Abstracts

Primary membranous nephropathy (MN) is an autoimmune disease mainly caused by autoantibodies against the recently discovered podocyte antigens: the M-type phospholipase A2 receptor 1 (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A). Assays for quantitative assessment of anti-PLA2R and anti-THSD7A antibodies are commercially available. The presence or absence of anti-PLA2R and anti-THSD7A antibodies adds important information to clinical and immunopathologic data in discriminating between primary and secondary MN. Levels of anti-PLA2R antibodies and possibly, anti-THSD7A antibodies tightly correlate with disease activity. Low baseline and decreasing anti-PLA2R antibody levels strongly predict spontaneous remission, thus favoring conservative therapy. Conversely, high baseline or increasing anti-PLA2R antibody levels associate with nephrotic syndrome and progressive loss of kidney function, thereby encouraging prompt initiation of immunosuppressive therapy. Serum anti-PLA2R antibody profiles reliably predict response to therapy, and levels at completion of therapy may forecast long-term outcome. Re-emergence of or increase in antibody titers precedes a clinical relapse. Among patients with preserved kidney function and no evidence of secondary causes, a positive PLA2R antibody test highly predicts a tissue diagnosis of PLA2R-associated MN. An individualized serology-based approach to MN, complements and refine the traditional proteinuria-driven approach.

Complement activation and accumulation is seen in both proliferative glomerulonephritis and non-proliferative glomerulopathy. The proliferative glomerulonephritis includes immunoglobulin/immune complex-mediated glomerulonephritis such as proliferative glomerulonephritis secondary to monoclonal Ig, infection-related glomerulonephritis, lupus nephritis, etc. Proliferative glomerulonephritis due to predominantly complement deposition and absence of immunoglobulins includes C3 glomerulopathy. The non-proliferative glomerulonephritis includes membranous nephropathy. Using case based examples along with proteomics the talk will focus on the complement pathway activation and accumulation of complement proteins in the different types of glomerulonephritis.

Systemic lupus erythematosus is considered a prototypic autoimmune disease, characterized by the production of autoantibodies and involvement of multiple organ systems.  The myriad manifestations of lupus can make diagnosis difficult and necessitates involvement of clinicians with varying expertise to effectively diagnose and manage patients.

Original classification criteria for studies of lupus were published in 1971 and were updated in 1982 and 1997.  Newer classification criteria were published in 2012 by the Systemic Lupus International Collaborating Clinics (SLICC).  Recent publications highlight the need for improved classification, and hopefully at some point diagnostic, criteria.

Glucocorticoids and hydroxychloroquine were approved in the US for management of lupus in the 1950s.  Subsequently cyclophosphamide, methotrexate, azathioprine, mycophenolate mofetil, and calcineurin inhibitors, as well as other agents, have been utilized for their immunosuppressive effects.  The only additional agent approved in the US for treatment of lupus is the anti-BAFF agent belimumab.  The European League Against Rheumatism (EULAR) recently has published guidelines about management of lupus.  Clinical trials of anti-CD20 therapy utilizing rituximab did not meet trial end points.  Current studies are examining combination therapy with ritixumab and belimumab.  Multiple other potential therapeutic targets have been identified, with agents targeting innate immune mechanisms including type I interferon, T cell mechanisms, complement, and other immune system targets including IL-12/23 and Janus kinase (JAK) inhibitors.

Selected references:

Fanouriakis A, Kostopoulou M, Alunno A, et al.  2019 update of the EULAR recommendations for the management of systemic lupus erythematosus.  Ann Rheum Dis 2019; 29 Mar, Epub.

Dall’Era M, Bruce IN, Gordon C, et al.  Current challenges in the development of new treatments for lupus.  2019; 12 Jan, Epub.

Narain S, Furie R.  Update on clinical trials in systemic lupus erythematosus.  Curr Opin Rheumatol 2016; 28: 477-487.

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasian adults. MN is classified as primary and secondary MN. Phospholipase A2 receptor (PLA2R) is the target antigen in approximately 70-80% primary MN.  In most remaining primary and secondary MN, the target antigen is unknown. Using proteomics and immunohistochemistry, we describe the detection of novel proteins, exostosin 1 (EXT1) and exostosin 2 (EXT2) in the GBM of PLA2R-negative MN. EXT1 and EXT2 are absent in all PLA2R-associated MN and control cases. Clinical and biopsy findings show features of autoimmune disease, including membranous lupus nephritis, in 81% of EXT1/EXT2-associated MN cases. To summarize, EXT1/EXT2-associated MN represents a distinct subtype of MN, most commonly associated with autoimmune diseases (secondary MN).

