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ObjectiveRheumatoid arthritis (RA) is the most common form of autoimmune inflammatory arthritis. Intra-articular gene delivery to block proinflammatory cytokines has been studied in pre-clinical models and human clinical trials. It has been demonstrated that the level of programmed death-ligand 1 (PD-L1) is associated with rheumatoid arthritis (RA). This study examined the therapeutic role of PD-L1 by intra-articular delivery via adeno-associated virus (AAV) vectors in the mouse collagen-induced arthritis (CIA) model.MethodsMice were intra-articularly injected with AAV5 vectors encoding human PD-L1 on day 0 and immunized with bovine type II collagen to induce CIA simultaneously. On day 49 post AAV administration, joints were collected for histo-pathological and cytokine analysis. Additionally, the systemic impacts of intra-articular injection of AAV5/PD-L1 vectors were also studied. To study the therapeutic effect of PD-L1, AAV5/PD-L1 vectors were administered into the joints of RA mice on day 21.ResultsAfter administration of AAV5/PD-L1 vectors, strong PD-L1 expression was detected in AAV transduced joints. Joints treated with PD-L1 at the time of arthritis induction exhibited significantly less swelling and improved histopathological scores when compared to untreated joints. Additionally, the infiltration of T cells and macrophages was decreased in joints of CIA mice that received AAV5/PD-L1 vectors (PConclusionThe results from this study demonstrate that local AAV mediated PD-L1 gene delivery into the joints is able to prevent the development and block the progression of arthritis in CIA mice without impacting systemic immune responses. This study provides a novel strategy to effectively treat inflammatory joint diseases using local AAV gene therapy by interference with immune checkpoint pathways.

T regulatory cells (Tregs) are a heterogeneous group of immunoregulatory cells that dampen self-harming immune responses and prevent the development of autoimmune diseases. In anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis, Tregs possess diminished suppressive capacity, which has been attributed to the expression of a FOXP3 splice-variant lacking exon 2 in T cells (FOXP3Δ2 CD4We developed a custom mass cytometry panel and performed deep immune profiling of Tregs in healthy controls, patients with active disease and in remission. Using these data, we performed multidimensional reduction and discriminant analysis to identify associations between Treg subsets and disease activity.Total Tregs were expanded in ANCA vasculitis, which was associated with remission and the administration of rituximab and/or prednisone. The frequency of FOXP3Δ2 CD4Treg heterogeneity can discriminate disease activity and should be explored as a biomarker of disease activity in ANCA vasculitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) is a small vessel vasculitis associated with asthma and eosinophilia. Despite its rarity, continuous gains are being made in understanding the disease with knowledge advancements regarding its epidemiology, heterogeneous clinical manifestations, management, and outcomes. Large knowledge gaps remain, however, particularly surrounding pathophysiologic and diagnostic uncertainties. There is still an incomplete understanding of the interplay between the eosinophilic and vasculitic processes that are features of disease pathogenesis. EGPA is also a conceptually difficult disorder given its dual categorization with hypereosinophilic syndromes and systemic vasculitides and the absence of a biomarker that can reliably distinguish between the two. In addition, recent evidence points to distinct, but partly overlapping, disease phenotypes, yet there is insufficient understanding to inform phenotype-tailored therapies. EGPA also remains a diagnostic challenge in part because asthma may be the primary or predominant manifestation for years, and the chronic corticosteroid requirement may mask other disease features. Efforts are ongoing to better elucidate pathophysiologic mechanisms, resolve classification issues, better characterize disease manifestations, and further clarify disease subcategorization, all of which will translate into better diagnosis and treatment with the possibility of specifically adapted therapies.

