents a special challenge requiring interdisciplinary collaboration. Dermatologists should be aware of their important role especially for making an early diagnosis.
Familial Henoch-Schönlein Syndrome.
Ostini Alessandro,Simonetti Giacomo D,Pellanda Giorgia,Bianchetti Mario G,Ferrarini Alessandra,Milani Gregorio P
Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases
Little attention has been so far paid to familial cases of Henoch-Schönlein syndrome. We performed a search of the Medical Subject Headings terms (Henoch or Schönlein OR anaphylactoid purpura OR IgA nephropathy OR Berger nephropathy) AND (family OR familial). We identified no more than 19 reports including 47 families with a total of 100 affected cases: their ages ranged from 1.3 to 51 years (median, 11 years), with a male-to-female ratio of 1.4. Familial cases developed simultaneously in 45% and nonsimultaneously in 55% of the families. Age, male-to-female ratio, and clinical findings were not statistically different in cases with simultaneous and nonsimultaneous familial occurrence of Henoch-Schönlein syndrome. Henoch-Schönlein syndrome occurs almost always sporadically. Age at presentation, male-to-female ratio, and findings are similar in familial (both simultaneously and nonsimultaneously occurring) and sporadic Henoch-Schönlein cases.
Hemorrhagic bullous lesions in Henoch-Schönlein purpura: a case report and review of the literature.
Su Hung-Wen,Chen Chiu-Yu,Chiou Yee-Hsuan
BACKGROUND:Henoch-Schönlein purpura (HSP) is a common vasculitis in childhood characterized by purpura, arthritis, abdominal pain and renal involvement. However, bullous HSP is a rare cutaneous manifestation, and a few cases have been reported. CASE PRESENTATION:Herein, we report a 15-year-old male with bullous HSP who presented with severe abdominal pain and hemorrhagic bullous lesions over his lower extremities. He was treated with corticosteroid, after which the symptoms improved dramatically. No recurrence was noted after follow-up, though scarring was present. We also reviewed the literature related to bullous HSP and identified 39 cases, most of whom were treated with corticosteroids. CONCLUSION:Clinicians should be aware of the atypical types of HSP, including bullous HSP. Most patients with bullous HSP have a good prognosis.
IgA Cutaneous Purpura Post-Renal Transplantation in a Patient With Long-Standing IgA Nephropathy: Case Report and Literature Review.
Sotoodian Bahman,Robert Janet,Mahmood Muhammad N,Yacyshyn Elaine
Journal of cutaneous medicine and surgery
BACKGROUND:IgA vasculitis is a small-vessel vasculitis caused by deposition of IgA antibodies in tissues. IgA nephropathy and IgAV have long been considered related conditions. OBJECTIVE:To assess the prevalence and implications of new-onset Henoch-Schönlein purpura (HSP) after renal transplant in patients with underlying IgA nephropathy. METHODS:The PubMed database was searched for keywords such as IgAV, IgA vasculitis, Henoch-Schönlein purpura, HSP, IgA nephropathy, and renal transplant. RESULTS:Two cases of new-onset IgA vasculitis post-renal transplant after stopping the prednisone or receiving seasonal influenza vaccine have been reported. We report the case of new-onset IgA cutaneous vasculitis in a renal transplant patient with IgA nephropathy after reduction in his prednisone dosage. CONCLUSION:The new development of cutaneous IgA vasculitis is unusual in renal transplant patients with IgA nephropathy. Despite these patients' being immunosuppressed, the presence of IgA vasculitis could signal the recurrence of IgA nephropathy.
Azathioprine therapy for steroid-resistant Henoch-Schönlein purpura: a report of 6 cases.
Fotis Lampros,Tuttle Paul V,Baszis Kevin W,Pepmueller Peri H,Moore Terry L,White Andrew J
Pediatric rheumatology online journal
BACKGROUND:A small percentage of children with Henoch-Schönlein purpura (HSP) develop a chronic form of the disease that often requires prolonged corticosteroid therapy. Disease modifying anti-rheumatic agents (DMARDs) or biologics have been successfully used to treat those refractory cases. Azathioprine is a DMARD that has been reported to be effective in HSP nephritis and in adult cutaneous leukocytoclastic vasculitis, a condition with cutaneous histology similar to HSP. CASE PRESENTATION:A description of 6 cases with relapsing HSP without significant renal involvement, treated with azathioprine are reported. All 6 cases met the classification criteria for the diagnosis of HSP, had relapsing symptoms despite corticosteroid use, were successfully treated with azathioprine and were tapered off of corticosteroids. The duration of azathioprine therapy ranged from 7-21 months and no adverse events were reported. CONCLUSIONS:Azathioprine is effective in controlling prolonged relapsing symptoms of HSP, allowing earlier discontinuation of corticosteroids. This report shows that azathioprine can be included in the therapeutic options for relapsing HSP and is the first case series in the literature of azathioprine use in HSP without significant renal involvement.
Unusual presentation of Henöch-Schonlein purpura.
