Effect of canakinumab on clinical and biochemical parameters in acute gouty arthritis: a meta-analysis.

BACKGROUND: Targeted anti-IL-1ß therapy may be a valuable option for the management of gouty arthritis. The present meta-analysis has evaluated the effect of canakinumab, an anti-IL-1ß monoclonal antibody in gouty arthritis. METHODS: A standard meta-analysis protocol was developed and after performing a comprehensive literature search in MEDLINE, Cochrane, and International Clinical Trial Registry Platform (ICTRP), reviewers assessed eligibility and extracted data from three relevant articles. A random-effects model was used to estimate the pooled effect size as the mean difference in Visual Analouge Scale (VAS) score, serum hsCRP, serum Amyloid A, and risk ratio for global assessment between the groups. Quality assessment was done using the risk of bias assessment tool and summary of findings was prepared using standard Cochrane methodology with GradePro GDT. RESULTS: Treatment with canakinumab showed a mean reduction of VAS score by 14.59 mm [95% CI - 19.42 to - 9.77], serum hsCRP by 15.36 mg/L [95% CI 1.62-29.11], serum Amyloid A by 67.18 mg/L [95% CI 17.06-117.31], and improvement in patient global assessment (RR = 1.478; 95% CI 1.29-1.67) and physician global assessment (RR = 1.44; 95% CI 1.28-1.61). The probability that future studies may have a mean difference in VAS score less than zero has been calculated to be 27.3% using a cumulative distribution function (CDF) calculator. CONCLUSION: This meta-analysis shows the beneficial effect of canakinumab over triamcinolone by reducing VAS score, serum hsCRP, serum amyloid A, and improvement in global assessments in acute gouty arthritis.

Characteristics of voltage-gated potassium currents in monosodium urate induced gouty arthritis in mice.

OBJECTIVE: To evaluate the role of K+ channels in pain following gouty arthritis. METHODS: The model of acute gouty arthritis was induced by monosodium urate (MSU) in mice. The swelling degree was determined by measuring the circumference of the ankle joint. Mechanical hyperalgesia was detected by von Frey filaments. Two types of K+ currents, A-type currents (IA) and delayed rectifier currents (IK), were recorded in dorsal root ganglion (DRG) neurons using patch-clamp techniques. RESULTS: The swelling degree reached its maximum at 10 h and the minimum pain threshold was maintained between 8 and 48 h after MSU treatment in mice. The amplitudes of IA and IK in DRG neurons were moderately increased on day 1 after MSU treatment, and then, they were gradually decreased with times and reached their minimums on day 4 (for IA) or 5 (for IK). Compared with control group, the activation curve of IA was significantly shifted to more positive potential and the recovery time of IA from inactivation was markedly prolonged, but inactivation and frequency dependence of IA appeared unaffected in MSU-treated group. Additionally, no change was observed in the activation curve of IK after MSU treatment. The excitability was significantly higher in the MSU group than in the control group. CONCLUSIONS: MSU-induced gout pain may be related to the hyperexcitability of DRG neurons elicited by decreasing K+ currents.

Better understanding of acute gouty attack using CT perfusion in a rabbit model.

OBJECTIVE: To assess hemodynamic changes related to acute gouty knee arthritis in a rabbit with CT perfusion (CTP) METHODS: Forty-two rabbits were randomly separated into two groups: the treated group of 30 and the control group of 12. The right knee was injected with monosodium urate solution and polymyxin in the treated group and saline and polymyxin in the control group. At 2, 16, 32, 48, 60, and 72 h after injection, five rabbits from the treated group and two rabbits from the control group were selected for CTP. At each time point, blood flow (BF), blood volume (BV), and clearance rate (CL) were measured, and microvessel density (MVD) was evaluated with a microscope. RESULTS: In the treated group, BF, BV, CL, and MVD were significantly higher than in the control group (p < 0.001). Differences within paired comparison of BV, BF, CL, and MVD were all significant (all p < 0.001). Peak time of BV, BF, and MVD was 32 h and 48 h for CL. After multivariate stepwise linear regression analysis, BV was linearly associated with MVD and vice versa, which also applied to BF with MVD and BF with CL, separately. The ascending rate of MVD was the highest among that of all parameters; so was the descending rate of CL. CONCLUSION: CTP in this rabbit knee model accurately detected hemodynamic changes during a gouty attack. KEY POINTS: • Acute gouty arthritis can be evaluated with CTP in a rabbit knee model. • Following injection of MSU crystals, producing an acute gouty attack, CTP successfully assessed hemodynamic changes. • The ascending rate of MVD was the highest among that of all parameters; so was the descending rate of CL.

