Immediate moxifloxacin hypersensitivity: Is there more than currently meets the eye?

Immediate drug hypersensitivity reactions (IDHR) to moxifloxacin constitute a pathomechanistic conundrum and a diagnostic challenge. Our objective was to study whether simultaneous phenotyping and quantification of histamine release might add to our knowledge about the basophil activation properties of moxifloxacin and constitute a reliable diagnostic aid. Fifteen patients with an IDHR to moxifloxacin and nine moxifloxacin challenged controls were selected. All had a basophil activation test (BAT) with moxifloxacin. Flow cytometric analysis of basophil responses implied labeling for CD63, CD203c, and intracellular histamine. Unlike tolerant challenged controls, basophilic upregulation of CD203c in response to moxifloxacin was observed in seven of 15 patients. Only two of these seven patients demonstrated appearance of CD63 and release of histamine. In the remainder eight patients, no basophil responses were demonstrable. In conclusion, immediate hypersensitivity to moxifloxacin might involve mechanisms difficult to capture by traditional CD63-/CD203c-based BAT. Deciphering the complexity of quinolone IDHR seems mandatory.

Cannabis sativa allergy: looking through the fog.

IgE-mediated Cannabis (C. sativa, marihuana) allergy seems to be on the rise. Both active and passive exposure to cannabis allergens may trigger a C. sativa sensitization and/or allergy. The clinical presentation of a C. sativa allergy varies from mild to life-threatening reactions and often seems to depend on the route of exposure. In addition, sensitization to cannabis allergens can result in various cross-allergies, mostly for plant foods. This clinical entity, designated as the 'cannabis-fruit/vegetable syndrome', might also imply cross-reactivity with tobacco, natural latex and plant-food-derived alcoholic beverages. Hitherto, these cross-allergies are predominantly reported in Europe and appear mainly to rely upon cross-reactivity between nonspecific lipid transfer proteins or thaumatin-like proteins present in C. sativa and their homologues, ubiquitously distributed throughout plant kingdom. At present, diagnosis of cannabis-related allergies predominantly rests upon a thorough history completed with skin testing using native extracts from crushed buds and leaves. However, quantification of specific IgE antibodies and basophil activation tests can also be helpful to establish correct diagnosis. In the absence of a cure, treatment comprises absolute avoidance measures. Whether avoidance of further use will halt the extension of related cross-allergies remains uncertain.

Predictive value of allergy tests for neuromuscular blocking agents: tackling an unmet need.

BACKGROUND: Neuromuscular blocking agents (NMBAs) are a predominant cause of perioperative anaphylaxis in Europe. Diagnosis of NMBA allergy relies upon the careful review of the anaesthetic report complemented with skin tests. Additional diagnostic tests are quantification of specific IgE antibodies (sIgE) and basophil activation test (BAT). However, data on the predictive value of the skin tests, the BAT and the sIgE assays (drug-specific and substituted ammonium structures) are limited or not available, mainly because such exploration requires dangerous NMBA provocation tests. METHODS: In this study, the predictive value of skin test, BAT and measurement of sIgE to substituted ammonium structures is gathered from a review of anaesthetic records of subsequent surgical procedures with NMBA administration and/or occurrence of perioperative incidents. RESULTS: We investigated a series of 272 patients with perioperative anaphylaxis, of whom 100 had undergone second general anaesthesia. Negative skin test and negative BAT assisted the selection of alternative NMBA, which were well tolerated in all cases. Five patients with a positive sIgE to rocuronium but with negative skin testing and BAT safely received rocuronium during second anaesthesia. Twelve patients with sIgE reactivity to morphine, but negative skin test and BAT to benzylisoquinolines, tolerated administration of cisatracurium or atracurium. Alternatively, benzylisoquinoline allergy went undetected in the morphine solid-phase assay. CONCLUSIONS: Skin test and BAT have an excellent negative predictive value in our series. The uneventful re-exposure of rocuronium in patients with an isolated positive sIgE result to rocuronium calls into question the predictive value of this assay and suggests sIgE serology to be less clinically predictive than the functional investigations relying upon activation of mast cells or basophils. The presence of a positive sIgE to substituted ammonium structures such as morphine does not preclude further use of benzylisoquinolines.