A disruption of regulatory T cell (Treg) homeostasis caused by an acquired deficiency of IL-2 is a crucial event in the pathogenesis of systemic lupus erythematosus (SLE). Low-dose IL-2 therapy in SLE intends to restore Treg activity and thus can be considered a novel targeted treatment option with a unique mode of action. Here we highlight the key findings and rationales that led to the clinical translation of low-dose IL-2 therapy in SLE and summarize the most important results from an investigator-initiated phase 1/2a uncontrolled clinical study addressing the immunological and clinical responses to low-dose IL-2 therapy in patients with active and refractory SLE. This study shows that low-dose IL-2 therapy safely promotes the selective expansion of a functionally competent and thymic-derived Treg population and provides first evidence for its potential to decrease disease activity in patients with refractory SLE. In conclusion, this proof-of-concept study offers important rationales and the scientific basis for more comprehensive and placebo-controlled trials in the future.

Lupus nephritis is one of the leading causes of mortality and morbidity in SLE. It has been estimated that more than half of all SLE patients will develop lupus nephritis and 10–15% of these patients will progress to end‐stage renal disease. Although treatment is available, approximately 50% of patients have failed to achieve remission in recent trials. The current gold standard of care for the evaluation of renal involvement in SLE is a renal biopsy. However, renal biopsy is invasive cannot be performed repeatedly, and poses risks to the patient. Moreover, sampling errors may occur. As such, a need for noninvasive biomarker tools for diagnosis and management of lupus nephritis has been postulated.

Key references:

1. Rovin BH et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012 Apr;64(4):1215-26
2. De Vriese AS, Fervenza FC. Biomarkers in glomerular diseases: putting the cart before the wheel? Nephrol Dial Transplant. 2015 Jun;30(6):885-90.

Antineutrophil cytoplasmic antibodies (ANCA) targeting proteinase 3 (PR3) or myeloperoxidase (MPO) are associated with the small vessel vasculitis syndromes GPA, MPA and EGPA. Recent methodologic advances have led to changes in recommended testing algorithms (1). Testing for PR3-ANCA and MPO-ANCA has a high positive predictive diagnostic value for GPA, MPA or EGPA if ordered in a clinical setting of high likelihood of such a vasculitis syndrome. Indiscriminate testing is likely to generate false positive test results. Diagnostic pitfalls and specific clinical situations in which a positive PR3- or MPO-ANCA test result can be expected (infections, drugs) need to be recognized.  The clinical utility of serial ANCA testing in the follow-up of patients remains controversial but recent studies have clarified the clinical settings in which it provides useful information (2). The clinical utility is best documented for PR3-ANCA in patients presenting with disease manifestations of capillaritis (alveolar hemorrhage, glomerulonephritis) and following treatment with rituximab.

Key references:

Bossuyt X et al. Revised International Consensus on testing of anti-neutrophil cytoplasm antibodies in small vessel vasculitis. Nature Rev Rheum. 2017; 13:683-92.
Fussner LA et al. Factors determining the clinical utility of serial measurements of antineutrophil cytoplasmic antibodies targeting proteinase 3.  Arthritis Rheumatol. 2016; 68:1700-10.

Vascular changes that clinically manifest as Raynauds phenomenon (RP), and characterized by structural abnormalities of the peripheral microcirculation play a central role in the pathogenesis of systemic sclerosis (SSc) and may also be evident in dermatomyositis and other SSc spectrum diseases. At the nailfolds, capillaries lie parallel (rather than perpendicular) to the skin surface and can be visualized noninvasively using the simple, low-cost and reproducible technique of nailfold capillary (NFC) microscopy. Clinically, this forms a key investigation for differentiation of primary vs. secondary RP and evaluation of suspected SSc.

The inclusion of abnormal nailfold capillaries as one of the 2013 American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) classification criteria for SSc has given new impetus to the use of NFC, making it critical that all rheumatologists making the diagnosis of SSc be familiar with this technique to avoid missing the diagnosis. Different capillaroscopic techniques are available. While the ‘gold standard’ is high magnification videocapillaroscopy (200×), there is also increasing interest in lower magnification, hand-held techniques including the dermatoscope and more recently the USB microscope to assist the busy clinician at beside. Characteristic abnormalities include dilated capillaries, hemorrhages, areas of avascularity, distortion of the normal nailfold architecture and neovascularization that are best evident with higher magnification.

The significance, indications, different methodologies (low and high magnification) for performing NFC, and key abnormalities of significance for diagnosis of secondary RP and SSc spectrum disorders will be discussed. The role of NFC as an imaging biomarker in research, and a tool to predict prognosis including visceral and vascular complications of SSc (digital ulcers, pulmonary hypertension, mortality) will also be reviewed. This talk will expand the clinician’s understanding and utilization of this procedure critical for comprehensive rheumatic disease evaluation.

Key References:

1. Ingegnoli F et al. Capillaroscopy in Routine Diagnostics: Potentials and Limitations. Curr Rheumatol Rev, 2018 Apr 20;14(1):5-11.
2. Van den Hoogen et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 2013 Nov; 65(11): 2737-47.

