Idit Shirazi

Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2, and hyaluronic acid production in human synovial cells and synovial tissue cultures.

OBJECTIVE To evaluate the effects of fluoxetine and amitriptyline on nitric oxide (NO), prostaglandin E2 (PGE2), and hyaluronic acid (HA) production in human synovial cells and synovial tissue cultures. METHODS Human synovial cells, synovial tissue, and cartilage were cultured in the presence or absence of cytokines, lipopolysaccharides (LPS), fluoxetine, or amitriptyline. Production of NO, PGE2, and HA was determined in culture media. Sulfated glycosaminoglycan (S-GAG) synthesis was evaluated in cartilage by 35S incorporation. RESULTS Fluoxetine (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) inhibited NO release by 56%, 62%, and 71%, respectively, in the media of synovial cells stimulated by interleukin-1alpha (IL-1alpha; 1 ng/ml) plus tumor necrosis factor alpha (TNFalpha; 30 ng/ml). Amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) caused a 16%, 27.3%, and 51.4% inhibition of NO release. Fluoxetine and amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) significantly (P<0.05) inhibited PGE2 release in the media of human synovial cells in the presence of IL-1alpha plus TNFalpha, in a dose-dependent manner (up to 88% inhibition). Fluoxetine (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) and amitriptyline (1 microg/ml and 3 microg/ml) significantly (P<0.05) inhibited PGE2 release in the media of human synovial tissue in the presence of LPS. Fluoxetine and amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) also significantly (P<0.05) inhibited HA production by human synovial cells in the presence of IL-1beta plus TNFalpha. Fluoxetine and amitriptyline (1 microg/ml) partially reversed IL-1beta-induced inhibition of 35S-GAG synthesis by human cartilage cultures (P<0.05). Neither fluoxetine nor amitriptyline had a toxic effect on cells in the concentrations used. CONCLUSION Inhibition of NO and PGE2 production by connective tissue cells is a mechanism by which some antidepressant medications may affect pain, articular inflammation, and joint damage.

RIN2 Deficiency Results in Macrocephaly, Alopecia, Cutis Laxa, and Scoliosis: MACS Syndrome

Inherited disorders of elastic tissue represent a complex and heterogeneous group of diseases, characterized often by sagging skin and occasionally by life-threatening visceral complications. In the present study, we report on an autosomal-recessive disorder that we have termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis). The disorder was mapped to chromosome 20p11.21-p11.23, and a homozygous frameshift mutation in RIN2 was found to segregate with the disease phenotype in a large consanguineous kindred. The mutation identified results in decreased expression of RIN2, a ubiquitously expressed protein that interacts with Rab5 and is involved in the regulation of endocytic trafficking. RIN2 deficiency was found to be associated with paucity of dermal microfibrils and deficiency of fibulin-5, which may underlie the abnormal skin phenotype displayed by the patients.

Serum levels of IL-10, IL-6, IL-1ra, and sIL-2R in patients with psoriatic arthritis

Abstract Our objective was to evaluate the levels of interleukin-6 (IL-6), soluble receptors of IL-2 (sIL-2R), IL-10, and IL-1 receptor antagonists (IL-1ra) in the serum of patients with psoriatic arthritis (PsA) and to assess the correlation between these levels and parameters of clinical activity of skin and joint disease.In total, 34 patients with PsA and ten healthy volunteers participated in the study. Assessment of joint disease included duration of morning stiffness, number of tender and swollen joints, right and left grip, the presence of inflammatory spinal back pain, and Schober test. Current severity of skin disease was graded according to the psoriasis area and severity index (PASI). Erythrocyte sedimentation rate (ESR) was determined as a marker of disease activity. Serum levels of IL-6, sIL-2R, IL-1ra, and IL-10 were measured by an enzyme immunoassay kit.Significantly higher serum levels of IL-6, sIL-2R, IL-1ra, and IL-10 were found in patients with PsA in comparison with healthy volunteers. A statistically significant correlation was found between levels of sIL-2R and PASI, whereas no association was found with clinical parameters of joint severity. Levels of IL-1ra correlated with the number of tender and swollen joints. No correlation was found between levels of IL-6, IL-10, and clinical parameters of skin and joint severity. In the group of patients with PsA, serum levels of sIL-2R clearly correlated with severity of skin disease, whereas levels of IL-1ra were associated with joint severity.