Allergy to illicit drugs and narcotics.

Despite their frequent use, allergy to illicit drugs and narcotics is rarely reported in literature. We present a review of the different classes of drugs of abuse that might be involved in allergies: central nervous system (CNS) depressants (such as cannabis, opioids and kava), CNS stimulants (cocaine, amphetamines, khat and ephedra) and hallucinogens such as ketamine and nutmeg. Diagnosis of drug and narcotic allergy generally relies upon careful history taking, complemented with skin testing eventually along with quantification of sIgE. However, for various reasons, correct diagnosis of most of these drug allergies is not straightforward. For example, the native plant material applied for skin testing and sIgE antibody tests might harbour irrelevant IgE-binding structures that hamper correct diagnosis. Diagnosis might also be hampered due to uncertainties associated with the non-specific histamine releasing characteristics of some compounds and absence of validated sIgE tests. Whether the introduction of standardized allergen components and more functional tests, that is, basophil activation and degranulation assays, might be helpful to an improved diagnosis needs to be established. It is anticipated that due to the rare character of these allergies further validation is although necessary.

Flowcytometric diagnosis of atracurium-induced anaphylaxis.

BACKGROUND: Allergy to atracurium is a rare condition with serious consequences of diagnostic error. However, correct diagnosis is not always straightforward. The aim of this study is to assess the utility of the basophil activation test (BAT) in atracurium sensitization and to investigate its role in identifying cross-reactivity between muscle relaxants. METHODS: For validation, eight patients with perioperative anaphylaxis to atracurium and seven individuals experiencing perioperative anaphylaxis but not exposed to neuromuscular blocking agents (NMBA) were included. Furthermore, five other patient groups were included in the study, and all individuals exposed to different NMBA, either sensitized or not to the drug. Basophil activation with atracurium was analysed flow cytometrically. RESULTS: ROC analyses between eight atracurium-sensitized patients and seven nonexposed controls allowed identification of 5% as the decision threshold for BAT positivity. For this cutoff, the BAT attained a sensitivity of 63%, specificity of 100%, positive predictive value of 100% and negative predictive value of 70%. Of the atracurium-exposed individuals with a negative atracurium skin test (ST), two individuals had a clear positive BAT. BAT atracurium was positive in one cisatracurium-sensitized patient and negative in all cisatracurium-exposed patients with a negative ST to cisatracurium. All rocuronium- and suxamethonium-sensitized patients displayed a negative BAT with atracurium. CONCLUSIONS: The BAT proves to be a useful diagnostic for atracurium-induced anaphylaxis and may be complementary to STs. The technique enables quick and simultaneous testing of potentially crossreactive NMBA and the identification of safe alternatives for future surgery.

Component-resolved diagnosis of wasp (yellow jacket) venom allergy.

BACKGROUND: Wasp venom allergy is a potentially life-threatening condition with serious consequences of diagnostic error. OBJECTIVE: To assess whether component-resolved diagnosis, using non-glycosylated recombinant allergen components from yellow jacket can add to the diagnosis of wasp venom allergy. METHODS: In total, 148 patients with a wasp (yellow jacket) allergy were included, 91 with unequivocal tests, 26 with double positivity of serum-specific IgE (sIgE) to both venoms, 21 with discrepant sIgE and skin test results and finally 10 having their diagnosis only confirmed by basophil activation test (negative sIgE and skin test results). Specific IgE to recombinant species-specific allergen components Ves v 1 and Ves v 5 from yellow jacket, Api m 1 from honeybee and Ves v 5 complemented wasp venom were tested by ImmunoCAP. RESULTS: Overall, combined use of sIgE to rVes v 1 and rVes v 5 allowed correct diagnosis in 139 of the 148 patients (94%) and rApi m 1 was demonstrable in only one patient. Supplementing the traditional yellow jacket allergosorbent with rVes v 5 allowed to correctly diagnose wasp allergy in patients sensitized to Ves v 5 but demonstrating a negative sIgE to wasp venom. CONCLUSION: Component-resolved diagnoses with the wasp-specific recombinant allergen components Ves v 1 and Ves v 5 is a reliable method to diagnose yellow jacket allergy and can help to take out the sting of difficult cases. However, as the number of patients with doubt after conventional tests is small, larger collaborative studies are needed to draw more definitive conclusions. Whether the rVes v 5 supplemented yellow jacket allergosorbent constitutes an asset in the diagnostic management of wasp venom allergy remains to be further established.