Dysadipokinemia in patients with gout and its association with the disease activity.

OBJECTIVE: Introduction: In recent years, the role of adipokines in the development of rheumatic diseases has been a pressing issue. The available data suggest the dysadipokinemia in patients with rheumatoid arthritis, osteoarthritis and psoriatic arthritis. However, there is no data on changes in the levels of adipokines in patients with gout and their association with the activity of inflammatory process. The aim was to study the levels of adipokines in gout patients and evaluate their association with the disease activity. PATIENTS AND METHODS: Materials and methods: We examined 151 male patients with gout. The control group consisted of 31 practically healthy men, represented by age. We used the Gout Activity Score (GAS) to assess gout severity. The levels of leptin and adiponectin were determined using the ELISA kit. For comprehensive evaluation of dysadipokinemia, we used a logarithmic ratio of leptin to adiponectin (lg A/L). Primary processing of results was carried out using MS Excel and Statistica SPSS22 statistical software packages. RESULTS: Results: The patients with gout demonstrated higher leptin levels, lower levels of adiponectin, and lower lg A/L compared to practically healthy individuals. Among patients with gout, the disturbance of adipokin status was most pronounced in patients with tophi. Patients with high GAS activity had maximum disturbance of adipokin profile by lg A/L, while the manifestations of dysadipokinemia were minimal in the group with low activity of the disease. It was established that GAS disease activity, BMI, and the number of joints under attack may be considered the most significant independent predictors of dysadipokinemia. CONCLUSION: Conclusions: The patients with gout presented an increase in leptin level, a decrease in adiponectin level, and a decrease in the ratio lg A/L. Dysadipokinemia was associated with high disease activity and could serve as a prognostic factor for assessing the severity of the disease.

Effects of Mollugo pentaphylla extract on monosodium urate crystal-induced gouty arthritis in mice.

BACKGROUND: Gout is an inflammatory condition induced by the deposition of monosodium urate (MSU) crystals in joints and soft tissues, and it can lead to acute or chronic arthritis. MSU are pro-inflammatory stimuli that can initiate, amplify and sustain an intense inflammatory response. In this study, we evaluated the anti-inflammatory effect of an extract of Mollugo pentaphylla (MPE) on MSU-induced gouty arthritis in a mouse model. METHOD: An MSU crystal suspension (4 mg/50 µL) was injected intradermally into the right paw. The mice were orally administered MPE (150 mg/kg or 300 mg/kg) or the positive control drug colchicine (1 mg/kg) 1 h before the MSU crystals were injected and then once daily for 3 days. The effects of MPE included inflammatory paw edema and pain upon weight-bearing activity, and we evaluated the inflammatory cytokine expression and paw tissue inflammation-related gene expression. RESULTS: MPE suppressed inflammatory paw edema and pain in the MSU-induced mice. MPE showed anti-inflammatory activity by inhibiting the production of TNF-α, interleukin (IL)-1ß, NLRP3 inflammasome and NF-κB. CONCLUSION: These results suggest that MPE has potent anti-inflammatory activities and may be useful as a therapeutic agent against gouty arthritis.

[Histopathophysiology of Gout]. / Histo-Pathophysiologie der Gichtarthritis.

Despite being a frequent cause of arthritis and bone erosions, the underlying cellular and subcellular reaction in gout is insufficiently understood. The inflammasome as intracellular sensor for crystals plays an important role, notably resulting in interleukin (IL)-1 production. Morphologically, hyperplasia of the synovial membrane with joint effusion, along with fibrinogen deposition and influx of neutrophils and lymphocytes are observed. Extracellular NET formation by neutrophils is involved in the regulation of inflammatory tissue reaction. Furthermore, the release of IL-10 and tumor necrosis factor (TNF)-receptors along with lymphocyte proliferation induce the natural resolution of acute gouty arthritis which typically occurs after several days. In contrast to acute gout, tophi consisting of urate crystals are surrounded by histiocytes and multinucleated cells, resembling a foreign body reaction. The deposition of extracellular matrix by fibrocytes is usually observed around tophi. This fibrotic reaction is likely enhanced by Th2-lymphocytes. Bone erosions in gout occur around tophi and are triggered by osteoclast activation through RANK-ligand expression by lymphocytes. In conclusion, understanding the orchestration of inflammation in gout might help to identify new therapeutic targets.