Soulaidopoulos S et al. Role of nailfold capillaroscopy in the assessment of internal organ involvement in systemic sclerosis: A critical review. Autoimmun Rev, 2017 Aug; 16 (8):787-795.

Ocular inflammation can complicate various multisystem inflammatory disorders (MID). The range of ocular inflammatory manifestations shows a broad variety and may present strong, intermediate, or low grade intensity. Ocular inflammation can induce a broad spectrum of damage to the eye with irreversible destruction of the whole eye or parts of it, intermediate damage with permanent or limited reduction of visual function, or low grade damage with irritation and/or discomfort of the eye. As important examples of MID, giant cell arteritis (GCA) has a high potential for insidious ocular blindness due to large vessel vasculitis located at the optic nerve. In contrast to that, in GPA ocular blindness can result from chronic progressive granulomatous orbital inflammation. Ophthalmologists taking care for multisystem inflammatory disorders should be aware of eye manifestations as primary event before systemic disease manifestation becomes obvious. In that situation ophthalmologists are responsible for correct diagnosis and treatment of inflammatory disease. However, eye manifestations as complication of any known MID demands the ophthalmologist to look for typical eye manifestations using special eye relevant anamnesis, visual function testing and biomicroscopy. New diagnostic tools like optical coherence tomography (OCT) for in vivo tissue scanning can better and objectively analyse macular disorders or optic nerve layer damage than  methods before. Special attention should be given to eye complications arising from therapeutic interventions in MID, e.g. opportunistic infections and medication side effects are important point of interests during follow-up of MID-patients. As MID frequently take long courses, interdisciplinary reevaluation and reconsidering of the patients and their history is essential. Ophthalmologists routinely take care for a small, but important organ. With regard to MID, however, ophthalmologists should work and think interdisciplinary and contribute to optimal management of patients with multisystem inflammatory disorders.

Sarcoidosis is a systemic granulomatous disease that affects the lungs in 90% of cases, and can affect virtually every organ system. Systemic corticosteroids are the drugs of choice for the treatment of sarcoidosis, although there still is no clear consensus regarding the optimal time to initiate treatment, the optimal starting dose to induce disease “remission”, when to consider a corticosteroid sparing agent (and which agent to choose depending on specific organ involvement), whether dosing should be modified if the primary target of treatment is pulmonary vs extra-pulmonary disease, or for how long treatment should be maintained. Addressing these questions has proven to be challenging due to the unpredictable natural history of disease, the potential for spontaneous remission, the lack of biomarkers that predict clinical outcomes, and the relative paucity of prospective or randomized treatment trials. In addition to systemic corticosteroids, additional therapies with reported efficacy include inhaled corticosteroids, methotrexate (the most commonly used “second-line” agent), TNF-alpha inhibitors, hydroxychloroquine, minocycline, azathioprine, mycophenolate mofetil, and others. The management of sarcoidosis must also take into consideration the extent and types of organs involved (particularly in the context of ocular, nervous system, and cardiac involvement where insufficient or delayed therapy may result in devastating morbidity from permanent target organ injury), personal patient preferences, and other patient specific factors unrelated to sarcoidosis (age, presence of pre-existing osteopenia or osteoporosis, diabetes, obesity, kidney or liver disease, etc.).  Management of sarcoidosis should be individualized, and shared decision making with patients is recommended in the establishment of therapeutic plans that consider both disease specific factors (including which organs are involved), and personal patient preferences.

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are two distinct pulmonary vascular complications of liver disease with unique pathophysiology, clinical manifestations, treatment and implications for liver transplantation (Table 1). HPS is characterized by the clinical triad of advanced liver disease, intrapulmonary precapillary and capillary vasodilatation and abnormal arterial oxygen, defined by an elevated Alveolar-arterial oxygen gradient ≥15mmHg or >20 mmHg in patients >64 years of age. HPS affects 5-32% of patients with advanced liver disease and is associated with worse survival and quality of life. There are no approved medical therapies, but HPS is considered an indication for liver transplantation since hypoxemia related to HPS resolves following liver transplantation. POPH is a clinical and hemodynamic diagnosis characterized by pulmonary arterial hypertension that can lead to right heart failure and death. POPH affects 5-6% of patients with advanced liver disease and is treated with pulmonary arterial hypertension targeted therapy. POPH is associated with poor survival and an increased risk of perioperative cardiopulmonary mortality if poorly controlled at the time of liver transplantation. In contrast to HPS, POPH is not considered an indication for liver transplantation since outcomes following transplantation are variable.