Brodie Andrew,G Natasha,Nitiahpapand Rynda,Chowoo Liaqat
BMJ case reports
We present a rare case of a 4-year-old boy with newly diagnosed Henöch-Schonlein purpura (HSP) affecting the scrotum and penis. The patient presented to the emergency department with palpable purpura symmetrically distributed over the lower limbs. This was associated with arthritis of the right knee, abdominal pain and scrotal swelling. These symptoms were preceded by an upper respiratory tract infection (URTI). The patient was initially treated with empirical oral antibiotics for epididymitis and was discharged. He subsequently re-presented 12 days later with penile swelling, erythema and tenderness. An ultrasound scan of the penis revealed grossly oedematous subcutaneous tissue with normal penile architecture. His symptoms resolved spontaneously and the patient remains under close follow-up by the paediatric team for further sequelae of HSP.
Rabies post-exposure prophylaxis for a male with severe Henoch Schönlein purpura following rabies vaccination.
Zhu Zheng-Gang,Zheng Yi,Lu Sha,Hu Quan,Fang Yuan
Human vaccines & immunotherapeutics
Henoch Schönlein purpura (HSP) following vaccine administration has been described in case reports and in a small number of observational studies. We herein reported a case of HSP occurring in an otherwise healthy 37-year-old male after immunization with lyophilized purified vero cell rabies vaccine (PVRV). After the anti-allergy therapy with hormone, the purpuric lesions gradually disappeared. After evaluating, another PVRV with different dose (0.5 ml), strains, excipient and without residues was chosen for the new anti-rabies immunization program, and the patient has had no recurrence of allergic symptoms. Although significant lower than the levels of normal 20-50 year population at day 21, the neutralizing antibody (RVNA) titers of this boy showed adequate protective antibody (3.23 vs 7.15 IU/ml). This case report emphasizes the importance that clinicians should be aware of HSP as a potential adverse event associated with PVRV vaccination. And adverse events (AEs) after immunization should be carefully treated, changing immunization program in time is necessary. While enrolling a new anti-rabies immunization program, the properties of different rabies vaccines taking with special emphasis on strains, excipient and residues is imperative before vaccination so that an appropriate immune program can be managed to be initiated.
Cyclosporine A vs. methylprednisolone for Henoch-Schönlein nephritis: a randomized trial.
Jauhola Outi,Ronkainen Jaana,Autio-Harmainen Helena,Koskimies Olli,Ala-Houhala Marja,Arikoski Pekka,Hölttä Tuula,Jahnukainen Timo,Rajantie Jukka,Ormälä Timo,Nuutinen Matti
Pediatric nephrology (Berlin, Germany)
Knowledge about how to treat severe Henoch-Schönlein nephritis (HSN) is scarce. The aim of our study is to compare cyclosporine A (CyA) and methylprednisolone pulses (MP) in the treatment of severe HSN. Out of 24 pediatric HSN patients with nephrotic-range proteinuria or crescentic HSN in kidney biopsy, seven were randomized to receive CyA for 12 months at an initial dose of 5 mg/kg and eight to receive 3 MP pulses of 30 mg/kg followed by prednisone for 4 months. The other nine patients received identical treatment without randomization. Kidney biopsies were performed at inclusion and after 2 years. The primary outcomes were the duration of proteinuria and hematuria, estimated glomerular filtration rate, and renal biopsy histology. All the 11 CyA-treated patients achieved resolution of nephrotic-range proteinuria within 3 months, while the MP-group response was slower, and in 6/13 was not achieved with the initial treatment. Additional immunosuppressive treatment was needed in none of the CyA-treated patients but in six patients treated with MP (difference in proportion 46%, p = 0.008). The 2-year control biopsies were similarly improved in both groups. After mean 6.1 years (2.2-10.4 years), 16 patients (eight CyA, eight MP) had no renal symptoms and six (three CyA, three MP) had persistent nephropathy but normal renal function. One MP-treated patient had reduced renal function and another had developed ESRD and received a renal transplant. CyA gave a 100% resolution of nephrotic-range proteinuria and a 100% renal survival rate without additional therapy after a mean follow-up of 6 years. Treatment of HSN with CyA is efficacious, safe and not inferior to MP.
MicroRNA expression in the affected skin of adult patients with IgA vasculitis.
Hočevar Alojzija,Tomšič Matija,Pižem Jože,Bolha Luka,Sodin-Šemrl Snežna,Glavač Damjan
IgA vasculitis (IgAV) represents a common systemic vasculitis in pediatric and adult population. Our current knowledge of disease pathogenesis is still very limited, without information on miRNAs in IgAV. The aim of our study was to determine the expression of five pre-selected miRNAs (miRNA-146a-5p, miRNA-148-3p, miRNA-155-5p, miRNA-223-3p, and let-7b) in the affected skin of adult IgAV patients. The study included 65 skin samples from consecutive, untreated IgAV patients (61.5% male, median age 67.6 years, range 29-91), diagnosed between October 2014 and September 2016, and 20 samples of normal skin from healthy volunteers. Total RNA was isolated from tissue sections of formalin-fixed, paraffin-embedded samples. Expression of miRNAs was measured using qRT-PCR. To present relative miRNA expression, the ΔΔCT method was used. Skin miRNA expression was correlated to clinical characteristics of adult IgAV patients. We found significantly higher levels of miRNA-155-5p, miRNA-223-3p, and let-7b in the affected skin compared to controls (18.6-fold, 6.4-fold, and 7.9-fold higher respectively). Contrary, the miRNA 148-3p expression was significantly lower (2.2-fold). The expression of the miRNA-146-5p showed near normal levels. Patients with necrotic skin lesions had significantly higher miRNA-223 tissue expression than those with non-necrotic purpura (p = 0.029). Gastrointestinal tract involvement inversely correlated with the expression of miRNA-155-5p and/or miRNA-146a-5p in affected skin. Altered expression of miRNA-148b-3p, miRNA-155-5p, miRNA-223-3p, and let-7b was found in vasculitic skin lesions in IgAV. Additionally, we found a positive association between the severity of purpura and skin miRNA-223-3p expression. Aberrantly expressed miRNAs could represent a biomarker in adult IgAV.