[Time course of changes in the clinical manifestations of gout in men: data of a 7-year retrospective follow-up].

AIM: To estimate the time course of changes in the clinical manifestations of gout and their risk factors during a long-term follow-up. SUBJECTS AND METHODS: A total of 160 male patients with gout were examined and followed up for a mean of 6.9 ± 2.0 years. Their clinical assessment included determination of the type of arthritis over time, the frequency of arthritis attacks during one year prior to the examination, the presence and number of subcutaneous tophi, inflamed joints, comorbid or co-occurring diseases (CD), allopurinol adherence, dietary compliance, frequency of taking non-steroidal anti-inflammatory drugs (NSAIDs), diuretics, and alcohol. The serum levels of uric acid (UA), glucose, total cholesterol, and glomerular filtration rate were estimated. RESULTS: The number of patients taking allopurinol increased from 19% to 64% (p < 0.0001), its average daily dose was 167.6 ± 94.6 mg. The serum level of UA decreased; 16% of the patients achieved its target level. The number of patients with chronic arthritis was not significantly changed. Their serum level of UA was unchanged; the detection rate of subcutaneous tophi and CD rose. During one year, arthritis attacks were absent in 13% of the patients; 90% of them took allopurinol. In these patients, serum UA levels and body mass index significantly declined and the rate of CD was unchanged. None of 18 patients who had their diet and no allopurinol achieved the target level of UA. CONCLUSION: Among the gouty patients, 36% refrain from the use of allopurinol, only 23% out of them require that its dose be adjusted to achieve the target level of UA. Dietary compliance is insufficient to reach the target level of UA. Chronic arthritis is associated with the increased incidence of CD.

Management of gouty arthritis in patients with chronic kidney disease.

Chronic kidney disease (CKD) is a comorbid condition that affects, based on recent estimates, between 47% and 54% of patients with gouty arthritis. However, data from randomized controlled trials in patients with gouty arthritis and CKD are limited, and current gouty arthritis treatment guidelines do not address the challenges associated with managing this patient population. Nonsteroidal anti-inflammatory drugs and colchicine are recommended first-line treatments for acute gouty arthritis attacks. However, in patients with CKD, nonsteroidal anti-inflammatory drugs are not recommended because their use can exacerbate or cause acute kidney injury. Also, colchicine toxicity is increased in patients with CKD, and dosage reduction is required based on level of kidney function. Allopurinol, febuxostat, and pegloticase are all effective treatments for controlling elevated uric acid levels after the treatment of an acute attack. However, in patients with CKD, required allopurinol dosage reductions may limit efficacy; pegloticase requires further investigation in this population, and febuxostat has not been studied in patients with creatinine clearance<30 mL/min. This article reviews the risks and benefits associated with currently available pharmacologic agents for the management of acute and chronic gouty arthritis including urate-lowering therapy in patients with CKD. Challenges specific to primary care providers are addressed, including guidance to help them decide when to collaborate with, or refer patients to, rheumatology and nephrology specialists based on the severity of gout and CKD.

Pain and microcrystalline arthritis.

Microcrystals are responsible for some of the most common and complex arthropathies which are often accompanied by intense, severe pain and inflammatory reactions. The main pathogens are crystals of monosodium urate (MSU), responsible for the gout, calcium pyrophosphate (CPP), which deposits also in various clinical forms of arthopathies, and basic calcium phosphate associated with osteoarthritis. In this context, the microcrystal arthritis is characterized by multiple, acute attacks followed by chronic pain, disability, impaired quality of life, and increased mortality. Given their chronic nature, they represent an ever more urgent public health problem. MSU and CPP crystals are also able to activate nociceptors. The pain in mycrocrystalline arthritis (MCA) is an expression of the inflammatory process. In the course of these diseases there is an abundant release of inflammatory molecules, including prostaglandins 2 and kinins. Interleukin-1 represents the most important cytokine released during the crystal-induced inflammatory process. Therefore, clinically, pain is the most important component of MCA, which lead to functional impairment and disability in a large proportion of the population. It is fundamental to diagnose these diseases as early as possible, and to this aim, to identify appropriate and specific targets for a timely therapeutic intervention.