Immune-mediated myopathies have historically been classified as polymyositis, dermatomyositis and inclusion body myositis, characterized by inflammation on muscle biopsy, with muscle weakness being the predominant clinical manifestation.  It has been increasingly recognized that these conditions can have systemic manifestations and some patients may have systemic manifestations such as cutaneous or pulmonary features with minimal or no muscle involvement.  Amyopathic dermatomyositis is often seen by dermatologists.  Antisynthetase syndrome has been suggested as a separate entity.  More recently immune-mediated necrotizing myopathy, also known as necrotizing autoimmune myopathy, with minimal or no muscle inflammation, often associated with statin exposure, has been recognized.  Recent efforts have identified clinical and laboratory features which can aid in classification of patients.

Autoantibody testing is revolutionizing classification of patients with myositis.  In addition to the earlier known myositis specific antibodies including the anti-aminoacyl tRNA synthetase antibodies associated with antisynthetase syndome, anti-Mi2 antibodies associated with dermatomyositis, and anti-SRP antibodies associated with necrotizing myopathy, additional antibodies have been identified which are associated with specific clinical subgroups including patients with increased risk of malignancy associated with myositis.

Assessment of disease activity has been a problem in patients with myopathy and lack of consensus on appropriate activity measures have hampered development of therapeutic trials.  Recent international efforts have led to development of a disease assessment tool which will hopefully facilitate clinical trials.

Glucocorticoids remain the cornerstone of treatment for patients with immune-mediated myopathy.  Unfortunately, glucocorticoid-related adverse events remain a major problem.  Insufficient clinical evidence exists to support definitively any specific immune-suppressive agent but it is clear that use of such agents can minimize glucocorticoid side effects.  Rituximab was studied in the largest clinical trial of myositis to date.  Although the primary end point was not met, there is suggestion that seropositive patients benefit the most from rituximab.  Ongoing efforts are examining other potential therapeutic targets.  The importance of exercise as part of the therapeutic regimen for patients with myositis cannot be underestimated.

Selected references:

Lundberg IE, Tjärnlund A, Bottai M, et al. 2017 European League Against Rheumatism/ American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups.  Ann Rheum Dis 2017; 76: 1955-1964.

Aggarwal R, Rider LG, Ruperto N, et al.  2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organization collaborative initiative.  Arthritis Rheumatol 2017; 69: 898-910.

Betteridge Z, McHugh N.  Myositis-specific autoantibodies: an important tool to support diagnosis of myositis.  J Intern Med 2016; 280: 8-23.

Selva-O’Callaghan A, Pinal-Fernandez I, Trallero-Araguás E, et al.  Classification and management of adult inflammatory myopathies.  Lancet Neurol  2018; 17: 816-828.

This presentation provides an update on treatment strategies for rheumatoid arthritis (RA). International guidelines state that methotrexate should be used as the first disease-modifying antirheumatic drug (DMARD) for treatment of newly diagnosed RA. Clinical evidence supports the value of methotrexate often in combination with a tapered course of glucocorticoids as remission-induction therapy. However, recently published trials are challenging the MTX-first paradigm by introducing biologic or targeted synthetic DMARDs into early treatment strategies. The ‘treat-to-target’ strategy has proven efficacy in clinical trials over 5 years follow-up. Recent studies have shown that ultrasound- or MRI-steered therapy is not more effective than conventional treat-to-target strategies. Among patients who have failed to response to MTX or conventional synthetic DMARDs, treatment with either triple combination DMARD therapy or TNF vs. non-TNF biologic agents is indicated. Recent studies reveal evidence of favorable sustainability of triple therapy but different infection and gastrointestinal adverse effect profiles. After failure of a TNF biologic agent, clinical and serological features can assist in individualizing the selection of subsequent therapies. The comorbidity profile and use of glucocorticoids are the most important predictors of serious infections among people with RA treated with biologic therapies. Newer IL-6 targeted therapies and Janus Kinase inhibitors (JAKi) are disrupting current treatment paradigms, though for venous thromboembolic events (VTEs) are emerging as an uncommon but serious adverse event with JAKi agents. Among patients who attain sustained low disease activity or remission, current evidence supports attempts to taper/discontinue DMARDs, considering either methotrexate or bDMARDs, but the possibility of disease relapse warrants shared decision making about this option and careful clinical observation to ensure the best outcomes.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder associated with extra-articular manifestations which may cause significant comorbidity and premature mortality. Pulmonary involvement, including the airways (large as well as small airway involvement), parenchymal disease (interstitial lung disease, combined pulmonary fibrosis and emphysema, as well as parenchymal lung nodules), pleura (pleurisy and pleuritic), as well as vascular compartments may all be affected in RA. Rheumatoid lung disease may predate the clinical onset of joint disease, or occur concomitantly with presentation of articular disease. In some instances, lung manifestations become apparent years after the diagnosis of articular RA. The pathophysiology of lung disease is not well understood, but likely involves repetitive airway and alveolar epithelial injury that result in a chronic inflammatory response locally which eventually leads to breakdown of tolerance and development of autoimmunity. Cigarette smoking, infections, host genetic factors, and immune dysregulation are all involved in complex interactions that promote not only systemic RA but also lung disease. The management of RA related lung disease is empiric and subject to expert opinion: at this time, there are no specific guidelines for the treatment of either airway or interstitial RA lung disease. In most instances, the treatment of lung disease focuses on the use of therapeutic agents with known activity for articular RA. The potential efficacy of anti-fibrotic therapy (Pirfenidone or Nintedanib) in the management of RA interstitial lung disease is unknown, but is currently being addressed through prospective clinical trials. Small open label studies suggest that B cell depleting therapy may have a potential role in stabilizing interstitial lung disease in RA. The establishment of multi-center prospective cohorts of patients with RA lung manifestations is a critical step towards understanding natural history as well as develop necessary infrastructure to systemically test different agents for the treatment of RA associated lung diseases.

