Periodic Fever Abstracts 1

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Double-blind, placebo-controlled, randomized, pilot clinical trial of ImmunoGuard--a standardized fixed combination of Andrographis paniculata Nees, with Eleutherococcus senticosus Maxim, Schizandra chinensis Bail. and Glycyrrhiza glabra L. extracts in patients with Familial Mediterranean Fever.
            (Amaryan et al., 2003)  Download
Double blind, randomized, placebo controlled pilot study of ImmunoGuard--a standardized fixed combination of Andrographis paniculata Nees., Eleutherococcus senticosus Maxim., Schizandra chinensis Bail., and Glycyrrhiza glabra L. special extracts standardized for the content of Andrographolide (4 mg/tablet), Eleuteroside E, Schisandrins and Glycyrrhizin, was carried out in two parallel groups of patients. The study was conducted in 24 (3-15 years of both genders) patients with Familial Mediterranean Fever (FMF), 14 were treated with tablets of series A (verum) and 10 patients received series B product (placebo). The study medication was taken three times of four tablets daily for 1 month. Daily dose of the andrographolide--48 mg. The primary outcome measures in physician's evaluation were related to duration, frequency and severity of attacks in FMF patients (attacks characteristics score). The patient's self-evaluation was based mainly on symptoms--abdominal, chest pains, temperature, arthritis, myalgia, erysipelas-like erythema. All of 3 features (duration, frequency, severity of attacks) showed significant improvement in the verum group as compared with the placebo. In both clinical and self evaluation the severity of attacks was found to show the most significant improvement in the verum group. Both the clinical and laboratory results of the present phase II (pilot) clinical study suggest that ImmunoGuard is a safe and efficacious herbal drug for the management of patients with FMF.

Decreased vitamin D levels in children with familial Mediterranean fever.
            (Anik et al., 2014)  Download
OBJECTIVES: To determine the frequency of vitamin D deficiency in children with familial Mediterranean fever (FMF) and to investigate the factors associated with low vitamin D status. DESIGN AND METHODS: Forty-four patients with FMF and 39 age- and sex-matched healthy controls were enrolled in this study. Demographic data, FMF symptoms, disease duration, time to delay for diagnosis, duration of follow-up, disease severity score, MEFV gene mutation, cumulative colchicine dose, compliance to treatment and serum C-reactive protein levels were recorded for each patient. Serum 25-hydroxyvitamin D levels were measured by an original commercial kit based on chemiluminescent microparticle immunoassay (CMIA). RESULTS: The serum 25-hydroxyvitamin D levels were significantly lower in FMF patients than the healthy controls (12.9 +/- 3.6 and 16.3 +/- 5.5 ng/mL, respectively, P = 0.001). Vitamin D levels were similar in patients homozygous for M694V and other genotypes (11.8 +/- 3.7 and 13.2 +/- 3.6 ng/mL, respectively, P = 0.21). Stepwise multiple linear regression analysis confirmed that the cumulative colchicine dose was the strongest independent variable correlating with vitamin D levels (r(2) = 0.194, P = 0.001). CONCLUSION: Our results suggest that serum 25-hydroxyvitamin D levels are decreased in children with FMF. Cumulative colchicine dose appears to negatively affect vitamin D levels. The role of colchicine on vitamin D metabolism needs to be elicited.

Vitamin B12 levels in familial Mediterranean fever patients treated with colchicine.
            (Gemici et al., 2013) Download
OBJECTIVES: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterised by paroxysmal attacks of serosal inflammation. Colchicine is highly effective in preventing these attacks but it may also disrupt the intestinal absorption of vitamin B12. We hypothesised that patients treated with colchicine for a prolonged period could develop deficiency of the vitamin. METHODS: Ninety-five adult FMF patients on regular colchicine treatment for at least 2 years and age and sex-matched 90 healthy controls were enrolled and complete blood count with platelets, vitamin B12 and folic acid were measured in each person. We also investigated 15 adult FMF patients who were not yet on colchicine. RESULTS: The mean vitamin B12 values were not significantly different between the groups (352.12 (SD=171.62) pg/mL vs. 360.96 (SD=146.53) pg/mL, p=0.71), but there were significantly more vitamin B12 deficient cases among FMF patients (12 vs. 3; p=0.021) and 3 out of these 12 had megaloblastic anaemia. None of the vitamin B12 deficient controls had anaemia. We could not identify any disorder which might have causative effect for the deficiency among this subgroup. The mean vitamin B12 value of 15 colchicine-naive cases was not significantly different from patients on colchicine (p=0.356). CONCLUSIONS: We did not observe significant vitamin B12 deficiency among colchicine-treated FMF patients but some cases may be more prone to developing this potentially serious disorder.

