Characteristics associated with patient-reported treatment success in psoriatic arthritis.

OBJECTIVES: To determine characteristics associated with patient-reported treatment success in psoriatic arthritis (PsA). METHODS: Rheumatologist-diagnosed PsA patients fulfilling the CASPAR classification were recruited from a single center. PsA outcome measures included: 66/68 swollen/tender joint counts, Leeds/SPARCC dactylitis/enthesitis indices, psoriasis body surface area (BSA), and patient-reported outcomes (PROs) including PROMIS. The primary outcome was a patient-reported item: "Today, considering the level of control of your psoriatic arthritis and psoriasis, do you consider your treatment has been successful?" Descriptive and multivariate logistic regression analyses identified clinical predictors of patient-reported treatment success. Patient-reported reasons for lack of treatment success were explored. RESULTS: A total of 178 participants had a baseline visit. Mean (SD) CASPAR score was 3.7 (0.9), age 51.7 (13.5) years, and BMI 31.3 (7.2) kg/m2. Fifty-two percent were women, and 86.0% white. Treatment success was reported by 116/178(65%) patients in the analytic cohort. Among 76 patients who reported treatment failure, the most frequently selected reasons for lack of success were pain (n = 55, 72.4%), fatigue (n = 46, 60.5%), inflamed joints (n = 40, 52.6%), and stiffness (n = 40, 52.6%). Overall, 105 participants had complete data across variables in the logistic regression models. Patient-reported treatment success was independently associated with the 66-swollen/68-tender joint counts, psoriasis BSA, PROs (pain interference, physical function, fatigue), and TNF-inhibitor therapy, after controlling for BMI and demographics. CONCLUSION: Patient-reported treatment success in PsA may be achieved through improvement of inflammatory arthritis, psoriasis, pain, physical function, fatigue, and the use ofTNF-inhibitors. Patients reported treatment failure was most commonly due to symptoms of pain, fatigue and stiffness.

Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren's syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial.

BACKGROUND: Sjögren's syndrome is an autoimmune disease characterised by dry eyes and mouth, systemic features, and reduced quality of life. There are no disease-modifying treatments. A new biologic, ianalumab (VAY736), with two modes of suppressing B cells, has previously shown preliminary efficacy. This dose-finding trial aimed to assess the safety and efficacy of different subcutaneous doses of ianalumab in patients with moderate to severe primary Sjögren's syndrome. METHODS: VAY736A2201 was a randomised, parallel, double-blind, placebo-controlled, phase 2b dose-finding study done in 56 centres in 19 countries. Patients aged 18-75 years with primary Sjögren's syndrome with moderate to severe disease activity (European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI] score ≥6) and symptom severity (EULAR Sjögren's Syndrome Patient Reported Index score ≥5) were eligible. Participants were randomly assigned (1:1:1:1) to receive subcutaneous placebo or ianalumab (5 mg, 50 mg, or 300 mg) every 4 weeks for 24 weeks using a secure, online randomisation system. Randomisation was stratified by the ESSDAI score at baseline (≥10 or <10). Study personnel and patients were masked to treatment assignment. The primary outcome was the change in ESSDAI score from baseline to 24 weeks in all randomly assigned patients. Dose-related change in disease activity (ESSDAI) from baseline at week 24 was assessed by multiple comparison procedure with modelling analysis. Safety was measured in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02962895. FINDINGS: Between June 27, 2017, and Dec 06, 2018, 293 patients were screened, 190 of whom were randomly assigned (placebo n=49, ianalumab 5 mg n=47, ianalumab 50 mg n=47, ianalumab 300 mg n=47). Statistically significant dose-responses were seen for overall disease activity (ESSDAI score) in four of the five dose-response models tested (p<0·025 in four models, p=0·060 in one model). The ESSDAI score decreased from baseline in all ianalumab groups, with the maximal ESSDAI score change from baseline observed in the ianalumab 300 mg group: placebo-adjusted least-squares mean change from baseline -1·92 points (95% CI -4·15 to 0·32; p=0·092). There were four serious adverse events in three patients considered treatment-related (pneumonia [n=1] and gastroenteritis [n=1] in the placebo group; appendicitis plus tubo-ovarian abscess in the same patient in the ianalumab 50 mg group). INTERPRETATION: The study met its primary objective, showing a dose-related decrease in disease activity as measured by ESSDAI at week 24. Overall, ianalumab was well tolerated and safe, with no increase in infections. To our knowledge, this is the first large, randomised, controlled trial in primary Sjögren's syndrome that met its primary endpoint, and its results mean there is potential for more studies of this mechanism in the future. FUNDING: Novartis.

