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Axial spondyloarthritis (axSpA) is an important cause of chronic low back pain and affects approximately 1% of the US population. The back pain associated with axSpA has a characteristic pattern referred to as inflammatory back pain (IBP). Features of IBP include insidious onset before age 45 years, association with morning stiffness, improvement with exercise but not rest, alternating buttock pain, and good response to treatment with nonsteroidal anti-inflammatory drugs. In patients with IBP, it is essential to look for other features associated with spondyloarthritis (SpA), such as enthesitis, dactylitis, peripheral arthritis, extra-articular manifestations (eg, psoriasis, uveitis, or inflammatory bowel disease), human leukocyte antigen B27 positivity, and a family history of SpA. Axial SpA is underrecognized, and a delay of several years between symptom onset and diagnosis is common. However, with new and effective therapies available for the treatment of active axSpA, early recognition and diagnosis are of critical importance. For this narrative review, we conducted a literature search of English-language articles using PubMed. Individual searches were performed to identify potential articles of interest related to axSpA (search terms: ["axSpA" OR "axial SpA" OR "axial spondyloarthritis" OR "ankylosing spondylitis"]) in combination with terms related to IBP ("inflammatory back pain" OR "IBP" OR "chronic back pain" OR "CBP" OR "lower back pain" OR "LBP"), diagnosis (["diagn∗" OR "classification"] AND ["criteria" OR "recommend∗" OR "guidelines"]), and referral ("refer∗"). No date range was formally selected, as we were interested in providing an overview of the evolution of these concepts in clinical practice. We supplemented the review with insights based on our clinical expertise. Patients with chronic back pain should be screened for IBP and other SpA features; suspicion for axSpA should trigger referral to a rheumatologist for further evaluation.

Mouse and human data implicate the NOD1 and NOD2 sensors of the intestinal microbiome and the associated signal transduction via the receptor interacting protein kinase 2 (RIPK2) as a potential key signaling node for the development of inflammatory bowel disease (IBD) and an attractive target for pharmacological intervention. The TRUC mouse model of IBD was strongly indicated for evaluating RIPK2 antagonism for its effect on intestinal inflammation based on previous knockout studies with NOD1, NOD2, and RIPK2. We identified and profiled the BI 706039 molecule as a potent and specific functional inhibitor of both human and mouse RIPK2 and with favorable pharmacokinetic properties. We dosed BI 706039 in the spontaneous TRUC mouse model from age 28 to 56 days. Oral, daily administration of BI 706039 caused dose-responsive and significant improvement in colonic histopathological inflammation, colon weight, and terminal levels of protein-normalized fecal lipocalin (all

Objective.Pannus formation in the atlanto-axial joint is a well-recognized complication of rheumatoid arthritis (RA). Occasionally, atlanto-axial pannus is reported when patients without a history of RA undergo magnetic resonance imaging (MRI) of the cervical spine. We sought to further characterize these patients.Methods.The Partners HealthCare Research Patient Data Registry was free-text searched for “atlanto-axial” AND “pannus” in cervical spine MRI reports from 2001 to 2015. Cases with MRI reports describing pannus were reviewed. Clinical data were extracted by chart review in cases with confirmed atlanto-axial pannus (n = 105).Results.Twenty-nine patients (27.6%) had RA, all of whom except one carried this diagnosis at the time of the MRI scan. Only 1 of 77 patients without a history of RA was subsequently diagnosed with RA (1.3%, 95% CI 0.1–7.0%, median followup 3.6 yrs). Non-RA patients were significantly older (median age 79 vs 63 yrs, p < 0.0001), less frequently female (55% vs 86%, p = 0.0032), and more likely to have undergone prior cervical spine surgery (18% vs 0%, p = 0.016) compared with RA patients. Thirty-four non-RA patients (44.7%) either had a clinical diagnosis of calcium pyrophosphate dihydrate disease (CPPD) or imaging evidence for tissue calcification. There were no significant differences in age or sex between the CPPD subgroup and other non-RA patients. Twenty-eight patients (26.7%) underwent cervical spine surgery.Conclusion.Patients without RA diagnosis and incidental atlanto-axial pannus on cervical spine MRI are unlikely to have previously unrecognized RA. Degenerative disease and tissue calcification may contribute to pannus formation in these patients.

