Eamonn S. Molloy

Anti-tumour necrosis factor therapy in patients with refractory Takayasu arteritis: long-term follow-up

Objective: To assess the efficacy of anti-tumour necrosis factor (TNF) therapy to induce remission in patients with Takayasu arteritis (TAK) refractory to other immunosuppressive therapies. Methods: Retrospective single-centre study of 25 patients with refractory TAK. Results: Patients were treated with infliximab (IFX) or etanercept (ETA) for up to 7 years; 21 with IFX (median 28 months (range 2–84)) and 9 with ETA (median 28 months (range 4–82)); 5 patients initially treated with ETA subsequently switched to IFX. Following anti-TNF therapy, remission was achieved and prednisone was discontinued in 15 patients (60%) and successfully tapered below 10 mg/day in an additional 7 patients (28%). Of 18 patients treated with other immunosuppressive agents concurrent with anti-TNF therapy, 9 (50%) could taper or discontinue the additional agent. Major relapses occurred in four patients that initially achieved stable remission. Four patients suffered adverse events, including one with opportunistic infections and one with breast cancer. Conclusions: In this group of patients with refractory TAK, anti-TNF therapy was associated with remission in a majority of patients, facilitating dose reduction or discontinuation of prednisone and other immunosuppressive therapy. These findings strengthen the rationale for the conducting of a randomised controlled trial of anti-TNF therapy in TAK.

Progressive multifocal leukoencephalopathy: a national estimate of frequency in systemic lupus erythematosus and other rheumatic diseases.

OBJECTIVE Progressive multifocal leukoencephalopathy (PML) is a rare, typically fatal, central nervous system demyelinating disease that results from reactivation of the JC virus, which generally occurs in immunosuppressed hosts. The aim of this study was to generate a national estimate of the frequency of PML among patients with rheumatic diseases. METHODS Data were obtained from the Nationwide Inpatient Sample database. This is a 20% sample of all hospital discharges, weighted to represent the entire US inpatient population. Data were analyzed for the years 1998-2005 inclusive, representing 297,797,180 hospital discharges. Cases of PML, systemic lupus erythematosus (SLE), and other rheumatic diseases were identified by diagnostic codes from the International Classification of Diseases, Ninth Revision, Clinical Modification. RESULTS A total of 9,675 cases of PML were identified. The majority were associated with human immunodeficiency virus (HIV; 7,934 patients [82.00%]), hematologic cancers (813 patients [8.40%]), and solid cancers (274 patients [2.83%]). Among the rheumatic diseases, 43 cases of PML (0.44%) were associated with SLE, 24 (0.25%) with rheumatoid arthritis (RA), and 25 (0.26%) with other connective tissue diseases (CTDs). When patients with other potential risk factors for PML (HIV, malignancy, bone marrow or other organ transplantation) were excluded, the rates of PML per 100,000 discharges coded for SLE, RA, and other CTDs were 4, 0.4 and 2, respectively, compared with a rate of PML in the background population of 0.2/100,000 discharges. CONCLUSION This study was confined to hospitalized patients with rheumatic diseases, and it was also limited by the lack of information regarding immunosuppressive therapy. Nevertheless, the findings suggest that, although rare overall, PML occurs more commonly in SLE than in other rheumatic diseases.

Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: Evolving role of biologic therapies

OBJECTIVE To evaluate the association of progressive multifocal leukoencephalopathy (PML) with immunosuppressive therapy for autoimmune rheumatic diseases (ARDs). METHODS A Freedom of Information Act request was submitted for all cases of PML within the Food and Drug Administration Adverse Event Reporting System database. ARD cases were selected for further analysis. RESULTS A total of 34 confirmed cases of PML in the setting of ARDs were identified: 17 had systemic lupus erythematosus, 10 had rheumatoid arthritis, 4 had vasculitis, and 3 had dermatomyositis. Fifteen of these patients were treated with one or more biologic agents: 14 received rituximab (RTX), 6 received anti-tumor necrosis factor (anti-TNF) therapy (5 treated with anti-TNF agent prior to RTX). Four RTX-treated patients were not receiving additional immunosuppressive therapy at the time of PML onset, other than an antimalarial drug and/or low-dose glucocorticoids; all others who were receiving a biologic agent were also receiving one or more synthetic disease-modifying agents. All but 1 patient receiving a biologic agent had at least 1 potential confounding factor for the diagnosis of PML. The remaining 19 confirmed cases of PML among ARD patients were treated with synthetic disease-modifying antirheumatic drugs only, 14 of whom had received an alkylating agent. CONCLUSION PML has been reported in patients with ARD treated with various immunosuppressive agents. The limitations of this study preclude definitive attribution of causality. While the paucity of confirmed cases recently exposed to anti-TNF therapy suggests a causal relationship is unlikely, a specific signal is emerging with regard to rituximab and PML. Although this is a rare adverse event associated with RTX therapy, the devastating nature of PML mandates continued vigilance, particularly in patients with current or prior exposure to an alkylating agent.