[The specific features of gout in the elderly].

AIM: To determine the specific feature of gout at its onset in the elderly. SUBJECTS AND METHODS: The investigation included 100 patients (74 men and 26 women) with primary gout on the basis of the criteria proposed by S. Wallace et al. (1977). The patients were divided into 2 groups: 1) 51 patients aged over 60 years; 2) 49 patients aged less than 60 years. In Groups 1 and 2, the mean age at gout onset was 66.1 +/- 4.8 and 41.6 +/- 10.0 years, respectively. A comparative retrospective analysis was made to analyze the detection rate for the site of onset gout, the pattern of arthritis, the number of tophus forms, the use of diuretics, small-dose acetylsalicylic acid (ASA), comorbidities, such as hypertension, type 2 diabetes mellitus (T2DM), obesity, chronic renal failure, coronary heart disease, chronic heart failure, and prior myocardial infarction. RESULTS: The disease duration in both groups averaged 8 years. In Groups 1 and 2, first metatarsophalangeal joint arthritis was diagnosed at its onset in 77 and 61%, respectively. In these groups, chronic arthritis was also diagnosed in 19 (37%) and 19 (39%). Examinations revealed tophi in 21 and 37% of cases in Groups 1 and 2, respectively. The administration of diuretics was recorded in 25 (49%) and 17 (35%) patients in these groups. Group 1 patients took low-dose ASA more frequently than Group 2 ones (19 (37%) and 7 (14%) patients, respectively; p = 0.013). Hypertension was identified in 23 (45%) examinees in Group 1 and 17 (40%) ones in Group 2. Both groups were matched for the number of patients with obesity (41 and 43%) and for that of patients with T2DM (15 and 10%, respectively). There were significant differences between the compared groups in the incidence of coronary heart disease, myocardial infarction, and chronic heart disease. CONCLUSION: The patients' age of gout onset does not affect substantial differences in the clinical features of gout with its comparable duration in the young and elderly patients. The main clinical features of gout are unique to both young and elderly patients. Cardiovascular diseases are more common at gout onset in the elderly.

Acupuncture for gouty arthritis: a concise report of a systematic and meta-analysis approach.

OBJECTIVE: To assess the effectiveness of acupuncture as complementary therapy for gouty arthritis from randomized controlled trials (RCTs). METHODS: Five electronic databases, including English and Chinese, were systematically searched until August 2012. All RCTs involving acupuncture in combination with conventional therapy for gouty arthritis were included. RESULTS: Ten RCTs involving 852 gouty arthritis patients were systematically reviewed. Among them six studies of 512 patients reported a significant decrease in uric acid in the treatment group compared with a control group, while two studies of 120 patients reported no significant decrease in uric acid in the treatment group compared with the control group. The remaining four studies of 380 patients reported a significant decrease in visual analogue scale score in the treatment group. CONCLUSION: The results of the studies included here suggest that acupuncture is efficacious as complementary therapy for gouty arthritis patients. More research and well-designed, rigorous and large clinical trials are necessary to address these issues.

Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis.

It has been recently demonstrated that interleukin 1ß (IL-1ß) plays a central role in monosodium urate crystal-induced inflammation and that the NALP3 inflammasome plays a major role in IL-1ß production. These discoveries have offered new insights into the pathogenesis of acute gouty arthritis. In this review, we discuss the molecular mechanisms by which monosodium urate crystals induce acute inflammation and examine the mechanisms of action (MOAs) of traditional anti-inflammatory drugs (e.g., nonsteroidal anti-inflammatory drugs, colchicine, and glucocorticoids) and biologic agents (e.g., the IL-1ß antagonists anakinra, rilonacept, and canakinumab) to understand how their MOAs contribute to their safety profiles. Traditional anti-inflammatory agents may act on the IL-1ß pathway at some level; however, their MOAs are broad-ranging, unspecific, and biologically complex. This lack of specificity may explain the range of systemic adverse effects associated with them. The therapeutic margins of nonsteroidal anti-inflammatory drugs, colchicine, and glucocorticoids are particularly low in elderly patients and in patients with cardiovascular, metabolic, or renal comorbidities that are frequently associated with gouty arthritis. In contrast, the IL-1ß antagonists act on very specific targets of inflammation, which may decrease the potential for systemic adverse effects, although infrequent but serious adverse events (including infection and administration reactions) have been reported. Because these IL-1ß antagonists target an early event immediately downstream from NALP3 inflammasome activation, they may provide effective alternatives to traditional agents with minimal systemic adverse effects. Results of ongoing trials of IL-1ß antagonists will likely provide clarification of their potential role in the management of acute gouty arthritis.