BackgroundOverexpression of IL-23 in adult mice by means of hydrodynamic tail vein injection of IL-23 minicircles has been reported to result in spondyloarthritis-like disease. The impact of genetic background and sex on the disease phenotype in this model has not been investigated.MethodsWe compared male B10.RIII mice with male C57BL/6 mice, and male with female B10.RIII mice after hydrodynamic injection of IL-23 enhanced episomal vector (EEV) at 8-12 weeks of age. We monitored clinical arthritis scores, paw swelling, and body weight. Animals were euthanized after two weeks and tissues were harvested for histology, flow cytometry and gene expression analysis. Serum cytokine levels were determined by ELISA.FindingsMale B10.RIII mice developed arthritis in the forepaws and feet within 6 days after IL-23 EEV injection; they also exhibited psoriasis-like skin disease, colitis, weight loss, and osteopenia. In contrast to previous reports, we did not observe spondylitis or uveitis. Male C57BL/6 mice injected with IL-23 EEV had serum IL-23 levels comparable with B10.RIII mice and developed skin inflammation, colitis, weight loss, and osteopenia but failed to develop arthritis. Female B10.RIII mice had more severe arthritis than male B10.RIII mice but did not lose weight.ConclusionsSystemic IL-23 overexpression results in spondyloarthritis-like disease in B10.RIII mice. The development of extra-articular manifestations but absence of arthritis in C57BL/6 mice suggests organ-specific genetic control mechanisms of IL-23 driven inflammation. Discrepancies regarding the phenotype of IL-23 induced disease in different labs and the sexual dimorphism observed in this study warrant further exploration.

Background Overexpression of IL-23 in adult mice by means of hydrodynamic tail vein injection of IL-23 minicircles has been reported to result in spondyloarthritis-like disease. The impact of genetic background and sex on the disease phenotype in this model has not been investigated. Methods We compared male B10.RIII mice with male C57BL/6 mice, and male with female B10.RIII mice after hydrodynamic injection of IL-23 enhanced episomal vector (EEV) at 8–12 weeks of age. We monitored clinical arthritis scores, paw swelling, and body weight. Animals were euthanized after two weeks and tissues were harvested for histology, flow cytometry and gene expression analysis. Serum cytokine levels were determined by ELISA. Findings Male B10.RIII mice developed arthritis in the forepaws and feet within 6 days after IL-23 EEV injection; they also exhibited psoriasis-like skin disease, colitis, weight loss, and osteopenia. In contrast to previous reports, we did not observe spondylitis or uveitis. Male C57BL/6 mice injected with IL-23 EEV had serum IL-23 levels comparable with B10.RIII mice and developed skin inflammation, colitis, weight loss, and osteopenia but failed to develop arthritis. Female B10.RIII mice had more severe arthritis than male B10.RIII mice but did not lose weight. Conclusions The phenotype of IL-23 induced disease in mice is controlled by genetic background and sex of the animals. The development of extra-articular manifestations but absence of arthritis in C57BL/6 mice suggests that organ-specificity of IL-23 driven inflammation is genetically determined. The mechanisms behind the strain-specific differences and the sexual dimorphism observed in this study may be relevant for human spondyloarthritis and warrant further exploration.

Purpose of review This review encompasses a detailed history of spondyloarthritis (SpA) evolution as early as the 17th century, continues on to the current concept of SpA, and ends with current gaps in our understandings of SpA. Recent findings Until the early 1960s, ankylosing spondylitis and other SpA family members were considered to be variants of rheumatoid arthritis (RA). The formal medical community separated them from RA at that time, and shortly thereafter they were recognized to be inter-connected based on shared clinical, laboratory, and imaging features. The last two decades have witnessed the formal distinction between axial and peripheral SpA and the connections that exist between nonradiographic and radiographic axial SpA. Recent studies have revealed different microbial compositions among patients with SpA and healthy controls and also between HLA-B27 positive and negative healthy individuals. Summary Further investigation of the roles of intestinal microbiome and physical force transduction toward SpA pathogenesis, strategies to improve delay in SpA diagnosis, biomarkers to better predict radiographic progression, and modification of current classification criteria to better address the axial and peripheral groups are gaps in our understandings that pose top priorities for SpA research.

