David Fiorentino

Treatment recommendations for psoriatic arthritis

Objective: To develop comprehensive recommendations for the treatment of the various clinical manifestations of psoriatic arthritis (PsA) based on evidence obtained from a systematic review of the literature and from consensus opinion. Methods: Formal literature reviews of treatment for the most significant discrete clinical manifestations of PsA (skin and nails, peripheral arthritis, axial disease, dactylitis and enthesitis) were performed and published by members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Treatment recommendations were drafted for each of the clinical manifestations by rheumatologists, dermatologists and PsA patients based on the literature reviews and consensus opinion. The level of agreement for the individual treatment recommendations among GRAPPA members was assessed with an online questionnaire. Results: Treatment recommendations were developed for peripheral arthritis, axial disease, psoriasis, nail disease, dactylitis and enthesitis in the setting of PsA. In rotal, 19 recommendations were drafted, and over 80% agreement was obtained on 16 of them. In addition, a grid that factors disease severity into each of the different disease manifestations was developed to help the clinician with treatment decisions for the individual patient from an evidenced-based perspective. Conclusions: Treatment recommendations for the cardinal physical manifestations of PsA were developed based on a literature review and consensus between rheumatologists and dermatologists. In addition, a grid was established to assist in therapeutic reasoning and decision making for individual patients. It is anticipated that periodic updates will take place using this framework as new data become available.

Diversity of cytokine synthesis and function of mouse CD4+ T cells

The immune response is capable of invoking a variety of difTerent effector mechanisms, each of which is particularly effective against a certain set of pathogens. The regulation of the type of effector mechanisms chosen during an immune response is of critical importance to the host, and thus it is not surprising that this aspect of the immune system is subject to precise and complex regulation. Over the past few years, it has become clear that subsets of T cells secreting distinct patterns of cytokines have a major role in the regulation of the effector functions induced against a particular infectious agent. Two major patterns of cytokine synthesis were initially recognized, and these two patterns appear to correlate with the induction of delayed-type hypersensitivity (DTH) and help for antibody synthesis, thus providing a possible explanation for the separate and often reciprocal regulation of these two responses. Recent information suggests that additional cytokine secretion phenotypes exist, and that there is extensive regulation of the differentiation and effector function of the various cell types.

TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin

The rapamycin-sensitive signaling pathway is required to transduce specific mitogenic signals to the cell cycle machinery responsible for G1 progression. Genetic studies in yeast identified two related genes on this pathway, TOR1 and TOR2, thought to encode novel phosphatidylinositol kinases. We now show that an intact kinase domain is required for the G1 cell cycle functions of both proteins, for the ability of a mutation in a neighboring FKBP12-rapamycin-binding domain of the TOR1 protein to inhibit the growth of yeast cells when overexpressed, and for the essential function of the TOR2 protein. The G1 function of both TOR proteins is sensitive to rapamycin, but the essential function of TOR2 is not. Thus, FKBP12-rapamycin does not appear to inhibit the kinase activity of TOR proteins in a general way; instead, it may interfere selectively with TOR protein binding to or phosphorylation of G1 effectors.

The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): A retrospective study

BACKGROUND Dermatomyositis (DM) is a multisystem autoimmune disease, in which serologic evidence of immune responses to disease-specific antigenic targets is found in approximately 50% to 70% of patients. Recently, melanoma differentiation-associated gene 5 (MDA5) has been identified as a DM-specific autoantigen that appears to be targeted in patients with DM and mild or absent muscle inflammation and with an increased risk of interstitial lung disease. OBJECTIVE We wished to understand the role of MDA5 in DM skin inflammation by testing it to determine if a specific cutaneous phenotype is associated with MDA5 reactivity. METHODS We retrospectively screened plasma from 77 patients with DM in the outpatient clinics at the Stanford University Department of Dermatology in California. RESULTS We found that 10 (13%) patients had circulating anti-MDA5 antibodies, and had a characteristic cutaneous phenotype consisting of skin ulceration, tender palmar papules, or both. Typical areas of skin ulceration included the lateral nailfolds, Gottron papules, and elbows. Biopsy specimens of the palmar papules showed a vasculopathy characterized by vascular fibrin deposition with variable perivascular inflammation. Patients with anti-MDA5 antibodies also had an increased risk of oral pain and/or ulceration, hand swelling, arthritis/arthralgia, and diffuse hair loss. Consistent with previous reports, these patients had little or no myositis and had increased risk of interstitial lung disease. LIMITATIONS This study was conducted at a tertiary referral center. Multiple associations with MDA5 antibodies were tested retrospectively on a relatively small cohort of 10 anti-MDA5-positive patients. CONCLUSION We suggest that MDA5 reactivity in DM characterizes a patient population with severe vasculopathy.

Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway

Objective To characterise activation of the type I interferon (IFN) pathway in patients with systemic lupus erythematosus (SLE), dermatomyositis (DM), polymyositis (PM), rheumatoid arthritis (RA) and systemic scleroderma (SSc) and to evaluate the potential to develop a molecular diagnostic tool from the peripheral blood that reflects this activation in disease-affected tissues. Methods Overexpressed transcripts were identified in the whole blood (WB) of 262 patients with SLE, 44 with DM, 33 with PM, 28 with SSc and 89 with RA and compared with 24 healthy subjects using Affymetrix microarrays. A five gene type I IFN signature was assessed in these subjects to identify subpopulations showing both activation and concordance of the type I IFN pathway in the peripheral blood and disease-affected tissues of each disease and to correlate activation of this pathway in the WB with clinical measurements. Results A common set of 36 type I IFN inducible transcripts were identified among the most overexpressed in the WB of all subjects. Significant activation of the type I IFN pathway in subgroups of each of the five diseases studied was observed. Baseline disease activity measurements correlated with a type I IFN gene signature in the WB of subjects with SLE, PM and SSc, as did various serum autoantibody levels in subjects with SLE and DM. This signature was also well correlated between disease-affected tissue and WB in subjects with SLE, DM, PM and SSc. Conclusions The results indicate that the type I IFN pathway is activated in patient subsets of five rheumatic diseases and suggest that these subsets may benefit from anti-IFN therapy.

Immunophilins interact with calcineurin in the absence of exogenous immunosuppressive ligands

The peptidyl‐prolyl isomerases FKBP12 and cyclophilin A (immunophilins) form complexes with the immunosuppressants FK506 and cyclosporin A that inhibit the phosphatase calcineurin. With the yeast two hybrid system, we detect complexes between FKBP12 and the calcineurin A catalytic subunit in both the presence and absence of FK506. Mutations in FKBP12 surface residues or the absence of the calcineurin B regulatory subunit perturb the FK506‐dependent, but not the ligand‐independent, FKBP12‐calcineurin complex. By affinity chromatography, both FKBP12 and cyclophilin A bind calcineurin A in the absence of ligand, and FK506 and cyclosporin A respectively potentiate these interactions. Both in vivo and in vitro, the peptidyl‐prolyl isomerase active sites are dispensable for ligand‐independent immunophilin‐calcineurin complexes. Lastly, by genetic analyses we demonstrate that FKBP12 modulates calcineurin functions in vivo. These findings reveal that immunophilins interact with calcineurin in the absence of exogenous ligands and suggest that immunosuppressants may take advantage of the inherent ability of immunophilins to interact with calcineurin.

Capillary Regeneration in Scleroderma: Stem Cell Therapy Reverses Phenotype?

Background Scleroderma is an autoimmune disease with a characteristic vascular pathology. The vasculopathy associated with scleroderma is one of the major contributors to the clinical manifestations of the disease. Methodology/Principal Findings We used immunohistochemical and mRNA in situ hybridization techniques to characterize this vasculopathy and showed with morphometry that scleroderma has true capillary rarefaction. We compared skin biopsies from 23 scleroderma patients and 24 normal controls and 7 scleroderma patients who had undergone high dose immunosuppressive therapy followed by autologous hematopoietic cell transplant. Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels. The molecules defining this phenotype are: vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation (lost in the scleroderma tissue), antiangiogenic interferon α (overexpressed in the scleroderma dermis) and RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis (also overexpressed in scleroderma skin. Following high dose immunosuppressive therapy, patients experienced clinical improvement and 5 of the 7 patients with scleroderma had increased capillary counts. It was also observed in the same 5 patients, that the interferon α and vascular endothelial cadherin had returned to normal as other clinical signs in the skin regressed, and in all 7 patients, RGS5 had returned to normal. Conclusion/Significance These data provide the first objective evidence for loss of vessels in scleroderma and show that this phenomenon is reversible. Coordinate changes in expression of three molecules already implicated in angiogenesis or anti-angiogenesis suggest that control of expression of these three molecules may be the underlying mechanism for at least the vascular component of this disease. Since rarefaction has been little studied, these data may have implications for other diseases characterized by loss of capillaries including hypertension, congestive heart failure and scar formation.

Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1γ.