Brief Report: Rituximab for the Treatment of Adult-Onset IgA Vasculitis (Henoch-Schönlein).
Maritati Federica,Fenoglio Roberta,Pillebout Evangeline,Emmi Giacomo,Urban Maria L,Rocco Rossana,Nicastro Maria,Incerti Monia,Goldoni Matteo,Trivioli Giorgio,Silvestri Elena,Mohammad Aladdin J,Jayne David,Eriksson Per,Segelmark Mårten,Novikov Pavel,Harris Helen,Roccatello Dario,Vaglio Augusto
Arthritis & rheumatology (Hoboken, N.J.)
OBJECTIVE:Adult-onset IgA vasculitis (Henoch-Schönlein) (IgAV) is a rare systemic vasculitis characterized by IgA1-dominant deposits. The treatment of adult-onset IgAV is controversial and is based on the combination of glucocorticoids and immunosuppressive agents, but many patients have refractory or relapsing disease despite treatment. Rituximab (RTX) is a B cell-depleting antibody of proven efficacy in antineutrophil cytoplasmic antibody-associated vasculitis. We undertook this study to test the efficacy and safety of RTX in a multicenter cohort of patients with adult-onset IgAV. METHODS:In this multicenter observational study, we included patients with adult-onset IgAV who had received RTX either for refractory/relapsing disease or because they had contraindications to conventional glucocorticoid/immunosuppressive therapy. We analyzed the rates of remission (defined on the basis of the Birmingham Vasculitis Activity Score [BVAS]) and relapse as well as the variations over time in estimated glomerular filtration rate (GFR), proteinuria, C-reactive protein (CRP) level, BVAS, and prednisone dose. RESULTS:Twenty-two patients were included; their median duration of follow-up was 24 months (interquartile range 18-48 months). Sixteen patients received RTX as add-on therapy and 6 as monotherapy. Twenty patients (90.9%) achieved remission, and 7 of those 20 patients (35%) had subsequent relapse of disease. There were significant reductions in 24-hour proteinuria (P < 0.0001), CRP level (P = 0.0005), BVAS (P < 0.0001), and prednisone dose (P < 0.0001) from RTX initiation through the last follow-up visit; estimated GFR remained stable. RTX was generally well tolerated. One patient died after 60 months of follow-up. CONCLUSION:Our data suggest that RTX is an effective and safe therapeutic option for adult-onset IgAV.
Treatment of severe Henoch-Schönlein nephritis: justifying more immunosuppression.
Altugan Fatma Semsa,Ozen Seza,Aktay-Ayaz Nuray,Güçer Safak,Topaloğlu Rezan,Düzova Ali,Ozaltin Fatih,Beşbaş Nesrin
The Turkish journal of pediatrics
The prognosis of Henoch-Schönlein purpura (HSP) nephritis is more severe than originally thought, with a significant portion progressing to deterioration of renal function in adulthood. Proteinuria adversely affects the outcome. The aim of this study was to evaluate the initial single-center results of a treatment protocol for severe HSP nephritis based on the Heaton classification. Age, gender, clinical features and duration of disease follow-up were assessed. Glomerular filtration rate (GFR), urinalysis and 24-hour urinary protein excretion were analyzed. All patients with severe renal involvement were biopsied and a treatment plan was assigned: Class II received oral steroids, Class III (with crescentic nephritis) received additional oral cyclophosphamide 2 mg/kg/d for 12 weeks, and Classes IV and V received azathioprine for 9 months subsequent to the treatment for Class III. All patients received angiotensin converting enzyme (ACE) inhibitors regardless of their blood pressure values. Eighteen patients presenting with severe HSP nephritis, defined as heavy proteinuria and/or decreased renal function, were evaluated. Based on the renal histology, 5, 10, 1 and 2 of the patients were classified as Classes II, III, IV and V, respectively. At presentation, 7 of the patients had impaired renal function with GFR below 75 ml/min/1.73 m2. With the presented treatment schema, all GFR returned to normal at the end of four years of follow-up. There was no proteinuria in any of the patients; only 8 had microscopic hematuria. This preliminary study suggests a stepwise treatment according to the renal histology. The excellent results with complete disappearance of proteinuria and normal renal function justify the use of the aforementioned immunosuppressive protocol with ACE inhibition. Long-term, multicenter controlled studies are needed to verify our results.
IgA vasculitis in adults: the performance of the EULAR/PRINTO/PRES classification criteria in adults.