Progressive multifocal leukoencephalopathy in patients with rheumatic diseases: are patients with systemic lupus erythematosus at particular risk?

Progressive multifocal leukoencephalopathy (PML) is a rare, frequently fatal, infectious complication occurring in immunocompromised patients. PML has been well-reported in patients with chronic inflammatory rheumatic diseases taking immunosuppressive drugs. Awareness of the occurrence of PML in patients with rheumatic diseases has recently been highlighted by the occurrence of several cases of PML following administration of natalizumab and rituximab, biologic agents which have been used for the treatment of rheumatic diseases. Nearly two thirds of cases of PML in patients with rheumatic diseases reported in the medical literature occurred in patients with systemic lupus erythematosus (SLE). Over 40% of PML cases in SLE occurred in patients who had had minimal iatrogenic immunosuppression, suggesting that SLE itself may predispose to PML. The mechanism of this putative predisposition of SLE patients to the development of PML remains unexplained.

Tumour-like mass lesion: an under-recognised presentation of primary angiitis of the central nervous system

Objective: To describe the occurrence of mass lesions (ML) in primary angiitis of the central nervous system (PACNS) and assess the utility of diagnostic testing and treatment. Methods: We examined the case records of the Cleveland Clinic (CC), Massachusetts General Hospital (MGH), and the English language medical literature, for biopsy-proven PACNS cases presenting as a solitary ML. Relevant clinical variables were extracted and analysed with JMP software. Results: We identified a total of 38 ML: eight of 202 (4.0%) patients with CC/MGH and 30 of 535 (5.6%) patients with PACNS identified from the medical literature. A higher percentage (13 of 45; 29%) was seen in the amyloid-related angiitis subset. Poorer outcomes were reported in the amyloid group, with five deaths. Of the non-amyloid group, better outcomes were seen in the group treated with corticosteroids and cyclophosphamide as compared with the group treated with corticosteroids alone. Conclusions: Although rare, PACNS should be considered in the differential diagnosis of ML; greater awareness of this manifestation may facilitate more prompt diagnosis and treatment. Biopsy evidence of angiitis is required for diagnosis; specimens should routinely be stained for amyloid. While excision of the lesion may be curative, aggressive immunosuppressive therapy is associated with favourable outcomes and may obviate the need for surgery.

Therapy: Targeted but not trouble-free: efalizumab and PML

In April 2009, efalizumab was withdrawn from the market for the treatment of psoriasis after reports emerged of an association between long-term therapy and the development of progressive multifocal leukoencephalopathy (PML). This event highlights an urgent need for greater awareness and research into the screening, diagnosis and treatment of this potentially fatal disease in patients undergoing immunosuppressive therapy for chronic inflammatory disorders.

Single-organ vasculitis

Purpose of reviewTo provide a critical analysis of a rare disorder, single-organ vasculitis, emphasizing those organs in which the excision of the vasculitic lesion can be curative. To recommend a rational approach to diagnosis, longitudinal follow-up and treatment. Recent findingsPatients with focal single-organ vasculitis affecting abdominal and genitourinary organs, breast and aorta have been reported as individual cases and small series. Single-organ vasculitis differs from systemic forms of vasculitis in disease expression and prognosis. Occasionally, what appears to be a localized process evolves into a systemic disease. Depending on the organ affected, some clinical, serological and histopathologic features may be helpful in predicting the extent of the vasculitic process. With the exception of severe ischemic or hemorrhagic complications affecting the abdominal organs and dissection or rupture of the aortic arch, the prognosis of focal single-organ vasculitis tends to be excellent. Resection of the inflammatory lesion may be curative. SummaryThe diagnosis of focal single-organ vasculitis is always presumptive and requires exclusion of systemic illness at the time of diagnosis as well as throughout the period of continued care. Clues from clinical symptoms, laboratory tests and histopathologic features at the time of diagnosis may assist in devising surveillance strategies.