Scientific breakthroughs have culminated in the development of the spondyloarthritis (SpA) concept as a family of rheumatic diseases, distinct from rheumatoid arthritis. The demonstration of inflammatory lesions in the sacroiliac joints and spine of patients with axial symptoms of SpA who lacked radiographic features of ankylosing spondylitis (AS) helped refine the SpA concept. Axial SpA includes patients with AS and patients with axial symptoms previously categorized as undifferentiated SpA. This review examines the sources of knowledge that inform axial SpA pathogenesis, highlighting current limitations, and a basic working model of axial SpA pathogenesis.

Background:Ixekizumab (IXE), a high-affinity anti-interleukin-17A monoclonal antibody, is effective in patients (pts) with active non-radiographic axial spondyloarthritis (nr-axSpA), who had elevated C-reactive protein (CRP) and/or active sacroiliitis on magnetic resonance imaging (MRI).1Objectives:To determine if disease activity and patient-reported outcomes at Week 16 were similar between groups after stratifying pts by CRP/sacroiliac joint (SIJ) MRI status at baseline.Methods:COAST-X (NCT02757352) included pts with active nr-axSpA and objective signs of inflammation, i.e. presence of sacroiliitis on MRI (Assessment of Spondyloarthritis International Society [ASAS]/ Outcome Measures in Rheumatology criteria) or elevation of serum CRP (>5.0 mg/L). Pts were randomized 1:1:1 to receive subcutaneous 80 mg IXE every 4 weeks (Q4W) or Q2W, or placebo (PBO). Depending on the baseline values of CRP and MRI SIJ (Spondyloarthritis Research Consortium of Canada [SPARCC] score), pts in the intent-to-treat population (N=239) were divided into 3 subgroups (CRP >5 and MRI ≥2; CRP ≤5 and MRI ≥2; CRP >5 and MRI Results:The proportion of pts achieving ASAS40 (primary endpoint), ASDAS 5 and MRI ≥2; CRP ≤5 and MRI ≥2; CRP >5 and MRI Conclusion:Pts with active nr-axSpA and objective signs of inflammation at baseline who were treated with IXE showed an overall improvement in the signs and symptoms of the disease. The efficacy was not different between pts with both elevated CRP and active sacroiliitis on MRI and pts with either elevated CRP or active sacroiliitis on MRI.References:[1]Deodhar A, et al.Lancet.2020.Disclosure of Interests:Walter P Maksymowych Grant/research support from: Received research and/or educational grants from Abbvie, Novartis, Pfizer, UCB, Consultant of: WPM is Chief Medical Officer of CARE Arthritis Limited, has received consultant/participated in advisory boards for Abbvie, Boehringer, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, UCB, Speakers bureau: Received speaker fees from Abbvie, Janssen, Novartis, Pfizer, UCB., Helena Marzo-Ortega Grant/research support from: Janssen, Novartis, Consultant of: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Speakers bureau: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Takeda, UCB, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Lianne S. Gensler Grant/research support from: Pfizer, Novartis, UCB, Consultant of: AbbVie, Eli Lilly, GSK, Novartis, UCB, Joerg Ermann Grant/research support from: Boehringer-Ingelheim, Pfizer, Consultant of: Abbvie, Eli Lilly, Janssen, Novartis,Pfizer, Takeda, UCB, Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Denis Poddubnyy Grant/research support from: AbbVie, MSD, Novartis, and Pfizer, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, David Sandoval Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Rebecca Bolce Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Andris Kronbergs Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Soyi Liu Leage Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Gabriel Doridot Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Vladimir Geneus Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Ann Leung: None declared, David Adams Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Martin Rudwaleit Consultant of: AbbVie, BMS, Celgene, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB Pharma