Ocular and systemic morbidity in a longitudinal cohort of Sjögren's syndrome.

PURPOSE: To report vision-threatening ocular manifestations of primary Sjögren's syndrome (SS). DESIGN: Retrospective review. PARTICIPANTS: Consecutive patients evaluated at an SS center between January 2007 and May 2011. METHODS: Data collection was completed in March 2013. The 2002 American-European consensus criteria were used for diagnosis of SS. MAIN OUTCOME MEASURES: Frequency of extraglandular ocular findings and timing of their diagnosis relative to that of SS and dry eye were assessed. RESULTS: One hundred sixty-three patients were included. Almost all patients (98%) had a history of dry eye for an average of 10.4 years (median, 7.9 years) before presentation. One or more extraglandular ocular manifestations were present in 40 patients (25%), and vision-threatening findings were present in 22 patients (13%). Twelve patients (55%) with a vision-threatening ocular finding did not have a diagnosis of SS at presentation. Sixty-eight patients (42%) had extraglandular systemic manifestations of SS. Patients with vision-threatening ocular findings were 3.9 times more likely to have systemic involvement (95% confidence interval, 1.4-11.0; P = 0.010). Peripheral neuropathy, interstitial nephritis, and vasculitis were more common in those with vision-threatening ocular findings compared with patients without (P < 0.05 for all). CONCLUSIONS: These results from a tertiary referral-based cohort demonstrate that primary SS frequently is associated with ocular and systemic complications. Dry eye precedes these findings on average by 1 decade. Therefore, ophthalmologists should consider assessing for SS in patients with clinically significant dry eye.

Measurement of Minimal Disease Activity in Psoriatic Arthritis Using the Patient-Reported Outcomes Measurement Information System-Physical Function or the Health Assessment Questionnaire Disability Index.

OBJECTIVE: To assess the interchangeability of the Health Assessment Questionnaire disability index (HAQ DI) with the Patient-Reported Outcomes Measurement Information System-Physical Function (PROMIS-PF) in the calculation of minimal disease activity (MDA) in psoriatic arthritis (PsA). METHODS: Comprehensive PsA disease activity was collected concomitantly with the HAQ DI and the PROMIS-PF measures in a PsA cohort. The PROMIS-PF-based MDA definitions were built using the existing cross-walk between the scores: HAQ DI ≤0.5 equivalent to a PROMIS-PF T score of ≥41.3. We assessed agreement between MDA (MDA HAQ DI) and the PROMIS-PF MDA definitions (MDA PROMIS-PF short form 4a and MDA PROMIS-PF bank) at each visit and longitudinally (MDA state changes between consecutive visits) through the kappa statistic. The predictive value of the MDA PROMIS-PF for the MDA HAQ DI was assessed using receiver operator characteristic (ROC) curve analysis. RESULTS: A total of 100 participants contributed 352 observations with up to 5 visits. The mean ± SD age was 52 ± 12 years, 60% were female, and 43% were in MDA at baseline. The kappa statistic for the PROMIS-PF-based MDA reflected excellent agreement with the HAQ DI MDA: κ = 0.94 (95% confidence interval [95% CI] 0.90-0.97) for MDA PROMIS-PF bank, and κ = 0.90 (95% CI 0.80-0.95) for MDA PROMIS-PF4a. Higher longitudinal agreement was seen between the MDA HAQ DI and the MDA PROMIS-PF bank versus the MDA PROMIS-PF4a between consecutive visits: κ values ranged between 0.81 and 0.94 versus a range between 0.72 and 0.84, respectively. The area under the ROC curve for predicting the MDA HAQ DI was 0.97 for the MDA PROMIS-PF bank and 0.95 for the MDA PROMIS-PF4a. CONCLUSION: Excellent agreement was seen between the HAQ DI and the PROMIS-based MDA definitions both cross-sectionally and longitudinally. The PROMIS-PF bank and PROMIS-PF4a are accurate replacements for the HAQ DI in calculating MDA state in PsA.

PROMIS Provides a Broader Overview of Health-related Quality of Life Than the ESSPRI in Evaluation of Sjögren Syndrome.