Ustekinumab for the treatment of refractory giant cell arteritis

Giant cell arteritis (GCA) is the most common form of systemic vasculitis.1 Glucocorticoids are the mainstay of therapy, required in high doses for prolonged periods, with consequent serious complications in 86% of patients.2 There is a critical unmet need for a proven safe and effective immunosuppressive therapy in GCA, as agents such as methotrexate and infliximab have shown disappointing results in GCA.3 ,4 Interleukins 12 (IL-12) and 23 (IL-23) are implicated in Th1 and Th17 responses, respectively, both inflammatory pathways relevant to GCA pathogenesis.5 ,6 A recent case series reported the use of ustekinumab in three patients with Takayasu arteritis.7 The aim of this study was to evaluate the glucocorticoid-sparing efficacy of ustekinumab, an IL-12/IL-23-blocking monoclonal antibody, in patients with refractory GCA. Patients with GCA attending our centre are enrolled in a prospective registry and managed according to standardised …

Proneoplastic effects of PGE2 mediated by EP4 receptor in colorectal cancer

BackgroundProstaglandin E2 (PGE2) is the major product of Cyclooxygenase-2 (COX-2) in colorectal cancer (CRC). We aimed to assess PGE2 cell surface receptors (EP 1–4) to examine the mechanisms by which PGE2 regulates tumour progression.MethodsGene expression studies were performed by quantitative RT-PCR. Cell cycle was analysed by flow cytometry with cell proliferation quantified by BrdU incorporation measured by enzyme immunoassay. Immunohistochemistry was employed for expression studies on formalin fixed paraffin embedded tumour tissue.ResultsEP4 was the most abundant subtype of PGE2 receptor in HT-29 and HCA7 cells (which show COX-2 dependent PGE2 generation) and was consistently the most abundant transcript in human colorectal tumours (n = 8) by qRT-PCR (ANOVA, p = 0.01). G0/G1 cell cycle arrest was observed in HT-29 cells treated with SC-236 5 μM (selective COX-2 inhibitor) for 24 hours (p = 0.02), an effect abrogated by co-incubation with PGE2 (1 μM). G0/G1 arrest was also seen with a specific EP4 receptor antagonist (EP4A, L-161982) (p = 0.01). Treatment of HT-29 cells with either SC-236 or EP4A caused reduction in intracellular cAMP (ANOVA, p = 0.01). Early induction in p21WAF1/CIP1 expression (by qRT-PCR) was seen with EP4A treatment (mean fold increase 4.4, p = 0.04) while other genes remained unchanged. Similar induction in p21WAF1/CIP1 was also seen with PD153025 (1 μM), an EGFR tyrosine kinase inhibitor, suggesting EGFR transactivation by EP4 as a potential mechanism. Additive inhibition of HCA7 proliferation was observed with the combination of SC-236 and neutralising antibody to amphiregulin (AR), a soluble EGFR ligand. Concordance in COX-2 and AR localisation in human colorectal tumours was noted.ConclusionCOX-2 regulates cell cycle transition via EP4 receptor and altered p21WAF1/CIP1 expression. EGFR pathways appear important. Specific targeting of the EP4 receptor or downstream targets may offer a safer alternative to COX-2 inhibition in the chemoprevention of CRC.

Vasculitis Involving the Breast : A Clinical and Histopathologic Analysis of 34 Patients

Vasculitis of the breast (VB) may be an isolated finding or a manifestation of systemic vasculitis. In the current study we sought to characterize isolated VB (IVB) and compare it to VB in the setting of systemic vasculitis. We studied VB cases in the literature and patients cared for at our institution. We analyzed clinical, laboratory, and histologic features (including vessel size and type of inflammatory infiltrates); course of illness; biopsy procedure; and treatment. Based on the presence of localized or systemic disease at the time of disease presentation and during the follow-up, we divided patients into 3 groups: IVB (Group 1), VB with proven or indirect evidence of systemic vasculitis (Group 2), and VB with possible systemic involvement (Group 3). We identified a total of 34 cases of VB (30 from PubMed [National Library of Medicine, Bethesda, MD] and 4 from our pathology database). All patients presented with breast lesions, which were the only expression of disease in 16 (47%). Eighteen, 6, and 10 patients belonged to Group 1, 2, and 3, respectively. Constitutional symptoms were present less often in Group 1. Musculoskeletal symptoms occurred only in Groups 2 and 3. Patients in Groups 2 and 3 had higher erythrocyte sedimentation rates and lower hemoglobin levels, and also received corticosteroids more frequently than those in Group 1. No differences were found in the other analyzed parameters between groups. In summary, VB is uncommon, and in about half of the cases, occurs in the form of IVB. Histologic characteristics do not correlate with disease extent. In IVB patients, constitutional and musculoskeletal manifestations are usually absent. Such patients generally do not require systemic therapy and may be cured by resection alone. Abbreviations: ESR = erythrocyte sedimentation rate, IVB = isolated vasculitis of the breast, VB = vasculitis of the breast.