Etanercept-induced cutaneous and pulmonary sarcoid-like granulomas resolving with adalimumab.

A 59-year-old female with rheumatoid arthritis on etanercept therapy presented with a 7-cm-large subcutaneous forearm mass. Multiple smaller nodules subsequently developed on the upper and lower extremities. Except for a new cough, the patient was systemically well. Biopsy of the mass showed sarcoidal type granulomatous inflammation with nodular aggregations of non-necrotizing epithelioid histiocytes in the subcutis. A chest computed tomography (CT) scan showed mediastinal adenopathy consistent with pulmonary sarcoidosis. Etanercept was discontinued, and the patient was started on adalimumab for rheumatoid arthritis control. The cutaneous nodules fully resolved in 6 months with no additional treatment. A 4-month follow-up CT scan showed significant regression of mediastinal adenopathy. The patient has since been maintained on adalimumab therapy for 2 years with no recurrence of sarcoid-like manifestations. Biologic response modifiers targeting tumor necrosis factor alpha (TNFα) are effective treatments of chronic inflammatory conditions such as rheumatoid arthritis and psoriasis. TNFα represents a major cytokine in granuloma formation, and TNFα inhibitors are sometimes efficacious in the treatment of sarcoidosis. Paradoxically, there is a small volume of literature implicating TNFα inhibitors in the development of sarcoid-like disease. We present this case to promote the recognition of TNFα inhibitor-induced sarcoidosis and to illustrate the wide clinicopathologic differential of sarcoidal type granulomas.

Granulomatous vasculitis in Crohn's disease: a clinicopathologic correlate of two unusual cases.

Cutaneous complications occur not uncommonly in patients with Crohn's disease (CD). Gastrointestinal CD often shows non-caseating granulomas and a rare cutaneous finding in CD is a sterile granulomatous infiltrate not contiguous with the GI tract, termed extraintestinal CD (ECD). The clinical presentation of ECD is diverse. The most common histopathological presentation is a superficial and deep granulomatous infiltrate that often accompanies a mixed perivascular infiltrate. Here we report two patients with CD and skin lesions characterized on microscopy by granulomatous vasculitis. A 29-year-old female presented with papules and ulcerated nodules above the ankle. The biopsy showed dermal and superficial subcutaneous involvement by a vasocentric infiltrate of mononuclear and multinucleated histiocytes as well as mural fibrin deposition. A 35-year-old male presented with two tender indurated erythematous plaques with punched-out centers on the lower leg. Histopathologically, a granulomatous vasculitis of small and medium-sized vessels in the dermis and subcutis was evident. These two cases represent the rarely described phenomenon of cutaneous granulomatous vasculitis in CD. Previously reported examples of this entity are reviewed.

Gender-specific decrease in NUDR and 5-HT1A receptor proteins in the prefrontal cortex of subjects with major depressive disorder.

A variety of studies have documented alterations in 5-HT1A receptor binding sites in the brain of subjects with major depressive disorder (MDD). The recently identified transcription factor, nuclear deformed epidermal autoregulatory factor (NUDR/Deaf-1) has been shown to function as a transcriptional modulator of the human 5-HT1A receptor gene. The present study was undertaken to document the regional and cellular localization of NUDR in the human prefrontal cortex and to examine the levels of NUDR and 5-HT1A receptor protein in prefrontal cortex of female and male depressed and control subjects. NUDR immunoreactivity was present in neurons and glia across cortical layers and was co-localized with 5-HT1A receptor immunoreactive neurons. NUDR immunoreactivity as measured by Western blot was significantly decreased in the prefrontal cortex of female depressed subjects (42%, p=0.02) and unchanged in male depressed subjects relative to gender-matched control subjects. Similarly, 5-HT1A receptor protein level was significantly reduced in the prefrontal cortex of female depressed subjects (46%, p=0.03) and unchanged in male depressed subjects compared to gender-matched control subjects. Reduced protein expression of NUDR in the prefrontal cortex of female subjects with MDD may reflect a functional alteration in this transcription factor, which may contribute to the decrease in 5-HT1A receptors observed in the same female subjects with MDD. In addition, the gender-specific alterations in cortical NUDR and 5-HT1A receptor proteins could represent an underlying biological mechanism associated with the higher incidence of depression in women.

Characterization of rat rostral raphe primary cultures: multiplex quantification of serotonergic markers.

Previous reports establishing raphe cultures typically yield less than 1% serotonin (5-HT)-positive neurons and are impractical for transcriptional studies. In this study, we have established primary cultures enriched in 5-HT neurons and quantified the proportion of cells expressing serotonergic and non-serotonergic markers. We have also shown the feasibility of using the multiplex real-time PCR technique to measure the relative amounts of RNA for some of these markers. Rostral raphe cells derived from E13-15 rat embryos were cultured for 7 days and analyzed by quantitative immunofluorescence and western blot analysis. In these cultures, approximately 8% of neurons were immunopositive for serotonergic markers (5-HT or tryptophan hydroxylase (TPH)). The percentage of cells labeled for GFAP (glial marker), tyrosine hydroxylase (catecholaminergic), and GAD65/67 (GABAergic) was 5, 1, and 54%, respectively. Transcription factors REST/NRSF and Deaf-1 were present in 9 and 98% of cells, respectively. Multiplex quantitative RT-PCR (Q-PCR) analysis was done for TPH2, 5-HT1A receptor or Deaf-1 RNAs paired with GAPDH RNA as control. Using this approach, standard curves for each RNA were obtained over 200-fold concentration range of dilution with r2 values >0.99. The relative abundances determined by Q-PCR are consistent with the expression of TPH2>Deaf-1>5-HT1A receptor RNA in serotonergic raphe cells. The standard error of TPH2 RNA levels between cultures was <20%, indicating a consistent purity of 5-HT neurons. Thus, we have generated a highly consistent and reproducible model system that is enriched in 5-HT neurons and that will be valuable in future investigation of serotonergic regulation.