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant disorder with variable expressivity [1] and results from mutations in the PSTPIP1 gene. The PSTPIP1 protein is a cytoskeletal protein within hematopoietic cells that serves as a scaffold for the binding of other cellular proteins, such as pyrin, protein tyrosine phosphatases, c-Abl, CD2, and WASP. Through these interactions, PSTPIP1 regulates several cellular functions including IL-lβ release, cytoskeleton organization, cell migration, and T-cell activation [2, 3]. Depending on the mutation location within the PSTPIP1 gene and consequent alterations in protein-protein interactions, a spectrum of autoinflammatory disorders may result and are collectively referred to as PSTPIP1-associated inflammatory diseases (PAID). While the underlying pathogenesis is not completely understood, the PAID spectrum is characterized by dysregulated IL-lβ release and neutrophil responses [4] and clinically manifests as recurrent bouts of untriggered inflammation involving various organ systems [5]. PAPA syndrome is only one entity within the PAID spectrum and classically presents with sterile pyogenic arthritis, pyoderma gangrenosum (PG), and cystic acne. Due to heterogeneous presentations, delays in diagnosis and misdiagnoses as autoimmune or immunodeficiency conditions are common. Given the rarity of PAPA syndrome and other disorders in the PAID spectrum, no guideline-based treatment approaches exist and previous reports highlight the significant variability in responses to monotherapy with two of the most common long-term therapies utilized: IL-1β antagonists and TNF-α inhibitors [2, 6]. Other anti-inflammatory agents are reserved for treatment failures, and dual therapy, except in combination with steroids, is rarely reported for treatment of PAPA syndrome [3, 6]. Early diagnosis and initiation of effective treatment to induce remission, however, are vital to decreasing the morbidity and mortality associated with these autoinflammatory disorders. We present here a case of an adolescent female referred to our immunology clinic for suspected immunodeficiency, but who was subsequently diagnosed with and treated for PAPA syndrome with combination adalimumab and tacrolimus therapy. To our knowledge, this is the first report of the effective and safe use of tacrolimus in combination with adalimumab for PAPA syndrome. Case Presentation A 12-year-old female was referred to our immunology clinic for evaluation of a possible immunodeficiency given her history of recurrent infections since 1 year of age. Her pertinent clinical history is summarized in Figure 1a. She initially developed recurrent purulent otitis media (OM), requiring multiple sets of tympanostomy tubes. At 5-years-old, she developed erythema, bruising, swelling, and pain of her left ankle that was initially attributed to trauma. Over several months, her symptoms extended to involve her bilateral ankles, knees, wrists, and hands. Following a rheumatology evaluation, she was diagnosed with seronegative polyarticular juvenile idiopathic arthritis (JIA). After failing therapy with naproxen, methotrexate was attempted but discontinued after four months due to an increase in OM. Her arthritis interestingly resolved spontaneously over the next several months without further treatment. Open in a separate window Figure 1: a) Our patient’s clinical history was significant for recurrent episodes of purulent otitis media, polyarticular juvenile idiopathic arthritis (JIA), two episodes of pyogenic sterile arthritis and osteomyelitis of the right elbow, and various cutaneous manifestations including recurrent episodes of cellulitis and abscesses, pyoderma gangrenosum (PG), and nodulocystic acne. Arrows indicate initiation of adalimumab and addition of tacrolimus. * represents PG flare during lapse of adalimumab therapy for 6–8 weeks. b) Dermatopathology from biopsy of left breast lesion revealed a mixed lobular panniculitis with interstitial neutrophils and lymphocytes and features consistent with a neutrophilic dermatosis. c) Erythematous, violaceous ulcerated plaque that represents PG lesion prior to treatment. d) PG lesion following treatment with adalimumab with reduction in erythema, ulceration, and size. e) PG lesion following addition of tacrolimus to adalimumab has healed into a hypertrophic scar.

Sweet’s syndrome (SS) is classically considered a hypersensitivity reaction often associated with autoimmune disorders and malignancy. SS has also been increasingly reported to occur with immunodeficiencies. We present a case of treatment-refractory, systemic SS as the initial manifestation in a young child with common variable immunodeficiency (CVID). We also review current literature about SS and concurrent immunodeficiencies and autoimmunity in CVID patients. Few case reports exist regarding the co-occurrence of Sweet’s syndrome and primary immunodeficiencies. SS is characterized by a pro-inflammatory state with a neutrophil predominance resulting in a spectrum of clinical manifestations. CVID is a multifactorial antibody deficiency that can be associated with autoimmunity, which some studies have proposed to be secondary to altered CD21 expression. SS occurring in patients with CVID has been infrequently reported, and one case study demonstrated improvement of Sweet’s associated skin lesions with immunoglobulin replacement. In our case, the patient had multi-system SS refractory to multiple immunomodulatory therapies. To our knowledge, this is the first report of the effective and safe use of intravenous tocilizumab and oral lenalidomide to treat SS in a child with CVID. Immunoglobulin replacement reduced the frequency of infections and may have contributed to the opportunity to wean the immunosuppressive therapies for Sweet’s syndrome. Sweet’s syndrome as an initial manifestation of co-occurring immunodeficiencies is rare, and providers need a high index of suspicion. In addition, treatment of SS associated with an immunodeficiency can be a challenge. Treatment with immunoglobulin replacement reduces the frequency of infections, and in some patients with concurrent SS may improve skin lesions and reduce the need for immunomodulator therapy. Further study is necessary to better understand the pathogenesis of CVID in patients with SS and to identify possible biomarkers that predict who with SS are at risk for developing hypogammaglobulinemia.