New food allergies in a European non-Mediterranean region: is Cannabis sativa to blame?

BACKGROUND: Allergy to fruit and vegetables exhibit geographic variation regarding the severity of symptoms and depending on the sensitization profile of the patient. These sensitization profiles and routes remain incompletely understood. Cannabis is a very popular drug and derived from Cannabis sativa, a plant containing lipid transfer proteins (LTP) also known as important allergens in plant and fruit allergies. In this study we sought to elucidate a potential connection between C. sativa allergy and plant food allergies. METHODS: A case-control study involving 21 patients consulting for plant food allergies. Twelve patients were cannabis allergic and 9 had a pollen or latex allergy without cannabis allergy. Testing for cannabis IgE implied measurement of specific IgE, skin testing and basophil activation tests. Allergen component analysis was performed with a microarray technique. RESULTS: Plant food allergy in patients with documented cannabis allergy had more severe reactions than patients without cannabis allergy and frequently implied fruits and vegetables that are not observed in a (birch) pollen-related food syndrome. With the exception of 1 patient with cannabis allergy, all were sensitized to nonspecific (ns)-LTP. CONCLUSION: Our data suggest that illicit cannabis abuse can result in cannabis allergy with sensitization to ns-LTP. This sensitization might result in various plant-food allergies. Additional collaborative studies in different geographical areas are needed to further elucidate on this hypothesis.

Age-dependent sensitization to the 7S-vicilin-like protein Cor a 11 from hazelnut (Corylus avellana) in a birch-endemic region.

BACKGROUND: Hazelnut (Corylus avellana) allergy exhibits age and geographically distinct sensitization patterns that have not yet been fully resolved. OBJECTIVE: To study sensitization to Cor a 11 in different age groups of hazelnut-allergic patients and infants with atopic dermatitis (AD) sensitized to hazelnut in a birch-endemic region. METHODS: Sera from 80 hazelnut-allergic patients, 33 infants under 1 year of age with AD (24 sensitized and 9 not sensitized to hazelnut), 32 healthy control individuals, and 29 birch pollen-allergic but hazelnut-tolerant individuals were tested for immunoglobulin (Ig) E reactivity to Cor a 11 by ImmunoCAP. IgE reactivity to Cor a 1.01, Cor a 1.04, Cor a 8, and Cor a 9 was studied by ISAC microarray. RESULTS: Forty patients (22 preschool children, 10 schoolchildren, and 8 adults) with systemic reactions on consumption of hazelnut were sensitized to Cor a 11 (respective rates of 36%, 40%, and 12.5%). Forty patients (6 preschool children, 10 schoolchildren, and 24 adults) reported oral allergy syndrome but only 2 of them (of preschool age) were sensitized to Cor a 11. Two (8%) of the AD infants sensitized to hazelnut showed IgE reactivity to Cor a 11. This reactivity was not observed in any of the AD infants without sensitization to hazelnut, in any of the birch-pollen allergic patients without hazelnut allergy, or in any of the healthy control individuals. CONCLUSION: Sensitization to Cor a 11 in a birch-endemic region is predominantly found in children with severe hazelnut allergy, a finding that is consistent with observations concerning sensitization to Cor a 9.

Allergy to chlorhexidine: beware of the central venous catheter.

The example reported here illustrates the frequent belief that "innocent" products such as central venous catheters do not produce allergic reactions. However, they might be impregnated with chlorhexidine and elicit serious life-threatening anaphylaxis in patients with allergy to this antiseptic agent.

Peroxisome proliferator activated receptor alpha activation decreases inflammatory and destructive responses in osteoarthritic cartilage.