OBJECTIVE: Sjögren syndrome (SS) has a significant impact on health-related quality of life (HRQOL). We sought to evaluate how the Patient Reported Outcome Measurement Information System (PROMIS) domains in SS may supplement the European League Against Rheumatism (EULAR) Sjögren Syndrome Patient Reported Index (ESSPRI). METHODS: A cross-sectional evaluation was performed on consecutive adult patients during visits to an SS clinic between March 2018 and February 2020. Each patient completed PROMIS short forms related to HRQOL and the ESSPRI, and had a clinical assessment. Patients were either classified as SS by 2016 American College of Rheumatology (ACR)/EULAR criteria, or as "sicca not otherwise specified (NOS)" and used as a comparison group. Univariable and multivariable linear regression models were used to evaluate predictors of PROMIS fatigue (-F), pain interference (-PI), and ability to participate in social roles and activities (-APS). RESULTS: Two hundred twenty-seven patients with SS and 85 with sicca NOS were included and did not differ in ESSPRI domains; 26% of the SS and 20% of the sicca NOS group had concurrent autoimmune disease. In SS, PROMIS-PI, PROMIS-F, and PROMIS physical function were at least one-half SD worse than US population normative values. PROMIS-PI (r = 0.73) and PROMIS-F (r = 0.80) were highly correlated with ESSPRI pain and fatigue subdomains. Fatigue and pain interference, but not dryness or mood disturbance, were the strongest predictors of social participation in multivariable analysis. CONCLUSION: In our SS cohort, PROMIS instruments identified a high disease burden of pain interference, fatigue, and physical function. PROMIS-F strongly predicted PROMIS-APS. PROMIS-PI and PROMIS-F scores correlated highly with their respective ESSPRI domains. PROMIS instruments should be considered to identify relevant HRQOL patterns in SS.

Designing an electronic medical record alert to identify hospitalised patients with HIV: successes and challenges.

OBJECTIVES: Electronic medical record (EMR) tools can identify specific populations among hospitalised patients, allowing targeted interventions to improve care quality and safety. We created an EMR alert using readily available data elements to identify hospitalised people with HIV (PWH) to facilitate a quality improvement study intended to address two quality/safety concerns (connecting hospitalised PWH to outpatient HIV care and reducing medication errors). Here, we describe the design and implementation of the alert and analyse its accuracy of identifying PWH. METHODS: The EMR alert was designed to trigger for at least one of four criteria: (1) an HIV ICD-10-CM code in a problem list, (2) HIV antiretroviral medication(s) on medication lists, (3) an HIV-1 RNA assay ordered or (4) a positive HIV-antibody result. We used manual chart reviews and an EMR database search to determine the sensitivity and positive predictive value (PPV) of the overall alert and its individual criteria. RESULTS: Over a 24-month period, the alert functioned as intended, notifying an intervention team and a data abstraction team about admissions of PWH. Manual review of 1634 hospitalisations identified 18 PWH hospitalisations, all captured by the alert (sensitivity 100%, 95% CI 82.4% to 100.0%). Over the 24 months, the alert triggered for 1191 hospitalisations. Of these, 1004 were PWH hospitalisations, PPV=84.3% (95% CI 82.2% to 86.4%). Using fewer criteria (eg, using only ICD-10-CM codes) identified fewer PWH but increased PPV. CONCLUSION: An EMR alert effectively identified hospitalised PWH for a quality improvement intervention. Similar alerts might be adapted as tools to facilitate interventions for other chronic diseases.

Antibodies to Both Ro52 and Ro60 for Identifying Sjögren's Syndrome Patients Best Suited for Clinical Trials of Disease-Modifying Therapies.