Decreased vitamin D levels in patients with familial mediterranean fever.
            (Kisacik et al., 2013)  Download
Familial mediterranean fever (FMF) is an autosomal recessive disorder caused by mutations in the FMF gene (MEFV). The gene causing FMF, designated MEFV, encodes a protein called pyrin or marenostrin that is expressed mainly in myeloid bone marrow precursors, neutrophils, and monocytes. Since there are several etiological factors, FMF is the most common periodic fever syndrome. However, it is still unknown what triggers or ends these periodical attacks. As a pleiotropic hormone, vitamin D has immunomodulation effects. The aim of this study was to evaluate the vitamin D levels in FMF patients. The study group was comprised of 26 patients diagnosed with FMF (men/women: 12/14), and 34 healthy control (men/women: 17/17). Vitamin D levels in FMF patients and healthy controls were 11.05 +/- 7.11, 17.15 +/- 6.49, respectively. FMF patients had significantly decreased vitamin D levels compared with healthy controls (P < 0.001). In conclusion, it is thought that vitamin D deficiency in FMF patients may trigger the attacks. Further studies with larger patient populations need to hold to investigate the vitamin D deficiency in patients with FMF and that may assist to clarify the mechanism behind the colchicines resistant cases.

Periodic fever responds to vitamin B12 treatment.
            (Naimer and Volkov, 2010) Download
Periodic fever of childhood is a group of diseases that cause repeated febrile illnesses with various associated symptoms. In our article, we present the case of a 6-year-old girl with unusual appearance of periodic fever syndrome. Our patient suffered from repeated episodes of high fever from the age of 2 years old. Each episode usually lasted 24-48 h, the interval between events was 1-3 weeks long. During high fever episodes the child usually felt well, without associated accompanying complaints. As a rule, the physical examination did not reveal any pathologic finding explaining the fever. During the 4 years of follow-up the patient sustained treatment attempts with prednisone for a number of months and half a year with colchicine without any response. We considered treatment with sublingual tablets of vitamin B12 (VIT B12). Beyond all expectation, we witnessed complete resolution of attacks during the first 2 months following treatment. After a long episode-free period, the parents withheld the treatment on their own accord, and in a short time the disease recurred. We advised to renew the treatment with VIT B12, and during approximately half year of follow-up there were no recurrences of periodic fever. CONCLUSION: we believe that our observation raises interest in systematic evaluation of the therapeutic role of VIT B12 as a treatment option for disorders of the periodic fever spectrum.

Association between colchicine resistance and vitamin D in familial Mediterranean fever.
            (Ozer et al., 2015)  Download
Although colchicines are the only effective treatment of familial Mediterranean fever (FMF), resistance to colchicines (CR) which is observed in up to 30% of the patients is still a problem. Clinically, resistance to colchicine is defined as three or more attacks within the last 6 months period while using >/=2 mg/day colchicine. Previous studies have shown decreased vitamin D levels in FMF patients compared with healthy controls. The aim of this study is to evaluate whether vitamin D levels differ between CR and non-CR FMF patients. This study included 64 FMF patients who were being followed in Nephrology Clinic of Samsun Research and Education Hospital for at least 1 year. FMF was diagnosed according to the criteria defined by Livneh et al. Serum 25-hydroxy vitamin D (25-OHD) concentration (ng/mL) was detected in all FMF patients who were not in an acute attack period. From 64 patients 29 were accepted as CR. Mean 25-OHD level was 9.39 +/- 1.00 ng/mL in CR patients and 18.48 +/- 1.09 ng/mL in colchicine responsive patients (p < 0.001). Plasma vitamin D levels were significantly lower in colchicine resistant patients. Vitamin D deficiency may be a factor in etiopathogenesis of CR. Studies in larger patient samples that particularly evaluate the response to vitamin D replacement in CR FMF patients are needed.