Hočevar Alojzija,Rotar Ziga,Jurčić Vesna,Pižem Jože,Čučnik Saša,Vizjak Alenka,van den Broeke Rianne,Tomšič Matija
Arthritis research & therapy
BACKGROUND:In 2010, EULAR/PRINTO/PRES proposed new classification criteria for paediatric IgA vasculitis (IgAV) that have a higher diagnostic sensitivity than the 1990 ACR criteria. These criteria have so far not been evaluated in adults, in whom IgAV is considered as a rare disease. Our main objective was to compare the diagnostic performance of EULAR/PRINTO/PRES and ACR classification criteria in adult IgAV. METHODS:Adult IgAV cases fulfilling the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (ICHCCNV) definition of IgAV at a secondary/tertiary rheumatology referral centre were critically reviewed in a partially retrospective and partially prospective manner. First, we compared the diagnostic sensitivity of ACR and EULAR/PRINTO/PRES criteria in this group of patients. Second, the diagnostic specificity of ACR and EULAR/PRINTO/PRES was determined by applying these criteria to a control group of patients with other systemic vasculitides. RESULTS:Between 1 January 2010 and 31 December 2014 350 new cases of systemic vasculitis were identified. IgAV was diagnosed in 129, and other systemic vasculitides in 221 (123 had large, six medium and 92 small vessel vasculitis) cases according to ICHCCNV. The diagnostic sensitivity and specificity of the IgAV EULAR/PRINTO/PRES criteria were 99.2 % (95 % CI 95.4-99.9 %) and 86.0 % (95 % CI 80.7-90.3 %), and of the ACR criteria 86.8 % (95 % CI 79.7-92.1 %) and 81.0 % (95 % CI 75.2-85.9 %), respectively with an inter-criteria agreement of 77.5 % (95 % CI: 70.8-84.1 %). CONCLUSIONS:In the adult population the EULAR/PRINTO/PRES IgAV classification criteria had a higher sensitivity and specificity than the ACR criteria.
Renal manifestations of Henoch-Schonlein purpura in a 6-month prospective study of 223 children.
Jauhola Outi,Ronkainen Jaana,Koskimies Olli,Ala-Houhala Marja,Arikoski Pekka,Hölttä Tuula,Jahnukainen Timo,Rajantie Jukka,Ormälä Timo,Turtinen Juha,Nuutinen Matti
Archives of disease in childhood
OBJECTIVE:To assess the risk factors for developing Henoch-Schönlein purpura nephritis (HSN) and to determine the time period when renal involvement is unlikely after the initial disease onset. DESIGN:A prospective study of 223 paediatric patients to examine renal manifestations of Henoch-Schönlein purpura (HSP). The patient's condition was monitored with five outpatient visits to the research centre and urine dipstick testing at home. RESULTS:HSN occurred in 102/223 (46%) patients, consisting of isolated haematuria in 14%, isolated proteinuria in 9%, both haematuria and proteinuria in 56%, nephrotic-range proteinuria in 20% and nephrotic-nephritic syndrome in 1%. The patients who developed HSN were significantly older than those who did not (8.2±3.8 vs 6.2±3.0 years, p<0.001, CI for the difference 1.1 to 2.9). Nephritis occurred a mean of 14 days after HSP diagnosis, and within 1 month in the majority of cases. The risk of developing HSN after 2 months was 2%. Prednisone prophylaxis did not affect the timing of the appearance of nephritis. The risk factors for developing nephritis were age over 8 years at onset (OR 2.7, p=0.002, CI 1.4 to 5.1), abdominal pain (OR 2.1, p=0.017, CI 1.1 to 3.7) and recurrence of HSP disease (OR 3.1, p=0.002, CI 1.5 to 6.3). Patients with two or three risk factors developed nephritis in 63% and 87% of cases, respectively. Laboratory tests or blood pressure measurement at onset did not predict the occurrence of nephritis. CONCLUSION:The authors recommend weekly home urine dipstick analyses for the first 2 months for patients with HSP. Patients with nephritis should be followed up for more than 6 months as well as the patients with HSP recurrence.
[Preventive effect of integrative medical therapy on children Henoch-Schonleln purpura with renal impairment].
Zhao Hong,Dou Zhi-Yan,Li Yu-Qiu
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine
OBJECTIVE:To observe the clinical effect of integrative medicinal therapy in treating children Henoch-Schonlein purpura (HSP) and its preventive effect on complicated renal impairment. METHODS:One hundred and twenty children with HSP were equally randomized into two groups, the treated group and the control group. Both were treated with conventional Western medical therapy, but Sanhuang Qingxue Yin (SQY, a Chinese herbal drug) was given additionally to the treated group. Besides, a group consisted of 30 healthy children was set up as a normal control. Changes of symptoms, physical signs, routine urine, plasma endothelin-1 (ET-1) and urinary levels of beta2-microglobulin (beta2-MG), albumin (ALB) and immunoglobulin G (IgG) before and after treatment were observed, and the recurrence was monitored. RESULTS:The cure rate and the total effective rate in the treated group were 80.0% and 98.3%, while those in the control group were 61.7% and 88.3%, showing significant differences between groups (P < 0.05); the disappearance time of clinical symptoms was shorter in the treated group than in the control group, also showing a significant difference (P < 0.01); after 1-month treatment, levels of plasma ET-1, and urinary beta2-MG, ALB and IgG were improved in the treated group, reaching the levels opproximate to those in the normal control (P > 0.05), significant difference was shown as compared with those in the control group and with those before treatment respectively (P < 0.01, P < 0.05). The recurrent rate was 13.33% in the treated group and 30.0% in the control group, and they were statistically different (P < 0.05). CONCLUSION:The integrative medicinal therapy is good for treating HSP in children, it could not only obviously relieve clinical symptoms, shorten the illness course and reduce the recurrent rate, but also effectively prevent the occurrence of renal impairment.