Granulomatous-lymphocytic interstitial lung disease (GLILD) has classically been associated with common variable immune deficiency (CVID), but is increasingly being reported in other immunodeficiencies. We describe the second reported case of GLILD in a patient with 22q11.2 deletion syndrome (22q11.2DS) and review the recent literature surrounding GLILD. GLILD is characterized by granulomata and lymphoproliferation. Consensus statements and retrospective and case-control studies have better elucidated the clinicopathological and radiographic manifestations of GLILD, allowing for its differentiation from similar conditions like sarcoidosis. Gaps of knowledge remain, however, particularly regarding optimal management strategies. Combination therapies targeting T and B cell populations have recently shown favorable results. GLILD is associated with poorer outcomes in CVID. Its recognition as a rare complication of 22q11.2DS and other immunodeficiencies therefore has important therapeutic and prognostic implications. Additional research is needed to better understand the natural history and pathogenesis of GLILD and to develop evidence-based practice guidelines.

Immune gamma globulin (IgG) has a long history in the treatment of both primary immune deficiency and autoimmune disorders. Disease indications continue to expand and new-generation products increase the versatility of delivery. This review encompasses a historical perspective as well as current and future implications of human immune globulin for the treatment of immune-mediated illness.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by immune dysregulation due to a defect in lymphocyte apoptosis. The clinical manifestations may be noted in multiple family members and include lymphadenopathy, splenomegaly, increased risk of lymphoma, and autoimmune disease, which typically involves hematopoietic cell lines manifesting as multilineage cytopenias. Since the disease was first characterized in the early 1990s, there have been many advances in the diagnosis and management of this syndrome. The inherited genetic defect of many ALPS patients has involved (FAS) pathway signaling proteins, but there remain those patients who carry undefined genetic defects. Despite ALPS having historically been considered a primary immune defect presenting in early childhood, adult onset presentation is increasingly becoming recognized and more so in genetically undefined patients and those with somatic FAS mutations. Thus, future research may identify novel pathways and/or regulatory proteins important in lymphocyte activation and apoptosis.

The complement system is a major, multifunctional part of innate immunity and serves as a bridge between the innate and adaptive immune systems. It consists of more than 30 distinct proteins that interact with one another in a specific sequence. There are three pathways of complement activation: the classical, the lectin, and the alternative pathways. The three pathways are initiated by distinct mechanisms, but they all generate the same core set of effector molecules. Inherited complete deficiencies in complement components are generally very rare and predispose to infections and autoimmune disease. One of the better described associations is between deficiencies in early classical pathway components and the development of systemic lupus erythematosus. The goal of this review will be to discuss the associations between and the causal mechanisms of complement deficiencies and systemic lupus erythematosus.

Background/Purpose: Localized scleroderma (LS) is a chronic inflammatory and fibrosing skin disease. We present baseline data on the juvenile LS (jLS) cohort from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry, a multicenter observational pediatric rheumatic disease registry. Methods: Descriptive statistics were used for demographic, clinical and laboratory features. Data analysis included the two-sample t-test, chi-square test, Fisher's exact test, and analysis of variance as appropriate. Results: Of 259 children in the database, 78% were female and 81% were Caucasian. Mean age at onset was 8.3 yr (± 4.2). Mean age at first pediatric rheumatology (PRH) evaluation was 9.5 yr (± 4.2), yet 37% had ≥5 yr delay from onset to first PRH visit. Linear scleroderma (LiS) was the most common subtype (54%), followed by circumscribed morphea (CM) (15%), generalized morphea (GM) (8%), eosinophilic fasciitis (2%), and pansclerotic morphea (1%). 20% of children had mixed subtype, and LiS-CM was the most frequent combination (60%). Among LiS patients with face-scalp localization (40%), neurologic and ocular diseases were reported in 7% and 4%, respectively. ANA positivity was found in 50% tested and was not associated with subtype, age at onset, extracutaneous manifestations, or features of disease damage. Children with new lesions were more likely to have an elevated creatine kinase (CK) (p=0.02) or aldolase (p=0.02); muscle atrophy (p=0.04) and extremity shortening (p=0.02) were also associated with an elevated CK. Children with any functional limitation (baseline worst ever ACR functional class II, III, and IV) (28%) had earlier first PRH visit (mean 0.88 yr ± 0.89) compared to those without limitation (class I) (mean 1.4 yr ± 1.8, p=0.03). The association was also significant when evaluating ≥1 yr (p=0.04), ≥2 yr (p=0.02), and ≥5 yr delay (p=0.02) in first PRH visit. Poorer function also correlated with presence of muscle atrophy, joint contracture, and extremity shortening (all p

Purpose Recent studies have implicated low vitamin D levels with greater disease activity in pediatric systemic lupus erythematosus (SLE) and we have reported an association between low vitamin D levels and greater disease activity in juvenile dermatomyositis. The objective of this study was to explore whether standardized vitamin D supplementation of low levels of 25-hydroxyvitamin D [25(OH)D] might be associated with improvements in disease activity.