OBJECTIVE: To assess anti-Ro52 and anti-Ro60 serologic profiles as markers of clinically relevant phenotypic subsets of patients with Sjögren's syndrome (SS). METHODS: From a cohort of 839 consecutive patients with suspected or established SS seen in our multidisciplinary SS center, we compared the association of key phenotypic features in 390 patients who fulfilled SS classification criteria and in the parent cohort, stratifed by the presence of both anti-Ro60 and anti-Ro52, anti-Ro60 alone, and anti-Ro52 alone. RESULTS: The SS cohort included 227 patients (58%) with both anti-Ro60 and anti-Ro52, 65 (17%) with anti-Ro60 alone, 58 (15%) with anti-Ro52 alone, and 40 (10%) with neither antibody. Those with both anti-Ro60 and anti-Ro52 had a significantly increased prevalence of abnormal ocular surface staining, focal lymphocytic sialadenitis with focus score ≥1, antinuclear antibody ≥1:320, anti-SSB/La, rheumatoid factor, and IgG ≥15.6 gm/liter (P < 0.0016 for all). The groups with isolated anti-Ro52 and anti-Ro60 were equivalent to each other in their phenotypic associations, except for rheumatoid factor, which was higher in the anti-Ro52 alone group. The associations of these Ro antibody serologic profiles were similar in the parent cohort, except for additional associations with salivary gland enlargement and parotid gland ultrasound score. CONCLUSION: SS patients with both anti-Ro60 and anti-Ro52 antibodies are distinguished by a higher prevalence of markers of B-cell hyperactivity and glandular inflammation. Antibody reactivity to both Ro60 and Ro52 may thus serve as an important inclusion criterion for SS patients in clinical trials where the therapeutic agent targets pathways mediating these pathogenic abnormalities.

Antibodies recognising sulfated carbohydrates are prevalent in systemic sclerosis and associated with pulmonary vascular disease.

BACKGROUND: Glycosylation represents an important modification that regulates biological processes in tissues relevant for disease pathogenesis in systemic sclerosis (SSc), including the endothelium and extracellular matrix. Whether patients with SSc develop antibodies to carbohydrates is not known. OBJECTIVES: To determine the prevalence and clinical phenotype associated with serum IgG antibodies recognising distinct glycans in patients with SSc. METHODS: Pooled serum samples from patients with SSc and controls were screened for the presence of specific anticarbohydrate antibodies using a novel array containing over 300 glycans. Antibody titres to 4-sulfated N-acetyl-lactosamine (4S-LacNAc, (4OSO3)Galß1-4GlcNAc) were determined in 181 individual serum samples from patients with SSc by ELISA and associated with disease phenotype. RESULTS: 4S-LacNAc was identified as a target in pooled SSc serum. Anti-4S-LAcNAc antibodies were detected in 27/181 patients with SSc (14.9%) compared with 1/40 healthy controls (2.5%). Sulfation at position C4 of galactose (4S-LacNAc) was found to be critical for immunogenicity. Anti-4S-LacNAc antibody-positive patients with SSc had a higher prevalence of pulmonary hypertension by echocardiography than anti-4S-LacNAc-negative patients (15/27 (55.7%) vs 49/154 (31.8%), p=0.02) with an OR of 2.6 (95% CI 1.1 to 6.3). Anti-4S-LacNAc-positive patients accounted for 23.4% of all patients with pulmonary hypertension. CONCLUSION: Serum from patients with SSc contains IgG antibodies targeting distinct sulfated carbohydrates. The presence of anti-4S-LacNAc antibodies is associated with a high prevalence of pulmonary hypertension. These results suggest that specific post-translational carbohydrate modifications may act as important immunogens in SSc and may contribute to disease pathogenesis.

Ultrasound-Guided Biopsy of Suspected Salivary Gland Lymphoma in Sjögren's Syndrome.

OBJECTIVE: To evaluate the safety and utility of core needle biopsy (CNB) for diagnosis of salivary gland lymphoma in Sjögren's syndrome (SS). METHODS: We analyzed data from consecutive SS patients who underwent ultrasound-guided major salivary gland CNB for lymphoma diagnosis and determined whether CNB yielded an actionable diagnosis without need for further intervention. RESULTS: CNBs were performed in 24 patients to evaluate discrete parotid (n = 6) or submandibular (n = 2) gland masses or diffuse enlargement (n = 16; 15 parotid). One patient had 3 CNBs of the same mass. Of the 26 CNBs, 24 included flow cytometry, using CNB and/or fine needle aspirate material, and 14 targeted sonographically identified focal lesions. No patient reported complications. In the 23 patients with 1 CNB, final diagnoses were marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT; n = 6), atypical lymphoid infiltration (n = 3), benign lymphoepithelial sialadenitis (n = 9), normal gland tissue (n = 4), and lymphoepithelial cyst (n = 1). In the patient with serial CNBs, the initial one without flow cytometry was benign, but the next 2 showed atypical lymphoid infiltration. Monoclonal lymphoid infiltration was detected in 12 patients: 6 with MALT lymphoma, 3 were benign, and 3 with atypical lymphoid infiltration. Of the latter 3, 1 was treated with rituximab and 2 with expectant observation. The diagnosis changed from atypical lymphoid infiltration to MALT lymphoma in 1 patient following biopsy of inguinal adenopathy 6 months post-CNB. CNB provided actionable results and avoided open excisional biopsies in all cases. CONCLUSION: CNB is safe and useful in the evaluation of suspected salivary gland lymphoma in SS.