[Clinical effect of gamma globulin pulse therapy for abdominal Henoch-Schönlein purpura in children].
Xia Li-Ping,Chen Xu,Jiang Yi
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics
OBJECTIVE:To study the clinical effect of high-dose gamma globulin pulse therapy for abdominal Henoch-Schönlein purpura (HSP). METHODS:Thirty-three children with abdominal HSP were randomly assigned to dexamethasone group (15 children) and gamma globulin group (18 children). The children in the dexamethasone group were treated with dexamethasone and conventional treatment, and those in the gamma globulin group were treated with high-dose gamma globulin pulse therapy in addition to the conventional treatment. Clinical outcome and recurrence rate were observed in both groups. RESULTS:Compared with the dexamethasone group, the gamma globulin group had a significantly shorter onset time of rash, a significantly shorter time to complete regression of rash, a significantly shorter time to abdominal pain remission, and a significantly shorter time to disappearance of bloody stool, as well as comparable time to vomiting remission and length of hospital stay. The gamma globulin group had a significantly higher response rate than the dexamethasone group (95% vs 65%; P<0.05) and a significantly lower recurrence rate within 6 months than the dexamethasone group (5.6% vs 33.3%; P<0.05). CONCLUSIONS:High-dose gamma globulin pulse therapy has a marked clinical effect in the treatment of abdominal HSP. It is safe and reliable and has a low recurrence rate, and therefore, it holds promise for clinical application.
Add-on therapy with montelukast in the treatment of Henoch-Schönlein purpura.
Wu Sheng-Hua,Liao Pei-Yuan,Chen Xiao-Qing,Yin Pei-Ling,Dong Ling
Pediatrics international : official journal of the Japan Pediatric Society
BACKGROUND:Previous studies suggested that leukotrienes (LT) were involved in the pathogenesis of Henoch-Schönlein purpura (HSP). This study investigated the efficacy of an add-on therapy with montelukast in the treatment of HSP. METHODS:In this four-center, double-blind, placebo-controlled, parallel paired comparative study, 130 children with HSP were divided into two large groups: 84 patients without nephritis and 46 patients with nephritis. For each pair of patients with the same severity of disease, one subject was randomly allocated to one subgroup and the other allocated to the other subbroup; one subgroup received routine treatment plus placebo treatment, while the other subgroup received routine treatment plus montelukast treatment for 3 months. The efficacy was determined using Severity Scale Score (SSS). Blood eosinophil count, eosinophil cationic protein (ECP), IgE, interleukin (IL)-4, IL-5, IL-6, IL-8, IL-17, LTB4 , and urinary LTE4 were measured. RESULTS:Add-on therapy with montelukast alleviated the symptoms of HSP including purpura, abdominal pain, stool occult blood, arthritis, proteinuria and hematuria, and, accordingly, shortened the length of hospital stay, and lowered blood eosinophil count, ECP, IgE, IL-4, IL-5, IL-6, IL-8, IL-17, LTB4 , and urinary LTE4 production, and also lowered the HSP relapse rate during the 3 months of treatment, but did not alter the outcome of nephritis at the end of follow up. CONCLUSIONS:Add-on therapy with montelukast alleviated the symptoms of HSP. HSP may be improved by add-on therapy with a leukotriene receptor antagonist.
Association between red blood cell distribution width and Henoch-Schonlein purpura nephritis.
Xu Hui,Li Wei,Mao Jian-Hua,Pan Yan-Xiang
To investigate whether red blood cell distribution width (RDW) is a marker of the risk of Henoch-Schonlein purpura (HSP) nephritis (HSPN), a total of 669 HSP patients and 168 healthy controls were included in this retrospective study. Two hundred fifty-six (38.3%) of the patients had kidney involvement. Compared with the HSP group, RDW was significantly higher in the HSPN group (P < .001). Binary logistic regression identified that HSPN was independently associated with age, RDW, platelet, and total cholesterol (odds ratio = 1.409, 1.353, 0.996, and 2.019, respectively). In addition, RDW values of HSPN patients with crescents on histopathology (classes III, IV, and V) were higher compared with those of HSPN without crescents (classes I and II) (P = .019). The receiver-operating characteristic curve analysis showed that the RDW at a cut-off point of 13.25 has 61% sensitivity and 79% specificity in predicting the presence of crescents on histopathology. It was first shown that RDW levels in HSPN are significantly higher than those in HSP without nephritis and healthy controls. RDW can be an independent predictor of HSPN and its levels greater than 13.25 were useful in the predicting the presence of crescents on histopathology.
Outcome of Henoch-Schönlein purpura 8 years after treatment with a placebo or prednisone at disease onset.