Objectives This study aimed to compare comorbidities and biologic DMARD (bDMARD) use between AS and non-radiographic axial SpA (nr-axSpA) patients, using a large cohort of patients from routine clinical practice in the United States. Methods We performed a cross-sectional study using electronic medical records from two academic hospitals in the United States. Data were extracted using automated searches (⩾3 ICD codes combined with text searches) and supplemented with manual chart review. Patients were categorized into AS or nr-axSpA according to classification criteria. Disease features, comorbidities (from a list of 39 chronic conditions) and history of bDMARD prescription were compared using descriptive statistics. Results Among 965 patients identified, 775 (80%) were classified as having axSpA. The cohort was predominantly male (74%) with a mean age of 52.5 years (s.d. 16.8). AS patients were significantly older (54 vs 46 years), more frequently male (77% vs 64%) and had higher serum inflammatory markers than those with nr-axSpA (median CRP 3.4 vs 2.2 mg/dl). Half of all patients had at least one comorbidity. The mean number of comorbidities was 1.5 (s.d. 2.2) and similar between AS and nr-axSpA groups. A history of bDMARD-use was seen in 55% of patients with no difference between groups. The most commonly prescribed bDMARDs were adalimumab (31%) and etanercept (29%). Ever-prescriptions of individual bDMARDs were similar between AS and nr-axSpA. Conclusion Despite age differences, nr-axSpA patients had similar comorbidity burdens as those with AS. Both groups received comparable bDMARD treatment in this United States clinic-based cohort.

ObjectivesTo develop classification algorithms that accurately identify axial SpA (axSpA) patients in electronic health records, and compare the performance of algorithms incorporating free-text data against approaches using only International Classification of Diseases (ICD) codes.MethodsAn enriched cohort of 7853 eligible patients was created from electronic health records of two large hospitals using automated searches (⩾1 ICD codes combined with simple text searches). Key disease concepts from free-text data were extracted using NLP and combined with ICD codes to develop algorithms. We created both supervised regression-based algorithms—on a training set of 127 axSpA cases and 423 non-cases—and unsupervised algorithms to identify patients with high probability of having axSpA from the enriched cohort. Their performance was compared against classifications using ICD codes only.ResultsNLP extracted four disease concepts of high predictive value: ankylosing spondylitis, sacroiliitis, HLA-B27 and spondylitis. The unsupervised algorithm, incorporating both the NLP concept and ICD code for AS, identified the greatest number of patients. By setting the probability threshold to attain 80% positive predictive value, it identified 1509 axSpA patients (mean age 53 years, 71% male). Sensitivity was 0.78, specificity 0.94 and area under the curve 0.93. The two supervised algorithms performed similarly but identified fewer patients. All three outperformed traditional approaches using ICD codes alone (area under the curve 0.80–0.87).ConclusionAlgorithms incorporating free-text data can accurately identify axSpA patients in electronic health records. Large cohorts identified using these novel methods offer exciting opportunities for future clinical research.

Retro-odontoid pseudotumor, or mass-like retro-odontoid soft tissue thickening, is an uncommon but important imaging finding that may be associated with rheumatoid arthritis, crystal deposition diseases, as well as non-inflammatory conditions such as cervical degenerative changes and mechanical alterations. Retro-odontoid pseudotumor is commonly associated with atlantoaxial microinstability or subluxation. MRI and CT have an important role in the detection and diagnosis of retro-odontoid pseudotumor. However, due to a wide range of imaging characteristics and ambiguous etiology, it is a frequently misunderstood entity. The purpose of this article is to review relevant anatomy of the craniocervical junction; describe various imaging appearances, pathophysiology and histology in both rheumatoid and non-rheumatoid etiologies; and discuss differential diagnosis of retro-odontoid pseudotumor in order to help guide clinical management.

Objective To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). Methods A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946–2014), PubMed (1966–2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. Results In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. Conclusion These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.

Biomarkers are needed to guide treatment decisions for patients with rheumatic diseases. Although the phenotypic and functional analysis of immune cells is an appealing strategy for understanding immune-mediated disease processes, immune cell profiling currently has no role in clinical rheumatology. New technologies, including mass cytometry, gene expression profiling by RNA sequencing (RNA-seq) and multiplexed functional assays, enable the analysis of immune cell function with unprecedented detail and promise not only a deeper understanding of pathogenesis, but also the discovery of novel biomarkers. The large and complex data sets generated by these technologies--big data--require specialized approaches for analysis and visualization of results. Standardization of assays and definition of the range of normal values are additional challenges when translating these novel approaches into clinical practice. In this Review, we discuss technological advances in the high-dimensional analysis of immune cells and consider how these developments might support the discovery of predictive biomarkers to benefit the practice of rheumatology and improve patient care.