OBJECTIVE: Peroxisome proliferator activated receptor α (PPARα) agonists are used in clinical practice as lipid-lowering drugs and are also known to exert anti-inflammatory effects on various tissues. We hypothesized that PPARα activation leads to anti-inflammatory and anti-destructive effects in human OA cartilage. METHODS: Cartilage explants obtained from six OA patients were cultured for 48 h with 10 ng/ml interleukin (IL)1ß as a pro-inflammatory stimulus. 100 µM Wy-14643, a potent and selective PPARα agonist, was added to the cultures and gene expression of matrix metalloproteinase (MMP)1, MMP3, MMP13, collagen type II (COL2A1), aggrecan and PPARα in cartilage explants and the release of glycosaminoglycans (GAGs), nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in the culture media were analyzed and compared to the control without Wy-14643. RESULTS: Addition of Wy-14643 decreased mRNA expression of MMP1, MMP3 and MMP13 in cartilage explants that responded to IL1ß, whereas Wy-14643 did not affect gene expression of COL2A1 and aggrecan. Wy-14643 also decreased secretion of inflammatory marker NO in the culture medium of cartilage explants responding to IL1ß. Wy-14643 inhibited the release of GAGs by cartilage explants in culture media. CONCLUSION: PPARα agonist Wy-14643 inhibited the inflammatory and destructive responses in human OA cartilage explants and did not have an effect on COL2A1 or aggrecan mRNA expression. These effects of PPARα agonists on osteoarthritic cartilage warrant further investigation of these drugs as a potential therapeutic strategy for osteoarthritis (OA).

Allergy to rocuronium: from clinical suspicion to correct diagnosis.

BACKGROUND: Allergy to rocuronium can be life-threatening. Correct diagnosis is a prerequisite because of serious consequences of diagnostic error. OBJECTIVE: To assess skin testing, quantification of specific IgE (sIgE) and flow-assisted activation of basophils [basophil activation test (BAT)] in the diagnosis of rocuronium allergy. METHODS: This study comprises 104 curarized patients with a history of profound hypotension and severe bronchospasm immediately after induction of anaesthesia. All patients had skin tests, quantification of sIgE and BAT to rocuronium, together with investigations for all relevant compounds administered during anaesthesia that could have evoked the reaction. Diagnosis of rocuronium allergy was considered definite when the patient demonstrated a positive outcome for at least two of the three aforementioned tests. RESULTS: The positive predictive value for skin testing, BAT and sIgE was 98% (CI 95%: 92-99%), 97% (CI 95%: 88-100%) and 83% (CI 95%: 74-89%), respectively. The negative predictive value for skin testing, BAT and sIgE was 96% (CI 95%: 86-99%), 75% (CI 95%: 67-75%) and 72% (CI 95%: 58-83%), respectively. Cross-reactivity with vecuronium was documented in 69% of the patients. CONCLUSION: Skin testing merits the status of primary diagnostic investigation to document rocuronium allergy and cannot be substituted by quantification of sIgE or BAT. SIgE can offer a diagnostic advantage in cases where skin tests yield negative results. However, additional tests (e.g. BAT) are of capital importance in patients with negative skin tests and positive sIgE results to help in interpreting the clinical significance of a positive sIgE result. Optimal assessment of cross-reactivity between rocuronium and vecuronium implies both skin testing and BAT.

Age-related sensitization profiles for hazelnut (Corylus avellana) in a birch-endemic region.