OBJECTIVE Since dermatomyositis (DM) is associated with an increased risk of malignancy, accurate identification of patients likely to harbor cancers is important. Using immunoprecipitations from radiolabeled cell lysates, several groups recently showed that anti-transcription intermediary factor 1γ (anti-TIF-1γ) antibodies are associated with malignancy in DM. We undertook this study to develop sensitive, specific assays to detect antibodies against TIF-1γ and nuclear matrix protein NXP-2 and to evaluate their association with malignancy in DM. METHODS To detect anti-TIF-1γ antibodies, immunoprecipitations were performed using lysates made from HeLa cells overexpressing TIF-1γ, with detection by immunoblotting. Anti-NXP-2 antibodies were assayed by immunoprecipitation using (35) S-methionine-labeled NXP-2 generated by in vitro transcription/translation. We analyzed patient sera from DM cohorts seen at the Stanford University Dermatology Clinic (n = 111) and the Johns Hopkins Myositis Center (n = 102). RESULTS A total of 17% and 38% of patients had antibodies against NXP-2 and TIF-1γ, respectively. Reactivity against either NXP-2 or TIF-1γ identified 83% of patients with cancer-associated DM. In addition to older age and male sex, cancer was associated with antibodies to NXP-2 or TIF-1γ on multivariate analysis (odds ratio 3.78 [95% confidence interval 1.33-10.8]). Stratification by sex revealed that anti-NXP-2 was specifically associated with cancer in males (odds ratio 5.78 [95% confidence interval 1.35-24.7]). CONCLUSION These studies demonstrate that anti-NXP-2 and anti-TIF-1γ antibodies are frequent DM specificities (found in 55% of patients) and are present in most patients with cancer-associated DM.

Risk of Serious Infection With Biologic and Systemic Treatment of Psoriasis Results From the Psoriasis Longitudinal Assessment and Registry (PSOLAR)

IMPORTANCE The efficacy of treatment for psoriasis must be balanced against potential adverse events. OBJECTIVE To determine the effect of treatment on the risk of serious infections in patients with psoriasis. DESIGN, SETTING, AND PARTICIPANTS A multicenter, longitudinal, disease-based registry (Psoriasis Longitudinal Assessment and Registry [PSOLAR]) at dermatology centers. Participants were adult patients with psoriasis who were receiving or were eligible to receive conventional systemic or biologic agents. The registry opened on June 20, 2007, and data included herein were collected through August 23, 2013. EXPOSURES Patients were prescribed psoriasis therapies as in standard clinical practice. Patients will be followed for up to 8 years. Data were collected and serious adverse events (including serious infections) were assessed at regular intervals. MAIN OUTCOMES AND MEASURES Cohort characteristics are described based on evaluation at entry into the registry. The cumulative incidence rates of serious infections are reported across treatment cohorts, including ustekinumab, infliximab, adalimumab, etanercept, and nonbiologics (with or without methotrexate). A multivariate analysis using a Cox proportional hazards regression model was used to identify predictors of the time to the first serious infection using the nonmethotrexate/nonbiologics cohort as the reference. RESULTS Data were analyzed from 11,466 patients with psoriasis (22,311 patient-years). Differences in patient characteristics were found between the biologics and nonmethotrexate/nonbiologics cohorts (eg, age, sex, body mass index, and disease characteristics), as well as among the individual biologic groups (eg, a higher prevalence of psoriatic arthritis in the infliximab cohort). The cumulative incidence rate of serious infections was 1.45 per 100 patient-years (n = 323) across treatment cohorts, and the rates were 0.83, 1.47, 1.97, and 2.49 per 100 patient-years in the ustekinumab, etanercept, adalimumab, and infliximab cohorts, respectively, and 1.05 and 1.28 per 100 patient-years in the nonmethotrexate/nonbiologics and methotrexate/nonbiologics cohorts, respectively. The most commonly reported types of serious infections across the registry were pneumonia and cellulitis. Increasing age, diabetes mellitus, smoking, significant infection history, infliximab exposure, and adalimumab exposure were each associated with an increased risk of serious infection. CONCLUSIONS AND RELEVANCE Results from PSOLAR suggest a higher risk of serious infections with adalimumab and infliximab compared with nonmethotrexate and nonbiologic therapies. No increased risk was observed with ustekinumab or etanercept. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00508547.

Consensus Guidelines for the Management of Plaque Psoriasis

The Canadian Guidelines for the Management of Plaque Psoriasis were reviewed by the entire National Psoriasis Foundation Medical Board and updated to include newly approved agents such as ustekinumab and to reflect practice patterns in the United States, where the excimer laser is approved for psoriasis treatment. Management of psoriasis in special populations is discussed. In the updated guidelines, we include sections on children, pregnant patients or pregnant partners of patients, nursing mothers, the elderly, patients with hepatitis B or C virus infections, human immunodeficiency virus-infected patients, and patients with malignant neoplasms, as well as sections on tumor necrosis factor blockers, elective surgery, and vaccinations.