Vitamin D levels and effects of vitamin D replacement in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome.
            (Stagi et al., 2014)  Download
BACKGROUND:  The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease characterized by regularly recurrent fever episodes due to seemingly unprovoked inflammation. OBJECTIVE:  To assess serum 25-hydroxyvitamin D [25(OH)D] concentrations in children with PFAPA syndrome and evaluate longitudinally the effect of wintertime vitamin D supplementation on the disease course. STUDY DESIGN:  We have evaluated 25 Italian patients (19 males, 6 females, aged 2.4-5.3 years), fulfilling the Euro-Fever PFAPA criteria. For each patient, we recorded demographic and anthropometric data, clinical manifestations, serum calcium, phosphate, and 25(OH)D. After 400 IU vitamin D supplementation during wintertime, clinical and auxological characteristics, calcium, phosphate, and 25(OH)D levels were re-evaluated. Data were compared with a sex- and age-matched control group. RESULTS:  PFAPA patients showed reduced 25(OH)D levels than controls (p<0.0001). Regarding the effect of seasons on vitamin D, winter 25(OH)D levels were significantly reduced than summer ones (p<0.005). Moreover, these levels were significantly lower than in healthy controls (p<0.005), and correlated with both fever episodes (p<0.005) and C-reactive protein values (p<0.005). After vitamin D supplementation, PFAPA patients showed a significantly decreased number of febrile episodes and modification of their characteristics (mean duration of fever episodes, p<0.05; number of febrile episodes per year p<0.005). CONCLUSIONS:  Deficient and insufficient vitamin D serum levels were found in most children with PFAPA syndrome, and hypovitaminosis D might be a significant risk factor for PFAPA flares. However, vitamin D supplementation seems to significantly reduce the typical PFAPA episodes and their duration, supporting the role of vitamin D as an immune-regulatory factor in this syndrome.

Hypovitaminosis D in children with familial Mediterranean fever.
            (Yilmaz et al., 2014)  Download
PURPOSE: Vitamin D deficiency or insufficiency plays a role in the initiation and perpetuation of certain autoimmune diseases. The purpose of this study was to measure the vitamin D status of children with Familial Mediterranean Fever (FMF) and compare it to their healthy peers. METHODS: A total of 50 FMF patients and 49 healthy children were enrolled in this prospective study. Vitamin D levels were measured via HPLC. Demographic data, FMF symptom severity scores and the levels of other disease activity markers were retrieved from our hospital database. RESULTS: The mean age and gender balance of patients and controls were similar, being 8.4 +/- 3.8 years and 19 male patients, and 9.1 +/- 3.0 years and 25 male controls, respectively. The mean 25(-OH) vitamin D3 levels were 15.94 +/- 9.66 microg/L in FMF patients and 41.22 +/- 21.31 microg/L in controls. Vitamin D levels were normal in 12% of FMF patients, insufficient in 62% and deficient in 26%. No vitamin D deficiency was evident in any control subject; 30% had insufficient and 70% had normal vitamin D levels. Plasma vitamin D3 levels were similar in all patients despite varying FMF symptom severity scores. CONCLUSIONS: Vitamin D deficiency is frequent in children with FMF but is not associated with disease severity score.


 

References

Amaryan, G, et al. (2003), ‘Double-blind, placebo-controlled, randomized, pilot clinical trial of ImmunoGuard--a standardized fixed combination of Andrographis paniculata Nees, with Eleutherococcus senticosus Maxim, Schizandra chinensis Bail. and Glycyrrhiza glabra L. extracts in patients with Familial Mediterranean Fever.’, Phytomedicine, 10 (4), 271-85. PubMedID: 12809357
Anik, A, et al. (2014), ‘Decreased vitamin D levels in children with familial Mediterranean fever.’, Int J Rheum Dis, 17 (3), 321-26. PubMedID: 24410734
Gemici, AI, et al. (2013), ‘Vitamin B12 levels in familial Mediterranean fever patients treated with colchicine.’, Clin Exp Rheumatol, 31 (3 Suppl 77), 57-59. PubMedID: 24064015
Kisacik, B, et al. (2013), ‘Decreased vitamin D levels in patients with familial mediterranean fever.’, Rheumatol Int, 33 (5), 1355-57. PubMedID: 22187059
Naimer, S and I Volkov (2010), ‘Periodic fever responds to vitamin B12 treatment.’, Rheumatol Int, 30 (12), 1661-63. PubMedID: 19777239
Ozer, I, et al. (2015), ‘Association between colchicine resistance and vitamin D in familial Mediterranean fever.’, Ren Fail, 1-4. PubMedID: 26067744
Stagi, S, et al. (2014), ‘Vitamin D levels and effects of vitamin D replacement in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome.’, Int J Pediatr Otorhinolaryngol, 78 (6), 964-68. PubMedID: 24746456
Yilmaz, R, et al. (2014), ‘Hypovitaminosis D in children with familial Mediterranean fever.’, Clin Invest Med, 37 (4), E211-6. PubMedID: 25090260