Jauhola Outi,Ronkainen Jaana,Koskimies Olli,Ala-Houhala Marja,Arikoski Pekka,Hölttä Tuula,Jahnukainen Timo,Rajantie Jukka,Örmälä Timo,Nuutinen Matti
Pediatric nephrology (Berlin, Germany)
BACKGROUND:Corticosteroids have been shown not to prevent the development of Henoch-Schönlein nephritis. However, long-term follow-up data are scarce. METHODS:The long-term outcome of patients in a randomized placebo-controlled prednisone study was evaluated 8 years later with a health questionnaire completed by 160/171 (94%) patients and by urine and blood pressure screening (138/171, 81%). RESULTS:Twelve patients had hematuria and/or proteinuria and seven had hypertension. The patients with nephritis at onset of Henoch-Schönlein purpura (HSP) had an increased risk of hypertension and/or urine abnormalities (odds ratio 3.6, p = 0.022, 95% confidence interval 1.3-10.0). There were no differences between the prednisone and placebo groups. Recurrences of purpura were reported by 15 patients, with some recurrences continuing for 10 years. All five reported pregnancies were complicated by proteinuria. Four patients presented with hematuria and/or proteinuria at the control visit, and four had hypertension. Of these, two had a decreased estimated glomerular filtration rate. CONCLUSIONS:HSP has a good long-term prognosis in unselected patients, although skin relapses with/without late-onset nephritis may occur, even a decade after the initial disease. Urine and blood pressure abnormalities 8 years after HSP are associated with nephritis at its onset. Early prednisone treatment does not affect the outcome and should not be routinely used.
Relationship between immune parameters and organ involvement in children with Henoch-Schonlein purpura.
Pan Yan-xiang,Ye Qing,Shao Wen-xia,Shang Shi-qiang,Mao Jian-hua,Zhang Ting,Shen Hong-qiang,Zhao Ning
Henoch-Schonlein purpura (HSP) is the most common type of connective tissue diseases which increasingly occurs in children in recent years and its pathogenesis remains unclear. In order to explore the immune parameters and underlying pathogenesis mechanism of children with HSP, the study involved 1232 patients with HSP having different clinical symptoms and their laboratory indicators were evaluated. Th1/Th2 imbalance and overactivity of Th2 cells can cause increase in the synthesis and release of immunoglobulins in children with HSP. The number of red blood cells and white blood cells in urine was directly proportional to the level of IgA and inversely proportional to the level of serum complements (C3 and C4). Activation of these complements caused by immunoglobulin in patients with HSP plays an important role in renal injury. The urinary protein content in children with HSP along with proteinuria was positively correlated with IgE level, and IgE mediated type 1 hypersensitivity can cause increase in capillary permeability and weakened the charge barrier; hence, it could be considered as one of the causes of proteinuria in HSP. Additionally, the NK cells percentage was reduced and impaired immune function of NK cells were related to the immune injury of the digestive tract and kidney.
Clinical course of extrarenal symptoms in Henoch-Schonlein purpura: a 6-month prospective study.
Jauhola Outi,Ronkainen Jaana,Koskimies Olli,Ala-Houhala Marja,Arikoski Pekka,Hölttä Tuula,Jahnukainen Timo,Rajantie Jukka,Ormälä Timo,Nuutinen Matti
Archives of disease in childhood
OBJECTIVE:To describe the extrarenal symptoms and clinical course of Henoch-Schönlein purpura (HSP). DESIGN:A prospective national multicentre trial with 6-month follow-up. Patients A total of 223 newly diagnosed paediatric HSP patients. RESULTS:Purpura was the initial symptom in 73% of the patients and was preceded by joint or gastrointestinal manifestations in the rest by a mean of 4 days. Joint symptoms, abdominal pain, melena, nephritis and recurrences occurred in 90%, 57%, 8%, 46% and 25% of the patients, respectively. Orchitis affected 17/122 (14%) of the boys. Seven patients developed protein-losing enteropathy characterised by abdominal pain, oedema and serum albumin under 30 g/l, and an additional 49 patients had subnormal albumin levels without any proteinuria. Positive fecal occult blood (26/117, 22%) and α1-antitrypsin (7/77, 9%) suggested mucosal injury even in the patients without gastrointestinal symptoms. HSP was often preceded by various bacterial, especially streptococcal (36%) and viral infections. Previous streptococcal infection did not induce changes in the level of complement component C3. Recurrences were more frequent in patients >8 years of age (OR 3.7, CI 2.0 to 7.0, p<0.001) and in patients with nephritis (OR 4.6, CI 2.3 to 8.9, p<0.001). Patients with severe HSP nephritis had more extrarenal symptoms up to 6 months. There was no difference in the clinical course between the prednisone-treated and non-treated patients during the 6-month follow-up. CONCLUSIONS:Serum albumin is often low in HSP patients without proteinuria, due to protein loss via the intestine. Although corticosteroids alleviate the symptoms, they seem not to alter the clinical course of HSP during 6 months of follow-up.
An analysis of the levels of the soluble form of the endothelial protein C receptor in children with Henoch-Schönlein Purpura.
Cayci Fatma Semsa,Ekim Mesiha,Egin Yonca,Gökce Hafize,Yalcinkaya Fatos,Ozcakar Birsin,Akar Nejat
Pediatric hematology and oncology
The pathogenesis of Henoch-Schönlein Purpura (HSP) has not been clearly defined. Inflammatory cytokines have been associated with HSP but there are only a few reports that have focused on coagulation. The endothelial protein C receptor (EPCR), which has anticoagulant and antiinflammatory activity, is the key component of the protein C pathway. Recent studies have implicated the soluble form of EPCR (sEPCR) in Wegener's granulomatosis, Behçet's disease, and systemic lupus erythematosus. The aim of this study was to evaluate the levels of sEPCR in HSP children. Twenty-two children with HSP and 17 healthy children were included. We found no significant differences (P > .05) between patient and control groups in the levels of von Willebrand factor and thrombomodulin. The median sEPCR values in the HSP group were lower than the control group (79 vs. 102 ng/mL, respectively) (P > .05). The mean sEPCR value in HSP patients with severe abdominal pain was lower than without (88.8 ± 54.9 vs. 108.2 ± 66.3 ng/mL, respectively) (P > .05). In addition, the mean IL-6 serum levels were significantly elevated in HSP patients during the acute stage of HSP (2.1 ± 1.7 vs. 1.5 ± 1.2 pg/mL, P = .038). We also observed a slight negative correlation between the levels of sEPCR and IL-6 (R = -.135, P > .05). To our knowledge, this was the first study to analyze sEPCR levels in HSP. Our results did not conclusively identify a direct role of sEPCR in HSP, but our findings warrant further investigations, especially in severe HSP cases characterized by gastrointestinal bleeding or renal involvement.