BACKGROUND: Symptoms of hazelnut allergy seem related to geographic and possibly age variations in allergen recognition. OBJECTIVE: To investigate sensitization profiles of hazelnut allergy in different age groups in a birch-endemic region using component resolved diagnosis (CRD) by microarray. METHODS: Sixty-five patients with hazelnut allergy, 27 healthy control individuals tolerant to hazelnut, and 34 birch pollen allergic but hazelnut tolerant individuals were included. All blood samples were analyzed using ISAC microarray. RESULTS: Twenty-nine patients with hazelnut allergy suffered from a systemic reaction (17 preschool children with a median age of 2 years, six school children, and six adults), whereas 36 patients reported an oral allergy syndrome (OAS; three preschool and nine school children and 24 adults). In the hazelnut allergic preschool children with systemic reactions, 65% were sensitized to Cor a 9, 12% to Cor a 8, 18% to Cor a 1.04, 6% to Cor a 1.0101, and 29% to Bet v 1. Of the school-aged systemic reactors, 50% were sensitized to Cor a 9, 17% to Cor a 8, 50% to Cor a 1.04 and Cor a 1.0101, and 67% to Bet v 1. In adults with hazelnut allergy, 3.3% were sensitized to Cor a 9, 6.7% to Cor a 8, 90% to Cor a 1.04 and Bet v 1, and 87% to Cor a 1.0101. In regard to systemic reactors in this group, 17% were sensitized to Cor a 9, 33% to Cor a 8 and Cor a 1.0101, and 50% to Cor a 1.04 and Bet v 1. In the patients with OAS, irrespective the age group, all were sensitized to Bet v 1 and over 97% to Cor a 1.04 and Cor a 1.0101. No sensitization to Cor a 9 or Cor a 8 was found in patients with only an OAS. Of the patients with birch pollen allergy, tolerant to hazelnut, none were sensitized to Cor a 9 or Cor a 8, 56% to Cor a 1.0101, 82% to Cor a 1.04, and 92% to Bet v 1. In healthy controls, no sensitization to components of hazelnut, hazel pollen or birch pollen was demonstrable. CONCLUSION: Hazelnut allergy in a birch-endemic region exhibits age-related sensitization profiles with distinct clinical outcomes that can be identified using CRD. The majority of hazelnut allergic preschool and school children in a birch-endemic region show systemic reactions on consumption of processed hazelnut, mostly being sensitized to the hazelnut legumin-like allergen Cor a 9 but unrelated to birch pollen allergy. In contrast, adults generally suffer from an OAS apparently as a result of cross-reactivity between Cor a 1.04 from hazelnut and Bet v 1 from birch pollen.

Basophil activation reveals divergent patient-specific responses to thermally processed peanuts.

INTRODUCTION: The impact of processing on the allergenicity of peanut (Arachis hypogaea) proteins has traditionally been studied using immunoglobulin (Ig) E binding assay. However, as this technique does not assess the potential of an allergen to trigger basophils and mast cells, studies based on it can hardly be considered complete. We evaluated the effect of processing on peanut allergenicity using flow-cytometric quantification of in vitro basophil activation (basophil activation test [BAT]). PATIENTS AND METHODS: Basophils from 10 patients with severe peanut allergy and 3 peanut-tolerant individuals were stimulated with extracts from 5 raw and thermally processed peanut varieties. Data were compared using protein staining (sodium dodecyl sulfate-polyacrylamide gel electrophoresis [SDS-PAGE]) and IgE immunoblotting. RESULTS: Stimulation with different extracts resulted in patient-dependent and variety-dependent effects on basophil activation. SDS-PAGE revealed a considerable loss of identifiable bands, especially for the South Africa Common Natal, Argentina Runner, and US Virginia varieties. The results of IgE immunoblotting in patients were similar, irrespective of the responses observed in the BAT. CONCLUSIONS: The impact of thermal processing on the capacity of peanuts to trigger basophils seems highly divergent between patients and cannot be predicted using SDS-PAGE or IgE binding. BAT can be considered a complementary tool for the evaluation of food allergenicity.

Human basophils: a unique biological instrument to detect the allergenicity of food.

BACKGROUND: Labeling of major food allergens is mandatory for the safety of allergic consumers. Although enzyme-linked immunosorbent assay, polymerase chain reaction, and mass spectrometry are sensitive and specific instruments to detect trace amounts of food proteins, they cannot measure the ability of food constituents to trigger activation of mast cells or basophils. AIM: We evaluated the basophil activation test as an instrument to determine the allergenic potential of trace amounts of food allergens in complex matrices. Peanut (Arachis hypogaea) allergy was selected as a proof-of-concept model. METHODS: The study population comprised 5 severely peanut-allergic patients (3 males/2 females; median age, 12 years) all sensitized to 3 major peanut allergens (Ara h 1, Ara h 2, and Ara h 3) and 5 peanut-tolerant individuals (2 males/3 females; median age, 8 years). Basophils from patients and controls were stimulated with pure peanut extract and blank and peanut-spiked (0.1, 0.01, and 0.001 ppm) biscuits (baking time 11, 16, 21, 26 minutes) and chocolate extracts. RESULTS: Blank biscuits and chocolate did not induce cell activation in patients or controls. A comparison between patients and controls showed significantly higher activation of basophils after stimulation with 0.1 and 0.01 ppm of peanut-spiked biscuit at all baking times and peanut-spiked chocolate (P < .05). CONCLUSIONS: The basophil activation test is a highly sensitive and specific tool to detect traces of functionally active food allergens. For biscuits, its accuracy seems independent of baking time. Furthermore, it allows even the most sensitive patients to be included in study protocols.