Saliva: An additional diagnostic tool in Sjögren's syndrome

OBJECTIVE To assess the available data and the place of salivary analysis in the diagnosis of Sjögrens syndrome (SS). METHODS A Medline search of English language articles published between 1985 and 1996 and a manual search of the reference lists of relevant articles formed the data sources. These were combined with our clinical and experimental experience in this field. Each method of salivary analysis was assessed according to study design, type of saliva used for the study, sensitivity/ specificity for the diagnosis of SS, and correlation to the histopathological findings. RESULTS Increased levels of salivary Na+, immunoglobulins (particularly IgA), anti-Ro and La antibodies, lactoferrin, lysozyme, beta 2 microglobulin, prostaglandin E2, thromboxane B2, interleukin-6, and hyaluronic acid have been detected in various studies. Results varied according to the different methods used for saliva collection. CONCLUSION Although many changes have been detected in various constituents of saliva in SS patients, no test has proved sensitive or specific enough for diagnosing SS.

Serum Levels of Hyaluronic Acid in Patients with Psoriatic Arthritis

Abstract: The purpose of this study was to evaluate the serum levels of hyaluronic acid (HA) in a group of patients with psoriatic arthritis (PsA), with special emphasis on the relationships between HA levels and clinical parameters of joint and skin activity. Thirty-four patients with PsA, 34 patients with rheumatoid arthritis (RA) and 49 healthy volunteers participated in the study. Assessment of joint disease in patients with PsA included duration of morning stiffness, number of tender and swollen joints, right and left grip, the presence of inflammatory back pain and Schober’s test. The current severity of skin involvement was graded according to the Psoriasis Area Severity Index (PASI). Serum levels of HA were measured by a radiometric assay. The mean HA serum levels of patients with PsA and RA were significantly increased in comparison with healthy controls (107 ± 39.6 μg/dl in patients with PsA, whereas in patients with RA it was 168 ± 32.4 μg/dl and 36.7 ± 5.5 μg/dl in healthy controls). A highly significant correlation was found between levels of HA and index of skin involvement, but no association was found between HA levels and clinical parameters of joint severity. We conclude that in this cohort of patients with PsA, HA levels clearly reflected psoriatic skin involvement although it did not correlate with joint disease.

Salivary and serum hyaluronic acid concentrations in patients with Sjögren's syndrome

OBJECTIVE To evaluate salivary hyaluronic acid (HA) concentration in patients with primary Sjögren’s syndrome (SS). METHODS Salivary and serum HA concentrations were evaluated using a radiometric assay. Thirty nine patients with SS served as the study group and their results were compared with 19 patients having clinical symptoms and signs of dry mouth and with 10 normal controls. RESULTS Salivary HA concentrations were significantly increased (p < 0.05) in the 39 patients with SS compared with the 19 patients with dry mouth and the 10 normal controls (240.7 (38.5) v 99.8 (14.6) and 91.3 (7.9) ng/ml, respectively) (mean (SEM)). No significant differences were noted in the serum HA concentrations between the three groups (42 (3.9) v 36.3 (4.1) and 32 (4.3) ng/ml, respectively) (mean (SEM)). No correlation could be found between salivary HA concentrations and the focus score of lip biopsies, nor between salivary HA concentrations and erythrocyte sedimentation rate or other serological tests. CONCLUSION Increased salivary HA concentrations can serve as a marker of local inflammation and may be of value in the diagnosis of SS.

Erythrokeratoderma variabilis caused by a recessive mutation in GJB3

Background.  Erythrokeratoderma variabilis (EKV) is a rare disorder of cornification usually associated with dominant mutations in the genes GJB3 and GJB4, which code for connexin (Cx)31 and Cx30.3, respectively, and contribute to the formation of functional gap junctions in the epidermis.

An unusual case of DRESS syndrome.