Clinical Characteristics of Hydralazine-induced Lupus.

Introduction The use of hydralazine has been associated with the development of lupus erythematosus and lupus-like syndromes. We performed this retrospective study to identify clinical characteristics of individuals who developed hydralazine-induced lupus. Material and methods We performed a single-center retrospective review of seven individuals who had a diagnosis of hydralazine-induced lupus by International Classification of Diseases, Ninth Revision (ICD9) code and were on hydralazine prior to their diagnosis. Clinical and laboratory data were obtained from a review of the medical record up to 12-month follow-up. Results Of the seven individuals with hydralazine-induced lupus, five were Caucasian (71%) and two were African-American. The mean age at the time of diagnosis was 62 years. Four (57%) were male. The majority of individuals were exposed to hydralazine for more than 12 months (83%). Four individuals had biopsy-proven lupus nephritis and four individuals had cardiopulmonary and skin involvement. Six patients were positive for antinuclear antibody (ANA) with a homogenous pattern, and five of those were positive for anti-histone antibody. Additionally, positive anti-double-stranded DNA (anti-dsDNA) antibody, anti-cardiolipin antibodies, low complements, positive lupus anticoagulant, and leukopenia were seen in 42% of our cohort. Of the five individuals in whom anti-myeloperoxidase (MPO) antibody was strongly positive, all had renal involvement defined by an elevated creatinine with three having biopsy-proven lupus nephritis. Three other individuals with MPO positivity had concurrent cardiopulmonary and skin involvement. Four individuals were positive for anti-proteinase 3 (PR3) antibody, three of whom were strongly positive with renal involvement defined by an elevated creatinine with two having biopsy-proven lupus nephritis. The level of anti-dsDNA antibody and anti-PR3 antibody normalized at three months while anti-MPO antibody took 12 months to normalize following cessation of hydralazine. When checked, low complement component 3 (C3) and anti-histone antibody persisted past 12 months. In addition to the withdrawal of hydralazine, six individuals were treated with hydroxychloroquine and five with mycophenolate mofetil. Three of four individuals with renal involvement received plasmapheresis and two received cyclophosphamide and hemodialysis. Conclusion Hydralazine can aggravate and unmask incipient lupus. Since the presentation can be varied, early recognition of symptoms is critical. Precautions should be taken before initiating this medication in individuals with certain risk factors. Once diagnosed, potential serological findings such as a positive anti-MPO/anti-PR3 antibody could predict more severe manifestations such as pulmonary-renal complications.

A validated method of labial minor salivary gland biopsy for the diagnosis of Sjögren's syndrome.

OBJECTIVES/HYPOTHESIS: To validate a technique and outcomes of labial minor salivary gland biopsy (LSGB) used for the diagnosis of Sjögren's syndrome (SS). STUDY DESIGN: Prospective cohort study. METHODS: Clinical data were prospectively obtained pre- and postbiopsy using patient-reported questionnaires. LSGB was performed using described methods. Specimens were analyzed by a pathologist with expertise in SS and assessed using established criteria to determine the focus score. Data were analyzed using cross-tabulations. RESULTS: Among the 58 patients in the study, 52 (90%) presented with sicca symptoms of dry eyes and/or mouth. Eight patients (14%) had histopathologic findings supportive of a diagnosis of SS. At 1 month postbiopsy, greater than 71% of patients denied any complaints of pain, swelling, numbness. or tingling. Sixteen patients (28%) had only a minor level of complaints. Only one patient complained of severe numbness at the biopsy site. Greater than 70% of patients would consider rebiopsy after the procedure, if requested by their physician. CONCLUSIONS: We present a safe and effective method of LSGB for the diagnosis of SS. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2041-2046, 2016.

Raynaud's phenomenon in mixed connective tissue disease.