Sensitization profiles in birch pollen-allergic patients with and without oral allergy syndrome to apple: lessons from multiplexed component-resolved allergy diagnosis.

BACKGROUND: Component-resolved diagnosis (CRD) using microarray technology has recently been introduced into the field of clinical allergology. OBJECTIVE: To further validate the use of CRD by microarray technology in allergy diagnosis. METHODS: Thiry-seven patients allergic to birch pollen were included. The discriminative value of apple-specific IgE (sIgE), recombinant Mal d 1 (rMal d 1) sIgE, apple skin prick test and rMal d 1 on the microarray was assessed between patients with a birch-related oral allergy syndrome to apple (OAS(+), n=20) and healthy control individuals (HC, n=8) without a history of inhalant allergies or apple-induced OAS. An additional comparative analysis was carried out with individuals allergic to birch pollen allergy without OAS (OAS(-); n=17). RESULTS: rMal d 1 coupled to the microarray constitutes a discriminative marker between OAS(+) and HC with a sensitivity 95% and a specificity of 100%. However, in parallel with the traditional sIgE assay, 15 out of 17 OAS(-) individuals (88%) also displayed IgE reactivity to rMal d 1 coupled to the microarray. OAS(-) individuals are more frequently sensitized to mite (about three to four times), cat and dog dander (about two to three times) and grass pollen (about 1.5 times) as compared with OAS(+) patients. CONCLUSION: At first glance, CRD by microarray seems to be a reliable instrument in the diagnosis of apple-mediated OAS in birch pollen allergy. However, for discriminating between sensitization and a real allergy, micro-arrayed rMal d 1 offers no advantage over conventional quantification of rMal d 1 sIgE. Most interestingly, within a single run, birch pollen-allergic patients without OAS to apple were shown to display a broader sensitization to classical inhalant allergens than birch pollen-allergic patients with an apple-related OAS.

Component-resolved diagnosis from latex allergy by microarray.

BACKGROUND: A positive specific IgE (sIgE) result for latex does not always mirror the clinical situation and is frequently found in individuals without overt latex allergy. OBJECTIVE: We sought to investigate the potential of component-resolved diagnosis (CRD) of latex allergy by microarray and to assess whether the technique allows discriminating genuine allergy from asymptomatic sensitization. METHODS: Twenty-six healthy controls without a history of latex allergy with a negative latex sIgE and skin test, 22 latex-allergic patients with a compelling history of latex allergy with a positive latex sIgE and prick test and 20 latex-sensitized individuals with a frequent asymptomatic exposure to natural rubber latex-containing devices with a negative latex skin test but a positive sIgE were also included. CRD was performed with the ImmunoCAP ISAC microarray and traditional singleplexed ImmunoCAP. RESULTS: In all patients, the diagnosis of latex allergy could be established by the combination of recombinant latex components present on the microarray (Hev b 1, Hev b 3, Hev b 5 and Hev b 6.02). Over three-quarters of our patients were sensitized for Hev b 5 and/or Hev b 6.02. Some patients also displayed reactivity for Hev b 1 and/or Hev b 3. In contrast, none of the individuals sensitized to natural rubber latex or control individuals demonstrated IgE reactivity for rHev b 1, rHev b 3, rHev b 5 or rHev b 6.02. Three-quarters of the patients sensitized to latex displayed a positive microarray result for recombinant latex profilin (rHev b 8). In contrast to the results obtained by traditional ImmunoCAP for bromelain, almost no sensitization for cross-reactive carbohydrates was demonstrated by bromelain spotted on the microarray. CRD by traditional singleplexed ImmunoCAP showed highly comparable results. CONCLUSION: CRD by microarray is a reliable tool for diagnosing latex allergy. In addition, the technique allows discrimination between genuine allergy and sensitization. CRD by microarray can improve the diagnosis of IgE-mediated latex allergy by discriminating between genuine allergy and sensitization. CRD by microarray is a reliable tool to diagnose latex allergy. In addition, the technique allows discrimination between a genuine allergy and simple sensitization.