Local delivery of therapeutics for the treatment of inflammatory arthritis (IA) is limited by short intra-articular half-lives. Since IA severity often fluctuates over time, a local drug delivery method that titrates drug release to arthritis activity would represent an attractive paradigm in IA therapy. Here we report the development of a hydrogel platform that exhibits disassembly and drug release controlled by the concentration of enzymes expressed during arthritis flares. In vitro, hydrogel loaded with triamcinolone acetonide (TA) releases drug on-demand upon exposure to enzymes or synovial fluid from patients with rheumatoid arthritis. In arthritic mice, hydrogel loaded with a fluorescent dye demonstrates flare-dependent disassembly measured as loss of fluorescence. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduces arthritis activity in the injected paw. Together, our data suggest flare-responsive hydrogel as a promising next-generation drug delivery approach for the treatment of IA.

Summary Background: Systemic lupus erythematosus (SLE) is a heterogenous disease with complex pathogenesis. Aim: In this review, we summarise recent progress in the understanding of SLE pathogenesis and discuss implications for the treatment of SLE patients using standard and experimental medications. Conclusions: The discovery that Toll-like receptor signalling and interferon-α abundance are central elements of the disease process has led to a new appreciation for hydroxychloroquine as an essential baseline medication. Although much needs to be learned, modulation of the immune system via B-cell depletion is entering clinical practice. Mycophenolate mofetil is an effective and safer alternative to cyclophosphamide for many patients with lupus nephritis. Several other therapeutic approaches are at various stages of preclinical and clinical development. These include anticytokine therapies, co-stimulatory blockade, antigen-specific immune modulation and haematopoietic stem cell transplantation.

There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Targeting drugs selectively to the inflamed intestine may improve therapeutic outcomes and minimize systemic toxicity. We report the development of an inflammation-targeting hydrogel (IT-hydrogel) that acts as a drug delivery system to the inflamed colon. Hydrogel microfibers were generated from ascorbyl palmitate, an amphiphile that is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. IT-hydrogel microfibers loaded with the anti-inflammatory corticosteroid dexamethasone (Dex) were stable, released drug only upon enzymatic digestion, and demonstrated preferential adhesion to inflamed epithelial surfaces in vitro and in two mouse colitis models in vivo. Dex-loaded IT-hydrogel enemas, but not free Dex enemas, administered every other day to mice with colitis resulted in a significant reduction in inflammation and were associated with lower Dex peak serum concentrations and, thus, less systemic drug exposure. Ex vivo analysis of colon tissue samples from patients with ulcerative colitis demonstrated that IT-hydrogel microfibers adhered preferentially to mucosa from inflamed lesions compared with histologically normal sites. The IT-hydrogel drug delivery platform represents a promising approach for targeted enema-based therapies in patients with colonic IBD.

In this Overview, common themes of the accompanying News & Views on RA, SLE, IDDM, thyroiditis and MS are discussed. A unifying concept for the development of these and other autoimmune diseases should incorporate genetic predisposition, environmental factors and immune dysregulation.