Disability due to gouty arthritis.

PURPOSE OF REVIEW: Disability, or activity limitation, is a common problem in patients with gout. This study explores recent studies examining the nature and extent of disability in gout and addresses the merits and limitations of current self-reported measures of disability. RECENT FINDINGS: Gout has a significant impact on patients' ability to perform normal self-care activities, recreational and social activities, and work. Comparative studies indicate that gout patients' physical functioning is strongly reduced and comparable to those with other severe rheumatic conditions. Moreover, gout has been shown to result in substantial work absence and reduced productivity. However, few studies have thoroughly examined the concept of disability in gout. Additionally, assessment of disability due to gout still seems particularly challenging and it is unclear whether current measurement instruments are sufficiently valid and accurate. SUMMARY: Gout-related disability is an underestimated and understudied problem. More qualitative and quantitative studies are needed that examine the concept of disability in gout and its impact on patients' lives, both during and between disease flares. Moreover, future studies should try to identify gout-specific disability issues and examine the relevance and comprehensiveness of existing measures to further improve the assessment of disability in gout.

Inflammatory gout: observations over a half-century.

This is a discussion of acute gouty arthritis, seen for over 50 years of engagement. It addresses the evolution of our current understanding of the interaction between urate crystals and key cellular components of the gouty inflammatory paroxysm, with new material on pathogenesis.

Axial (spinal) gout.

Gout is a common metabolic disorder resulting from supersaturation of uric acid in extracellular fluid and deposition of monosodium urate crystals in tissues. Gouty arthritis typically affects the peripheral joints of the appendicular skeleton, especially the feet and hands. Gouty involvement of the spine, however, is not as rare as generally perceived. Although it may be asymptomatic, tophaceous axial gout is also a well-documented cause of acute back pain, radiculopathy, and frank cord compression. As with the appendicular skeleton, it takes several years of gout before radiological evidence of erosive change or tophi is apparent in the axial skeleton. This is best detected by CT imaging. The sequelae of cord compression can be reversed with timely surgical intervention and maintenance of uric acid-lowering therapy. The long-term effects of urate-lowering therapies on axial gout have not been studied.

[Current opinions on gout, its diagnosis and treatment]. / Soucasný pohled na dnu, její diagnostiku a lécbu.

Gout is a heterogenous group of metabolic diseases characterized by formation and deposition of sodium urate crystals in various tissues. Gouty arthritis is a rheumatic syndrome occurring in individuals with hyperuricaemia; this is an inflammatory disease of the musculoskeletal system with a presence of sodium urate crystals. Hyperuricaemia, i.e. pathologically increased levels of uric acid in the serum, represents the most important risk factor for the development of gouty arthritis. The causes of hyperuricaemia may include an increased production of uric acid and/or its reduced elimination from the body. Acute gouty arthritis is an early manifestation of gouty arthritis. When deposition of sodium urate crystals in tissues leads to a destruction of musculoskeletal system structures, this is called chronic tophaceous gouty arthritis. To treat chronic tophaceous gout, the uric acid levels must be kept below 360 µmol/l, deposits of sodium urate in tissues dissolved and their further formation prevented. Pharmacological treatment of chronic hyperuricaemia involves administration of uric acid level lowering drugs, particularly xanthine oxidase inhibitors and uricosurics. Hyperuricaemia is an important risk factor not only for the development of chronic tophaceous gout and renal impairment but some data also suggests a risk associated with cardiovascular diseases.

[Pathophysiology of gout]. / Patofiziologija uricnog artritisa.