The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review.

INTRODUCTION: Osteoarthritis (OA) of the knee joint is caused by genetic and hormonal factors and by inflammation, in combination with biomechanical alterations. It is characterized by loss of articular cartilage, synovial inflammation and subchondral bone sclerosis. Considerable evidence indicates that the menisci, ligaments, periarticular muscles and the joint capsule are also involved in the OA process. This paper will outline the theoretical framework for investigating the infrapatellar fat pad (IPFP) as an additional joint tissue involved in the development and progression of knee-OA. METHODS: A literature search was performed in Pubmed from 1948 until October 2009 with keywords InFrapatellar fat pad, Hoffa fat pad, intraarticular adipose tissue, knee, cartilage, bone, cytokine, adipokine, inflammation, growth factor, arthritis, and OA. RESULTS: The IPFP is situated intracapsularly and extrasynovially in the knee joint. Besides adipocytes, the IPFP from patients with knee-OA contains macrophages, lymphocytes and granulocytes, which are able to contribute to the disease process of knee-OA. Furthermore, the IPFP contains nociceptive nerve fibers that could in part be responsible for anterior pain in knee-OA. These nerve fibers secrete substance P, which is able to induce inflammatory responses and cause vasodilation, which may lead to IPFP edema and extravasation of the immune cells. The IPFP secretes cytokines, interleukins, growth factors and adipokines that influence cartilage by upregulating the production of matrix metalloproteinases (MMPs), stimulating the expression of pro-inflammatory cytokines and inhibiting the production of cartilage matrix proteins. They may also stimulate the production of pro-inflammatory mediators, growth factors and MMPs in synovium. CONCLUSION: These data are consistent with the hypothesis that the IPFP is an osteoarthritic joint tissue capable of modulating inflammatory and destructive responses in knee-OA.

T cell signal transducer and activator of transcription (STAT) 4 and 6 are affected by adalimumab therapy in rheumatoid arthritis.

OBJECTIVES: TNF-alpha inhibition therapy affects the systemic immune response in rheumatoid arthritis by influencing T cell subtypes (Th1, Th2, Treg), but its effect on the intracellular signal transduction in T cells remains largely unexplored. Here we studied the activation of Th1-associated signalling molecule STAT4 and Th2-associated STAT6 in CD4+ T cells. METHODS: Eight rheumatoid arthritis patients were studied before and after 12 weeks of adalimumab therapy and compared to 8 healthy individuals. Peripheral blood mononuclear cells (PBMC) were analysed flow cytometrically either directly after isolation or after 24 hours of anti-CD3/anti-CD28 stimulation, to determine spontaneous and IL-4/IL-12-induced STAT4 and STAT6 phosphorylation in CD4+ T cells. Cytokine production by stimulated PBMC was measured in the supernatant using a cytometric bead array. Non-parametric statistical tests were applied. RESULTS: After adalimumab therapy, phospho-STAT6 increased, both in freshly isolated and anti-CD3/anti-CD28-stimulated CD4+ T cells. The STAT6 response to brief IL-4 stimulation did not change. In healthy individuals and adalimumab-treated patients, anti-CD3/anti-CD28 induced the phosphorylation of STAT4, but not in untreated patients. IFN-gamma production in untreated patients was significantly lower than in healthy individuals or adalimumab-treated patients. In contrast, the production of IL-4, IL-6 and IL-12 was not influenced. CONCLUSIONS: Adalimumab therapy increases Th2-associated STAT6 phosphorylation and restores the activation-induced STAT4 phosphorylation to the levels in healthy individuals. This advocates against a pro-inflammatory effect of Th1-associated STAT4 and might provide an explanation for the influence of TNF inhibition therapy on the systemic T cell response in rheumatoid arthritis.