This presentation reviews recent advances in targeted therapies for axial spondyloarthritis (axSpA, including radiographic and non-radiographic) and psoriatic arthritis (PsA). Based on current guidelines for axSpA, treatment with a TNF inhibitor (TNFi) is typically prescribed for patients who fail at least 2 NSAIDs. Recent studies demonstrate long-term effectiveness and safety of approved TNFi agents albeit with some differentiation among the TNFis. Health-related quality of life, physical function, and work productivity improve in patients treated with these agents. While methotrexate or other conventional synthetic DMARDs are often used for initial treatment of PsA, recent studies support the superiority of TNFi, which are now conditionally recommended first-line for PsA. IL-17A antagonists have emerged as important treatment options for both axSpA and PsA, and limited evidence suggests greater efficacy of IL-17A antagonists relative to TNFi therapy. IL-23 antagonists (e.g., guselkumab) are in development for psoriatic arthritis and may have particular benefit for enthesitis. Abatacept (T-cell co-stimulation blocker) and apremilast (PDE-4 inhibitor) are also options for PsA though with modest benefits for skin psoriasis. In contrast to known efficacy in PsA, targeting the p35 subunit of IL-12/IL-23 with ustekinumab is ineffective for axSpA. Exciting data are emerging regarding the efficacy of Janus kinase inhibitors for management of not only PsA but also axSpA. In comparison to RA, tapering or discontinuing biologic therapies in patients with axSpA or PsA has been less successful. Imaging studies of targeted therapies reveal evidence of modification of sacroiliac and spine inflammation and protection against structural damage in patients with axSpA. Further development of outcome measures that account for heterogeneity of treatment effects on disease manifestations may facilitate greater discrimination between agents in comparative effectiveness studies.

Giant cell arteritis (GCA) is an inflammatory vasculopathy that typically involves the extracranial branches of the carotid artery and frequently also affects the aorta, and aortic arch branches. Ominous consequences of arterial occlusive disease secondary to GCA may include vision loss, cerebrovascular ischemic events, and limb claudication.  The clinical presentation of GCA is highly variable; cranial GCA and large vessel GCA appear to represent two ends of the clinical spectrum of this disease.  Early recognition and treatment of GCA is important to mitigate long-term damage.

Glucocorticoids (GC) remain an essential component of remission induction therapy for GCA and are highly effective in suppressing signs and symptoms of the disease, as well as preventing vision loss. However, GC do not readily abrogate vascular inflammation and patients often relapse resulting in a prolonged treatment course. While the Th17 pathway is responsive to GC, chronic lesions of vasculitis are maintained by persistent Th1-driven inflammation. GC therapy is associated with significant morbidity and therefore steroid-sparing agents are often used. Of available conventional immunosuppressive treatments, methotrexate has been best studied and may reduce the risk of GCA relapses. Recent prospective clinical trials have demonstrated a remarkable efficacy of tocilizumab in reducing risk of relapse and steroid requirements in patients with GCA.  Optimal duration of therapy with tocilizumab is a subject of ongoing studies.

Despite advances in therapy, patients with GCA remain at risk of aortic complications including aneurysm formation, and require periodic screening to reduce risk of potentially fatal vascular events. Advances in understanding of disease pathogenesis continue to identify therapeutic targets and several novel agents are currently under investigation for treatment of GCA.

This presentation focuses on the management of GPA and MPA.  The tendency is to individualize therapy as much as possible. Treatment options are stratified based on disease severity.  Also, it is crucial to differentiate symptoms caused by active disease from those caused by damage resulting from disease related scarring or treatment toxicity.  Rituximab has largely replaced cyclophosphamide in the management of severe PR3-ANCA related disease, whereas for MPO-ANCA associated disease, which is associated with a substantially lower relapse tendency, cyclophosphamide remains an option.  For non-severe GPA a combination of glucocorticoids and methotrexate is often tried first.  For non-severe MPO-ANCA positive MPA the combination of glucocorticoids and mycophenolate mofetil (MMF) is also an option.  For remission maintenance following induction with cyclophosphamide, azathioprine or methotrexate are first-line options, whereas MMF is considered a second-line agent.  For patients with severe renal disease or diffuse alveolar hemorrhage with respiratory failure the combination of glucocorticoids with the combined use of cyclophosphamide pulses and rituximab as well as the use of plasma exchange have been proposed.  However, emerging data from the PEXIVAS trial and from large single center cohort studies do not support the combined use of cyclophosphamide and rituximab or the addition of plasma exchange.  The most significant factors to minimize damage from active vasculitis are the speed of diagnosis and implementation of therapy.  Most recent research efforts have focused on minimizing and avoiding glucocorticoid use, primarily because the predominant cause of death in the first 3-12 months of therapy is related to infections.  Novel  agents targeting neutrophil activation by blocking the effects of activated complement factor V are under investigation. The rationale and design of ongoing trials aimed at glucocorticoid avoidance will be reviewed.