Raynaud's phenomenon affects most patients who have mixed connective tissue disease (MCTD) and frequently represents the initial manifestation of the disease. It is the cutaneous symptom of a systemic vasculopathy that is characterized by intimal fibrosis and blood vessel obliteration that frequently leads to visceral involvement, particularly pulmonary hypertension. An association between Raynaud's phenomenon and the characteristic autoantibody in MCTD, anti-U1-RNP (ribonucleoprotein), is found across the spectrum of rheumatic diseases, including undifferentiated connective tissue disease, scleroderma, and systemic lupus erythematosus. Capillary nailfold examination represents a valuable tool to identify patients who are at risk for MCTD. The goal in the therapy of Raynaud's phenomenon in MCTD is to decrease the frequency of attacks, to prevent digital ulceration, and to limit progressive vascular damage. Therapeutic regimens include the traditional use of calcium channel blockers and novel vascular therapies.

Ocular complications of primary Sjögren syndrome in men.

PURPOSE: To report the ocular complications of primary Sjögren syndrome (SS) in men. DESIGN: Retrospective cohort study. METHODS: setting: Tertiary-care SS center. PATIENT POPULATION: Total of 163 consecutive primary Sjögren syndrome patients evaluated between January 2007 and March 2013. MAIN OUTCOME MEASURE: Frequency of extraglandular ocular and systemic manifestations and serologic results in men compared to women. RESULTS: Fourteen of the 163 primary SS patients (9%) were men. On initial presentation, men were a decade older (61 vs 50 years, P < .01) and less likely than women to have a prior diagnosis of SS (43% vs 65%, P = .09). A majority of men reported dry eye on presentation (92%), albeit less chronic compared to women (5.9 vs 10.8 years, P = .07). Men were more likely to present with serious ocular complications than women (43% vs 11%, P = .001). Extraglandular systemic complications of SS (ie, vasculitis, interstitial nephritis) were also more common in men (64% vs 40%, P = .07). Further, men were more likely to be negative for anti-SSA/Ro, anti-SSB/La, and antinuclear antibodies than women (36% men vs 11% women, P = .01). CONCLUSION: Men with primary SS have a higher frequency of serious ocular and systemic manifestations. Although primary Sjögren syndrome is typically considered a disease of middle-aged women, it may be underdiagnosed and consequentially more severe in men. Physicians should have a lower threshold to test for SS in men with dry eye.

Induction of immunologic tolerance for allogeneic hematopoietic cell transplantation.

The ability to achieve complete hematopoietic engraftment in the allogeneic setting without intensive myeloablative chemotherapy will have a profound effect on the practice of allogeneic hematopoietic cell transplantation (HCT). Novel methods to induce antigen-specific T-cell tolerance provide promise to ensure engraftment and reduce GVHD without producing generalized and other toxicities caused by myeloablative conditioning regimens. Compelling experimental evidence indicates that the antigen receptors on T-lymphocytes have dual potential to transmit crucial activation signals for initiating immune responses and to discharge equally potent inactivating signals to abort or inhibit immune responses. Many events impact on this fundamental decision-making process and one of the great challenges for modern immunology is to decipher the molecular wiring that integrates and converts the extrinsic and intrinsic variables into positive or negative cellular responses termed immunity and anergy, respectively. Our currently expanding understanding of the biochemical and molecular basis of T-cell anergy provides great promise to improve our ability to design novel clinical therapeutic approaches in order to induce antigen-specific tolerance in vivo. Importantly, strategies now exist to segregate graft versus tumor (GVT) effects from GVHD. Therefore, achievement of limited and specific tolerance to host alloantigens by selectively inactivating the indicated subsets of alloantigen-specific T-lymphocytes will prevent GVHD but retain the GVT effect of the graft. Such treatment approaches will expand the donor pool, because they will allow transplantation between individuals with increasing human leukocyte antigen (HLA) disparity, enable reduction of the need for non-specific immunosuppression, and reduce the risk of opportunistic infections and relapse of leukemia.

Apoptotic splenocytes drive the autoimmune response to poly(ADP-ribose) polymerase 1 in a murine model of lupus.