Hyperuricemia is rather often metabolic disorder in general population. It is multifactorial disorder influenced by purine rich diet, alcohol consumption, diuretics use and renal deterioration. In the presence of local urate superasturation and lower solubility, monosodium crystals are deposited in joints, kidneys and soft tissue leading to clinical manifestations, such as gout, tophaceus deposits, nephrolithiasis and uric nephropathy. Major advances in understanding the pathogenesis of hyperuricemia and gout have been made recently, including genetic studies of urate transporters in kidneys as well as innate immune inflammatory responses and cytokine production which will be discussed thoroughly in this paper.

Characteristics of monosodium urate crystal deposition in the foot in the different stages of gout by dual-energy computed tomography.

OBJECTIVE: To compare the characteristics of monosodium urate (MSU) crystal deposition at specific anatomical sites of the foot detected by dual-energy computed tomography in patients with different stages of gout. MATERIALS AND METHODS: This study included 101 patients with gout, 64 had early gout (<3 years) and 37 had late gout (>3 years). We retrospectively compared the total volumes of MSU crystals, the detection rates, and the morphology of MSU crystals at specific anatomical sites in the foot of the patients with different gout durations. RESULTS: The total volume of MSU crystals in patients with early gout was significantly smaller than that in patients with late gout (P < 0.05). The detection rates and morphology of MSU crystals in the anterior calf tendons, ankle joints, tarsometatarsal joints, and metatarsophalangeal joints differed significantly between the patients with early and late gout (P < 0.05). There were no significant differences in the detection rates of submillimeter MSU crystals at the other specific anatomical sites, except for the tendons of the anterior calf, the ankle joint, and the metatarsal joint (P > 0.05). The submillimeter MSU crystal deposition was most common in the tendons of the posterior calf, the proportions in patients with early gout and late gout were 85.9% and 70.3%. Only submillimeter deposition existed in 52 patients (81.3%) with early gout and 11 patients (29.7%) with late gout at all sites of the foot. CONCLUSION: Dual-energy computed tomography detection of submillimeter MSU crystal deposits in the foot is of great significance for the diagnosis of gout, especially along tendons.

Spontaneous resolution of acute gouty arthritis is associated with rapid induction of the anti-inflammatory factors TGFß1, IL-10 and soluble TNF receptors and the intracellular cytokine negative regulators CIS and SOCS3.

OBJECTIVE: The molecular basis for spontaneous resolution of acute gouty arthritis (GA) remains unclear. The hypothesis that extracellular and intracellular mechanisms play roles in resolving acute GA was tested. METHODS: Synovial fluid (SF) levels of transforming growth factor ß1 (TGFß1), interleukin 1 (IL-1) receptor antagonist (IL-1ra), IL-10 and soluble tumour necrosis factor (TNF) receptor I (sTNFRI) and II (sTNFRII) were measured by ELISA in patients with acute GA and osteoarthritis (OA). Monosodium urate (MSU) crystal-stimulated RAW264.7 mouse macrophages were analysed for cytokine inducible SH2-containing protein (CIS) and suppressors of cytokine signalling (SOCS)1-7 mRNA expression by reverse transcription (RT)-PCR. Immunohistochemical analysis, quantitative PCR and immunoblotting were performed to detect CIS and SOCS3 expression in synovial tissue, SF mononuclear cells (SFMCs) from patients with GA and MSU crystal-stimulated monocyte-derived macrophages from healthy donors. CIS overexpression and small interfering RNA-mediated knockdown in RAW264.7 cells were used to investigate the role of CIS in resolving MSU crystal-induced acute inflammation. RESULTS: SF levels of anti-inflammatory molecules TGFß1, IL-1ra, IL-10 and sTNFR-I/II were significantly elevated in GA compared to OA. CIS and SOCS3 were upregulated in the synovium and SFMCs from acute GA and MSU crystal-stimulated monocyte-derived macrophages and RAW264.7 cells. CIS overexpression in RAW264.7 cells attenuated MSU crystal-induced IL-1ß and TNFα but enhanced TGFß1 production via increased binding of signal transducer and activator of transcription 3 (STAT3) to the TGFß1 promoter. Conversely, CIS knockdown reversed the effect of CIS overexpression, resulting in enhanced IL-1ß and TNFα but reduced TGFß1 production in MSU crystal-stimulated RAW264.7 cells. CONCLUSIONS: Increased production of TGFß1, IL-1ra, IL-10 and sTNFR-I/II and upregulation of intracellular CIS and SOCS3 expression are associated with spontaneous resolution of acute GA.