Key References:

Specks U et al. Efficacy of remission induction regimens for ANCA-associated vasculitis.  NEJM. 2013; 369:417-27.

Unizony S et al.  Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Ann Rheum Dis. 2016; 75:1166-9.

Yates M el. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis 2016;75:1583–1594. Ann Rheum Dis 2016;75:1583–1594.

Takayasu arteritis (TAK) is a rare, chronic, idiopathic granulomatous vasculitis that affects large and medium-sized arteries. TAK is typically seen in younger individuals below age 40 years, with an annual incidence of 1-3 cases/million population.  Presenting clinical symptoms may be nonspecific, and there is often a significant delay in diagnosis.  Diagnostic biomarkers are not available, and the diagnosis primarily rests on use of imaging studies such as magnetic resonance angiography and FDG-PET scanning.  Clinical examination often underestimates the extent of disease involvement, and most patients already have evidence of extensive vascular damage at diagnosis. The thoracoabdominal aorta and its primary branches are most often affected, resulting in stenotic and/or aneurysmal arterial lesions.

Glucocorticoids (GC) remain the cornerstone first-line treatment TAK, and conventional immunosuppressive agents such as methotrexate, azathioprine and mycophenolate mofetil are often used. The majority of information regarding treatment of TAK is based on retrospective reports and small open-label trials.  Patients with refractory disease are often treated with TNF inhibitors (TNFi), and the efficacy of these biologics for the treatment of TAK has been demonstrated in multiple retrospective observational studies.  The proportion of patients without new vascular lesions appears to be highest in patients treated with TNFi, when compared to those treated with GC or immunosuppressive agents. A recent randomized, double blind, placebo-controlled, phase 3 trial evaluating the use of tocilizumab for TAK demonstrated evidence of benefit in a subset of patients. However, silent vascular progression may occur despite therapy with tocilizumab.

Regardless of the therapy used for treatment of TAK, patients often require invasive vascular reconstructive surgery and may be at risk of premature mortality, highlighting the ongoing need of more effective therapeutic agents.

Traditionally, treatment of patients with EGPA has been selected primarily based on prognostic factors that determine long-term mortality, such as those contained in the five-factor-score (FFS). For EGPA however, cardiac disease is the only relevant component of the FFS. Since it has been recognized that overall mortality of patients with EGPA is low, other outcomes such as long-term damage, reduction of GC exposure and control of severe asthma appear increasingly relevant. Recent data have shown that manifestations such as asthma, mononeuritis multiplex or severe skin disease are important factors that affect these outcomes. Furthermore, several studies have shown that biomarkers such as ANCA or the presence of eosinophilia are associated with the outcomes of certain manifestations and the response to specific therapies. Moreover, preliminary data from a genome wide association study indicate that subtypes of EGPA (ANCA positive versus ANCA negative) have a distinct genetic basis, are characterized by a specific clinical phenotype and may even differentially respond to certain treatments.

The FFS was derived from observation of cohorts treated with glucocorticoids (GC) and other conventional immunosuppressive agents such as cyclophosphamide. Recent studies indicate, that targeted biologic therapies are beneficial in patients with EGPA. Data from a randomized-controlled clinical trial have shown that the Interleukin-5 inhibitor mepolizumab is superior to standard of care in terms of disease control and GC-sparing properties in patients with relapsing EGPA who still had some blood eosinophilia. Retrospective open-label studies indicate that rituximab appears to be effective in ANCA-positive patients with EGPA, while the response in ANCA-negative patients was less convincing.

In summary, there is growing evidence that biomarkers, genetic factors and the presence of certain clinical manifestations are relevant for important long-term outcomes and also determine response to specific treatments. In view of these developments and the availability of novel targeted therapy, a more personalized treatment approach for patients with EGPA is on the horizon.