Although defects in apoptosis have been linked to both human and murine lupus, the exact mechanisms remain unknown. Moreover, it is not clear whether such defects are primary or secondary events in disease pathogenesis. To address these issues, we used an induced model of murine lupus, the parent-into-F(1) model of chronic graft-versus-host disease (cGVHD) in which a lupus-like phenotype highly similar to human systemic lupus erythematosus is reliably induced in normal F(1) mice. We addressed the role of nuclear Ags modified by caspases during apoptosis as potential targets of the autoantibody response and our results identify poly(ADP-ribose) polymerase 1 (PARP-1) as a frequently targeted autoantigen. Additional proteins cleaved during apoptosis were also targeted by the immune response. Importantly, female mice exhibited significantly greater numbers of apoptotic cells in germinal centers and higher serum anti-PARP-1 Ab levels compared with male cGVHD mice. Serum anti-PARP-1 levels in male cGVHD mice could be elevated to levels comparable to those of female cGVHD mice by the injection of apoptotic syngeneic F(1) splenocytes early in the disease course. These results provide a mechanism by which lupus autoantibodies target apoptotic molecules. Specifically, T cell-driven polyclonal B cell activation characteristic of systemic lupus erythematosus is sufficient to saturate otherwise normal apoptotic clearance mechanisms, permitting apoptotic material to accumulate, serve as autoantigens, and drive autoantibody production.

Elevation of intracellular cyclic AMP in alloreactive CD4(+) T Cells induces alloantigen-specific tolerance that can prevent GVHD lethality in vivo.

Cyclic AMP (cAMP) is an important negative regulator of T cell activation, and an increased level of cAMP is associated with T cell hyporesponsiveness in vitro. We sought to determine whether elevating intracellular cAMP levels ex vivo in alloreactive T cells during primary mixed lymphocyte reactions (MLR) is sufficient to induce alloantigen-specific tolerance and prevent graft-versus-host disease (GVHD). Primary MLRs were treated with exogenous (8)Br-cAMP and IBMX, a compound that increases intracellular cAMP levels by inhibition of phosphodiesterases. T cell proliferation and IL-2 responsiveness in the treated primary MLR cultures were greatly reduced, and viable T cells recovered on day 8 also had impaired responses to restimulation with alloantigen compared to control-treated cells, but without an impairment to nonspecific mitogens. Labeling experiments showed that cAMP/IBMX inhibited alloreactive T cell proliferation by limiting the number of cell divisions, increasing susceptibility to apoptosis, and rendering nondeleted alloreactive T cells hyporesponsive to alloantigen restimulation. cAMP/IBMX-treated CD4(+) T cells had a markedly reduced capacity for GVHD lethality in major histocompatibility complex class II disparate recipients, but maintained the capacity to mediate other CD4(+) T cell responses in vivo. Thus, our results provide the first preclinical evidence of using cAMP-elevating pharmaceutical reagents to achieve long-term alloantigen-specific T cell tolerance that is sufficient to prevent GVHD.

cAMP inhibits both Ras and Rap1 activation in primary human T lymphocytes, but only Ras inhibition correlates with blockade of cell cycle progression.

Cyclic adenosine monophosphate (cAMP) is a negative regulator of T-cell activation. However, the effects of cAMP on signaling pathways that regulate cytokine production and cell cycle progression remain unclear. Here, using primary human T lymphocytes in which endogenous cAMP was increased by the use of forskolin and 3-isobutyl-1-methylxanthine (IBMX), we show that increase of cAMP resulted in inhibition of T-cell receptor (TCR)/CD3 plus CD28-mediated T-cell activation and cytokine production and blockade of cell cycle progression at the G(1) phase. Increase of cAMP inhibited Ras activation and phosphorylation of mitogen-induced extracellular kinase (MEK) downstream targets extracellular signal-related kinase 1/2 (ERK1/2) and phosphatidylinositol-3-kinase (PI3K) downstream target protein kinase B (PKB; c-Akt). These functional and biochemical events were secondary to the impaired activation of ZAP-70 and phosphorylation of LAT and did not occur when cells were stimulated with phorbol ester, which bypasses the TCR proximal signaling events and activates Ras. Increase of cAMP also inhibited activation of Rap1 mediated by TCR/CD3 plus CD28. Importantly, inhibition of Rap1 activation by cAMP was also observed when cells were stimulated with phorbol ester, although under these conditions Ras was activated and cells progressed into the cell cycle. Thus, TCR plus CD28-mediated activation of ERK1/2 and PKB, cytokine production, and cell cycle progression, all of which are inhibited by cAMP, require activation of Ras but not Rap1. These results indicate that signals that regulate cAMP levels after encounter of T cells by antigen will likely determine the functional fate toward clonal expansion or repression of primary T-cell responses.