Lack of Association between Interleukin-8 Gene +781 C/T Polymorphism and Henoch-Schönlein Purpura in Childhood.
Xu Hui,Pan Yan-Xiang,Zhang Junfeng,Liu Yujie,Mao Jian-Hua,Li Wei
Iranian journal of allergy, asthma, and immunology
Henoch-Schönlein purpura (HSP), a common allergic hemorrhagic disease, occurs frequently in children affecting kidney, joint and skin. While interleukin-8 (IL-8) plays an important role in inflammation, the association between IL-8 gene +781 C/T polymorphism and HSP remains unclear. Interleukin-8, an important chemokine related to the initiation and amplification of acute inflammatory responses, has been reported to be involved in the pathogenesis of some autoimmune and inflammatory diseases. In this study, we aimed to investigate whether IL-8 gene +781 C/T (rs2227306) polymorphism has an influence on susceptibility and clinical manifestations of patients to HSP. This hospital-based case-control study comprised 192 patients with HSP and 202 healthy controls. The genotypes of IL-8 gene +781 C/T polymorphism were identified using PCR-TaqMan method. All genotype frequencies of both groups (patients and controls) conformed to the Hardy-Weinberg equilibrium. No significant differences in allele or genotype frequencies of IL-8 gene +781 C/T polymorphism were observed between patients with HSP and controls (p=0.98, χ2=0.000 and p=0.49, χ2=1.432, respectively). When patients were stratified for the presence of joint, gastrointestinal and renal manifestations, genotype frequencies of IL-8 gene polymorphism were found no statistically significant differences (p>0.05). Our findings do not support that IL-8 gene +781 C/T polymorphism has an effect on the susceptibility to HSP in Chinese children.
Association between anti-α-1,4-D-polygalacturonic acid antibodies and Henoch-Schönlein purpura in children.
Miao Meihua,Li Xiaozhong,Wang Qin,Zhu Yunfen,Cui Yanyan,Shao Xuejun
The Journal of international medical research
OBJECTIVE:To investigate the relationship between anti-α-1,4-D-polygalacturonic acid (PGA) antibodies, particularly immunoglobulin (Ig)A, and Henoch-Schönlein purpura (HSP) in children. METHODS:This observational case-control study investigated PGA-IgA, PGA-IgG, and PGA/PGA-IgA circulating immune complex (PGA/PGA-IgA CIC) in paediatric patients with HSP versus controls. Children with HSP were also evaluated for food specific IgG and food intolerance. Between-group differences in anti-PGA antibodies were analysed. RESULTS:Serum PGA-IgA and PGA-IgG levels were significantly increased in patients with acute HSP ( n = 251) versus those with urticaria ( n = 48), acute respiratory infections ( n = 95), surgical controls ( n = 53) and neonates ( n = 92). PGA/PGA-IgA CIC levels were also significantly higher in the acute HSP group versus surgical control and neonate groups. Levels of PGA/PGA-IgA CIC and PGA-IgA were significantly correlated ( r = 0.997), and PGA-IgA showed high diagnostic specificity for HSP. No statistically significant differences were observed in PGA-IgA and PGA-IgG between various degrees of food intolerance in children with HSP. CONCLUSION:Increased anti-PGA antibodies, particularly PGA-IgA and PGA/PGA-IgA CIC, were significantly associated with acute HSP in children. Food intolerance was not found to be associated with increased anti-PGA antibodies in children with HSP.
Effect of Montmorillonite powder on intestinal mucosal barrier in children with abdominal Henoch-Schonlein purpura: A randomized controlled study.
Gao Xiaolin,Miao Ruixue,Tao Yuhong,Chen Xiuying,Wan Chaomin,Jia Ruizhen
BACKGROUND:Our previous studies found that intestinal barrier function has been changed in children with abdominal Henoch-Schonlein purpura (HSP). Montmorillonite has been shown to be protective for digestive tract mucosa. OBJECTIVE:The present study aimed to investigate whether Montmorillonite powder could improve the intestinal mucosal barrier function in children with abdominal HSP. METHODS:Using a randomized controlled study design, we compared plasma levels of diamine oxidase (DAO), D-lactate, and endotoxin in children with abdominal HSP before and after Montmorillonite powder treatment. RESULTS:Among 28 patients in experimental group and 30 in control group, there was no significant difference in age, sex, height, weight, and course of disease between 2 groups (P > .05). Before treatment, there was no statistical difference in DAO, D-lactic acid, and endotoxin between experimental group and the control group (P > .05). However, significant differences were detected for DAO and D-lactate after treatment in comparison to before treatment in the Montmorillonite experimental group (P < .05). Such differences were not found in the control group (P > .05). CONCLUSION:Montmorillonite powder is effective in the treatment of HSP via maintaining intestinal mucosal barrier function.