Diffuse alveolar hemorrhage (DAH) can be immune-mediated or caused by capillary mechanical stress failure or other rare conditions. Most of the immune-mediated causes of DAH have capillaritis as their main underlying mechanism.  The most common causes of capillaritis in the lung are granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), whereas DAH occurring in the context of other systemic autoimmune diseases including systemic lupus erythematosus, antiphospholipid syndrome, cryoglobulinemia, IgA-vasculitis, eosinophilic granulomatosis with polyangiitis or anti-glomerular basement membrane disease are rare occurrences.  The management of DAH caused by GPA and MPA will be explained based on results from recent randomized controlled trials and analyses of large cohort studies.  The oxygen saturation at the first point of care is the strongest predictor for the progression of DAH to respiratory failure and therefore should influence patient disposition.  The duration of respiratory symptoms, presence or absence of constitutional symptoms, arthralgias, myalgias or renal disease allows decision making about implementation of glucocorticoid therapy even before a specific diagnosis has been established.  For GPA and MPA, recent data support the use of rituximab over cyclophosphamide even for patients requiring mechanical ventilation, whereas the supporting evidence for benefits of plasma exchange is dwindling.

Key References:

Cartin-Ceba R et al.  Diffuse alveolar hemorrhage secondary to ANCA-associated vasculitis: predictors of respiratory failure and clinical outcomes.  Arthritis Rheumatol. 2016;68:1467-76.

Thompson G et al.  Biopsy-proven pulmonary capillaritis: a retrospective study of etiologies including an in-depth evaluation of isolated pulmonary capillaritis.  Respirology. 2016;21:734-8.

Cartin-Ceba R. Primary antiphospholipid syndrome-associated diffuse alveolar hemorrhage. Arthritis Care Res. 2014;66(2):301-10.

Stone JH  et al.  Rituximab versus cyclophosphamide for ANCA-associated vasculitis.  N Engl J Med.  2010;363:221-32.

According to the most recent 6^th World Symposium on Pulmonary Hypertension (PH), pulmonary arterial hypertension (PAH) is defined as an elevated mean pulmonary arterial pressure >20 mmHg in the setting of an elevated pulmonary vascular resistance ≥3 Wood units and a normal pulmonary arterial wedge pressure ≤15mmHg. PAH can be further classified clinically as idiopathic, heritable, drug and toxin-induced, PAH associated with connective tissue disease, HIV, portal hypertension, congenital heart disease, or schistosomiasis or PAH with overt features of venous and capillary involvement. PAH is treated with a combination of pulmonary vasodilator therapy and supportive measures, such as diuretics and supplemental oxygen. In recent years, the therapeutic options for PAH have expanded and now include phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators that target the nitric oxide pathway, prostacyclin analogues and IP receptor agonists that target the prostacyclin pathway, and endothelin receptor antagonists. Calcium channel blockers are indicated in a small subset of patients with a significant response to vasodilator testing. The management of PAH is complex; risk stratification using available clinical, laboratory and hemodynamic data is recommended to help guide therapeutic decisions (Figure 1). In most patients, upfront combination therapy with a phosphodiesterase-5 inhibitor and endothelin receptor antagonist is now considered standard of care. The use of anticoagulation in Group 1 PAH is controversial but should be avoided in scleroderma associated PAH and can be considered in selected patients with idiopathic, heritable or drug and toxin-induced PAH.

Interstitial lung disease (ILD) is a leading cause of mortality in systemic sclerosis (SSc). While majority of SSc patients have ILD, it may have a widely variable clinical course. At present we lack the precision in predicting which subsets of patients will develop organ and potentially life-threatening disease but a high mortality risk is the impetus for rigorous monitoring for ILD development and progression.

High resolution chest imaging (HRCT) is more sensitive than pulmonary function tests (PFTs) alone for early diagnosis of SSc-ILD. Risk of developing ILD is higher in those with diffuse cutaneous SSc, African-american and Hispanic ethnicity, male gender, concomitant cardiac disease and positive Anti-Scl 70 antibody status. Elevated CRP and KL-6 levels have also been associated with risk of progression.

Observational studies have identified factors associated with SSc-ILD at baseline (FVC, HRCT extent) which can predict risk of mortality and offer guidance regarding treatment considerations. Several predictive models using readily available demographic and clinical data have been developed to assess prognosis in patients with connective tissue disease and ILD, some specifically validated for SSc-ILD. The GAP (sex, age and lung physiology), ILD-GAP, SADL (smoking history, age, DLCO), and SPAR (SpO2, arthritis) models will be discussed. The results of Scleroderma Lung Study I and II (SLS I, SLS II) have also offered valuable insights into physiologic and radiographic features, which help assess prognosis and potential response to treatment and will also be reviewed. Short-term progression of ILD (decline in FVC and DLCO over 2 years) is reported to be a better predictor of mortality than baseline severity of ILD.