Sir, Prospective cohort studies have demonstrated an increased risk of active tuberculosis in patients treated with tumor necrosis factor antagonists (anti-TNF agents) [1]. Current guidelines support chemoprophylaxis with isoniazid (INH) for 6–9 months prior to the initiation of anti-TNF agents in patients with evidence of latent tuberculosis [2]. We present two rheumatoid arthritis patients who had positive tuberculin skin tests (TST). Despite receiving an adequate course of INH for latent tuberculosis infection, both patients developed active tuberculosis after initiation of infliximab. Patient 1 is a 58-yr-old male Chinese immigrant with a 3 yr history of seropositive rheumatoid arthritis who was admitted to the hospital with three weeks of fevers, chills, productive cough, night sweats and altered mental status. His medical history was otherwise notable for chronic inactive hepatitis B and chronic obstructive pulmonary disease. Three yrs prior, he had a positive TST. Chest computed tomography (CT) revealed emphysematous changes and multiple calcified granulomas consistent with prior tuberculosis. He was treated with a 9 month course of INH, 300 mg/day. Despite treatment with methotrexate and sulfasalazine, his rheumatoid arthritis remained active, requiring frequent intra-articular steroid injections and oral corticosteroids. Fourteen months prior to admission he started infliximab infusions (6 mg/kg) in addition to methotrexate and sulfasalzine, and was successfully tapered off corticosteroids. On admission, the patient was ill appearing and thin. He had a temperature of 102.6° with normal respiratory rate and oxygen saturation. The breath sounds were decreased and there were diffuse expiratory wheezes in all the lung fields. There was no lymphadenopathy. Initial investigations included normal complete blood counts, electrolytes, liver and renal function tests, as well as negative tests for HIV, hepatitis C and rapid plasma reagent. Sputum stains for acid-fast bacilli, pneumocystis carinii and legionella species were negative. A chest radiograph and chest CT scan demonstrated no new infiltrates or pathological lymphadenopathy. A CT scan of the abdomen and pelvis revealed enlarged mesenteric and retro-peritoneal nodes. Bone marrow biopsy and right inguinal lymph node biopsy did not show evidence of malignancy or granulomatous disease. Given the high level of concern for tuberculosis, the patient was empirically started on INH, rifampin, pyrizinamide and ethambutol. Nine days after discharge the sputum cultures grew mycobacterium tuberculosis, with sensitivity to ethambutol, INH, pyrazinamide, rifampin and streptomycin. He has since made a full recovery. Patient 2 is a 77-yr-old woman originally from Trinidad with seronegative rheumatoid arthritis treated with infliximab who was admitted to the hospital with a three week history of worsening weakness and fatigue. One week prior to admission she developed a non-productive cough, fevers and chills. On the day of admission she was profoundly weak and was noted by family members to have slurred speech. Her medical history was also notable for sickle cell trait, glucose-6-phosphate dehydrogenase deficiency, sideroblastic anaemia and a single episode of bilateral pulmonary embolism. Ten yrs prior she had a positive TST; chest radiographs did not show any abnormalities suggestive of tuberculosis at the time. Seven yrs prior to admission she was treated with a 7 month course of INH after starting prednisone. She had a negative TST 4 yrs prior. She had previously failed methotrexate and subsequently failed combination therapy with leflunomide. She was started on treatment with infliximab at 4 mg/kg every 6 weeks 4 months earlier. Medications on admission included methotrexate (17.5 mg orally once per week), prednisone (5 mg/day), infliximab, warfarin and oxycodone. On admission, her temperature was 103 F and oxygen saturation was 92%. On chest auscultation, there were inspiratory crackles at the left lower lung base. She had right hip pain with very limited range of motion. Initial laboratory evaluation was notable for a white blood cell count of 2600 cells, with 59% neutrophils and 9% bands. Serum electrolytes were normal; blood and urine cultures were negative. A chest radiograph was consistent with left lower lobe pneumonia and the patient was initially treated for community-acquired pneumonia with levofloxacin. By the fourth hospital day she had failed to improve; a chest CT demonstrated bilateral multiple small pulmonary nodules consistent with miliary tuberculosis. A right hip joint aspiration yielded sterile, non-inflammatory synovial fluid. A bone marrow biopsy showed normal myeloid elements. On the ninth hospital day a sputum sample was positive by gen-probe amplified mycobacterium tuberculosis direct test. Treatment was started with rifampin, INH, ethambutol and pyrazinamide. The following day she developed respiratory failure requiring mechanical ventilation for the next 9 days. She gradually recovered and was discharged to a rehabilitation facility after a 34 day hospital course. Eventually, sputum cultures grew mycobacterium tuberculosis, with sensitivity to ethambutol, INH, pyrazinamide, rifampin and streptomycin.

Rheumatoid arthritis (RA) is an autoimmune arthritis, for which treatment options remain limited. This study investigated the potential role of adoptive cellular gene therapy as a novel means for treating the RA animal model collagen-induced arthritis (CIA). Adoptive transfer of antigen-specific T-cell hybridomas retrovirally transduced to express IL-4 1 day before booster immunization significantly reduced the number of inflamed joints. Cell transfer after clinical onset of disease had no therapeutic effect. Bioluminescence imaging showed that the hybridomas migrated to the inflamed joints, thus delivering the regulatory protein locally at the site of inflammation. The homing was, at least in part, due to chemotaxis in response to proinflammatory chemokines that are expressed in inflamed joints. There were no significant changes in the cytokine milieu of the draining lymph nodes, nor in the systemic levels of anti-collagen antibodies in treated mice. We conclude that the beneficial clinical effects observed in our model were most likely based on the local action(s) of IL-4 in the inflamed joints and that the local delivery (and effects) of regulatory cytokines, like IL-4, constitutes a novel and effective method of preventing organ-specific autoimmune disease and of minimizing systemic adverse effects.