BACKGROUND DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) is a rare but severe drug reaction. OBSERVATIONS A 27-year-old male with paranoid schizophrenia was hospitalized with all three diagnostic criteria of DRESS syndrome: cutaneous drug eruption, hematological abnormalities (presence of atypical lymphocytes on blood smear) and systemic involvement (generalized lymphadenopathy and hepatitis). On hospitalization the patient exhibited an unusual fever pattern of high temperatures in the morning hours and lower temperatures towards evening. In this case of a patient who needs life-long therapy, we demonstrated the value of the IFN-gamma release test, which showed positive reactivity to 3 out of 9 suspicious drugs: paracetamol, phenytoin and dypirone, allowing for more therapeutic options. After therapy, at 6-month follow-up the patient is doing well under haloperidol treatment, laboratory values including liver function tests are normal and his skin condition is good. CONCLUSION We suggest that clinicians take the fever pattern of high temperatures in the morning hours and lower temperatures towards evening into account in a patient presenting with a severe cutaneous drug eruption. An interferone-gamma release test may facilitate identification of drugs responsible for the drug reaction.

Acetaminophen-induced lichenoid keratosis : a new way to look at an old lesion

Editor Acetaminophen (paracetamol) is a widely used analgesicantipyretic drug, easily obtained over the counter and generally well tolerated. Its potential for drug interactions is often underestimated. Adverse skin reactions, some life threatening, involve almost all arms of the innate and acquired immune systems, and include urticarial anaphylactoid reactions, fixed drug eruptions, pigmented purpuras, acute generalized exanthematous pustulosis, toxic epidermal necrolysis, and even a case of IgA bullous dermatosis. The association of acetaminophen with lichenoid eruption is rare. We encountered a case of what appeared to be acetaminophen-induced lichenoid keratosis (LK) in a 63year-old, otherwise healthy Ashkenazi Jewish woman who presented with a 2-week history of an asymptomatic, solitary, flat-topped, small ovoid plaque on the ventral side of the right arm. The plaque was erythematous, with a brownish hue. She had ingested acetaminophen for a headache 1 day prior to appearance of the lesion. She reported a previous episode of clinically diagnosed lichenoid eruption in the same area following ingestion of acetominophen, which disappeared and reoccurred after challenge, leaving no pigmentary changes. The lag time between ingestion of the drug and appearance of the lesions at that time was much longer than in the current incident. Histological examination of a completely excised lesion revealed a lichenoid inflammatory infiltrate obscuring the dermo-epidermal junction, with vacuolar changes, occasional Civatte bodies and pigment incontinence. The inflammatory infiltrate consisted mainly of T cell lymphocytes, with mixed CD4 and CD8 populations (fig. 1), but no eosinophils or plasma cells. The epidermis showed focal acanthosis without hypergranulosis or parakeratosis. Hyperpigmentation features of solar lentigo were encountered. In vitro interferon gamma release test performed on the patient’s lymphocytes, described previously, showed a rise in interferon release, with acetaminophen over the predrug test level (480 pg/mL vs. 350 pg/mL, respectively). This test is recognized as a safe, informative tool for identifying drugs associated with various forms of adverse cutaneous drug reactions. Table 1 summarizes the major clinical and histological features of LP-associated lesions, showing the overlap between entities. Our case exhibited LK clinically, with mixed histological evidence of LK and lichenoid drug eruption, suggesting that the two are in fact reactive immunological processes, probably to the same insult. This observation was supported by the positive rechallenge to acetaminophen, accompanied by the in vitro rise in the release of interferon gamma, a key orchestrating cytokine in T-lymphocyte processes. In view of the usual slow growth of lichenoid lesions, their appearance the third time only 1 day after ingestion of acetominophen is intriguing. This might be explained by the fact that in reactive recurrent cases like ours, local T cells are already activated, rendering a shortened lag time. fig. 1 Lichenoid inflammatory infiltrate obscuring the dermal epidermal junction with occasional Civatte bodies. Immunohistochemical stains of the lymphocyte infiltrate show pronounced CD4 (× 20).

Interferon‐γ (INF‐γ) release test can detect cutaneous adverse effects to statins

Background  An increasing number of cutaneous adverse effects are being reported as use of statins becomes more widespread. A study was undertaken to establish the relationship between statin and a cutaneous reaction by the in vitro interferon‐γ (INF‐γ) release test.