Not all patients with SSc-ILD warrant intervention. Periodic monitoring of clinical symptoms and PFTs is key. Those with clinically meaningful decline in lung function (decline in FVC > 10% from baseline or > 5% to < 10% relative decline in FVC and > 15% relative decline in DLCO) should be treated. Recently published data (SLS-I and SLS-II) support use of cyclophosphamide or mycophenolate mofetil as first-line treatment of SSc-ILD both of which have shown modest improvements in FVC with treatment aimed at stablizing disease or attenuating disease progression. For patients not responding to first-line therapies, rituximab is utilized as rescue therapy. Recent trials of hematopoietic autologous stem cell transplantation have also demonstrated benefit in patients with progressive SSc-ILD. Studies with antifibrotics and biologics are underway for SSc-ILD, and will be reviewed. An approach to treatment and monitoring will be outlined.

Key References:

1. Roofeh et al. Management of systemic sclerosis associated-Interstitial Lung Disease. Curr Opin Rheumatol 2019, 31:241–249.
2. Mango RL et al. Assessing Mortality Models in Systemic Sclerosis-Related Interstitial Lung Disease. Lung 2018 Aug;196(4):409-416.
3. Volkmann ER et al. Short-term progression of interstitial lung disease in systemic sclerosis predicts long-term survival in two independent clinical trial cohorts. Ann Rheum Dis 2019;78:122–130.
4. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655–66.
5. Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med 2016;4:708–19.

Pulmonary hypertension, defined as an elevated mean pulmonary arterial pressure, affects more than 10% of patients with systemic sclerosis (SSc) and is associated with a poor prognosis. PH is a leading cause of mortality in SSc and can have varied phenotypes with unique clinical manifestations and therapeutic approaches. These phenotypes include pulmonary arterial hypertension secondary to an intrinsic arteriopathy (SSc-PAH, similar to idiopathic PAH), pulmonary veno-occlusive disease (PVOD) associated with obstruction of the small pulmonary veins, pulmonary hypertension secondary to interstitial lung disease (PH-ILD), and post-capillary PH associated with left sided heart disease. A combination of chest imaging, pulmonary function tests and right heart catheterization is necessary to accurately phenotype and classify PH in SSc. The presence and extent of ILD on chest imaging and the severity of pulmonary function test abnormalities can be used to differentiate SSc-PAH and PH-ILD, although patients may have overlapping phenotypes with varying degrees of PH and ILD. PAH specific therapy is indicated in SSc-PAH but does not have a proven role in the treatment of PH-ILD. PVOD is associated with hypoxia, a severely reduced diffusion capacity, typically <50% predicted, and specific chest computed tomography abnormalities such as centrilobular ground glass opacities, interlobular septal thickening and mediastinal lymphadenopathy. Patients with PVOD have a worse prognosis and may develop life-threatening pulmonary edema with initiation of pulmonary vasodilator therapy. An elevated pulmonary arterial wedge pressure on right heart catheterization differentiates PH secondary to left sided heart disease from the other PH phenotypes. Similar to PH-ILD, there is no proven role for PAH specific therapy in PH secondary to left heart disease.

Systemic sclerosis (SSc) is a severe life-threating disease with high morbidity combining clinical features of autoimmunity, vasculopathy, and fibrosis. SSc is also a heterogenous disease with variable symptoms and autoimmune features. The effects of autologous stem cell transplantation on vasculopathy and fibroses indicate an important role of the adaptive immune system as causal trigger of the disease. In addition, exposure to benzol, silicone, or toxic oil seem to be important in the disease pathogenesis. In contrast, genetic risks for SSc are low and not very different to other systemic autoimmune diseases. G protein-coupled receptors are a class of receptors modulated by the exposome as well as by autoantibodies (aabs). Our group has recently identified a network of anti-GPCR aabs, which is specifically skewed in SSc. Here, increased levels of antibodies against the angiotensin receptor type-1 (AT1R) as well as the endothelin receptor type-A (ETAR) were identified showing associations with vascular and fibrotic complications. High Anti-AT1R and ETAR aabs are predictive for SSc-related mortality, the development of PAH, of digital ulcers, and of therapeutic response to immunosuppressants. In addition, theses aabs induce collagen expression in fibroblasts, reduce regeneration of endothelial cells, induce adhesions molecules and cytokines in endothelial cells such as IL-8 and TGFß, and cytokines and chemokines in monocytes. All these cells express AT1R and ETAR and their expression is increased in SSc. In our ongoing experiments, the causal role of anti-AT1R aabs to induce SSc features such as skin fibrosis or interstitial lung fibrosis is now proven in animal experiments. Our group has generated monoclonal anti-AT1R aabs inducing clinical SSc symptoms. However; other aabs may also participate in SSc pathogenesis such as antibodies against the chemokine receptors CXCR3 and CXCR4. Here, low anti-CXCR3/4 aab levels are associated with progressive lung fibrosis. In summary, aabs against GPCR are a novel concept to explain SSc and its symptoms. The function of each aab and more important, their role as therapeutic target is an emerging field to understand and treat SSc. In addition, anti-GPCR aabs could explain the effects of the exposome in SSc as well as in other diseases.