Endothelial function in children with a history of henoch schonlein purpura.
Butbul Aviel Yonatan,Dafna Lotem,Pilar Giora,Brik Riva
Pediatric rheumatology online journal
BACKGROUND:Although Henoch-Schonlein purpura (HSP) is the most common form of systemic vasculitis in children, the long term effect of HSP on endothelial function is still not clear. The aim of our study was to evaluate the long term effect of HSP on endothelial function in children and adolescents. METHODS:This research was an observational prospective study. The study group comprised of 19 children diagnosed with HSP. The minimum interval between the diagnosis with HSP and endothelial testing was 5 months. Endothelial function evaluation was assessed by a noninvasive technology named peripheral arterial tonometry, using an EndoPAT™ device. This method measures blood flow in the limb, in response to arterial occlusion, and calculates a Reactive Hyperemic Index (RHI) as an index of endothelial function. RHI values of the study group were compared to those of a known control group. RESULTS:Nineteen children and adolescents with HSP underwent endothelial function studies. Endothelial function was compared to that of a known control group comprising of 23 healthy children and adolescents. The two groups had similar characteristics, including age, male to female ratio, height, weight and BMI. Mean RHI was 1.81 in the study group, and 1.87 in the control group (p = 0.18). Linear regression of the study group, showed a positive correlation between the time interval from HSP diagnosis to participation in the study, and between the RHI value (r = 0.542, p = 0.016). RHI levels were significantly higher in patients who had endothelial function measured more than 6 years since the diagnosis of HSP compared with those patients with less than 6 years follow up (1.98 + 0.74 vs. 1.38 ± 0.43 P = 0.037). CONCLUSIONS:These results suggest that HSP causes short term endothelial dysfunction that improves with time.
A retrospective comparison of skin and renal direct immunofluorescence findings in patients with glomerulonephritis in adult Henoch-Schönlein purpura.
Poterucha Timothy J,Wetter David A,Grande Joseph P,Gibson Lawrence E,Camilleri Michael J,Lohse Christine M
Journal of cutaneous pathology
BACKGROUND:Henoch-Sch¨onlein purpura (HSP) is a vasculitis tha tcan affect the skin and kidneys. It is characterized by immunoglobulin(Ig) A-predominant deposition in small blood vessels. To our knowledge, there has been no comparison of direct immunofluorescence (DIF) findings in skin and kidney biopsy specimens. METHODS:We retrospectively studied 21 adults with HSP who had IgA deposition in the skin and kidneys. The skin and kidney DIF findings were compared and tested for an association with the progression of renal disease. RESULTS:Mean age of the patients was 51.4 years. Follow-up data were available for 19 patients, of whom 5 had progression to chronic kidney disease or renal failure. Concordance between DIF findings onskin and renal biopsies was 100% for IgA, 80% for C3, 80% for IgG,71% for IgM and 53% for fibrinogen. A worse renal outcome was associated with renal IgG deposition (p=0.04). A trend for worse renal outcome was found with renal fibrinogen and skin IgM deposition(p=0.10 and 0.14, respectively). CONCLUSIONS:In this retrospective study of adult HSP, theconcordance between DIF findings in skin and kidney specimens was low-moderate. Further study is required to elucidate the mechanisms responsible for these differences in Ig deposition.
Off-label use of tacrolimus in children with Henoch-Schönlein purpura nephritis: a pilot study.
Zhang Dong-Feng,Hao Guo-Xiang,Li Chun-Zhen,Yang Yan-Jun,Liu Fu-Juan,Liu Ling,Yuan Xiao-Ying,Li Rui-Hong,Dong Lei,Dong Qian,Jacqz-Aigrain Evelyne,Zhao Wei
Archives of disease in childhood
BACKGROUND:Tacrolimus is used off-label in the treatment of Henoch-Schönlein purpura nephritis (HSPN) in children, with limited evidence-based data. Based on clinical empirical experience and mechanism of action, tacrolimus might be promoted as treatment for childhood HSPN. The objectives of this pilot study were to assess its effectiveness and safety, and to explore the potential impact of CYP3A5 genotype. METHODS:Children with HSPN receiving tacrolimus as empirical treatment were included in this prospective, observational study. Effectiveness was classified as complete remission, partial remission or non-response. General safety data analyses during and after study drug exposure included adverse events, reasons for discontinuation, deaths, laboratory data and vital signs. Trough concentration was determined using high-performance liquid chromatography with tandem mass spectrometry. Pharmacogenetic analysis was performed on the CYP3A5 gene. RESULTS:A total of 20 patients with a mean age of 7.5 (SD 2.1) years participated in the whole process of the study. Twelve patients reached complete remission and eight patients reached partial remission at the end of 6-month treatment. No patients discontinued tacrolimus treatment due to adverse events, and no drug-related adverse events were shown to have a causal association with tacrolimus therapy. Dose-adjusted trough concentration was significantly higher in children with CYP3A5*1 allele as compared with patients with CYP3A5*3/*3 genotype (170.7±100.9 vs 79.8±47.4 (ng/mL)/(mg/kg)). CONCLUSION:This pilot study showed that tacrolimus might be an effective and well-tolerated drug for the treatment of HSPN in children. CYP3A5 polymorphism had a significant impact on tacrolimus concentration.