Let’s Discuss: Insights from the ACR Convergence 2025 Review Course

CHICAGO—Each year, the ACR provides a tremendous service to the rheumatology community by organizing its annual Review Course sessions at Convergence. Not only are the subjects selected for these sessions consistently timely and relevant, but also the speakers who present the material are invariably skilled at distilling complex topics down to their essence. This makes for talks that are engaging, high yield and always popular among conference attendees.

Systemic Lupus Erythematosus

Dr. Ardoin

The first lecture this year was given by Stacy Ardoin, MD, division chief of pediatric rheumatology, Nationwide Children’s Hospital and The Ohio State University, Columbus, and its focus was on both pediatric and adult systemic lupus erythematosus (SLE). Dr. Ardoin began by laying out several goals that all clinicians should have in caring for patients with SLE, namely: 1) controlling disease activity, 2) preventing organ damage, 3) improving patients’ quality of life, and 4) minimizing side effects from therapy. At the moment, only one medication—belimumab—is approved for pediatric SLE by the U.S. Food & Drug Administration (FDA), but Dr. Ardoin explained that pediatric rheumatologists often employ a range of therapies that, although off label, are still found to be helpful in managing patients’ disease. Without question, hydroxychloroquine is indicated for every pediatric and adult patient with SLE unless an absolute contraindication to its use exists or if a patient has significant side effects with the medication; in the latter case, Dr. Ardoin recommended trying a lower dose of the medication or using chloroquine in its place.

Similar to other rheumatic conditions, SLE can now be managed using a treat-to-target approach, with the target being either remission or low disease activity state. In the past, Dr. Ardoin explained, such targets would have been aspirational, but in recent years they have become realistic thanks to better treatments and a better understanding of how to use these targets. The Lupus Low Disease Activity State is characterized by the absence of activity in major organ systems, a prednisone dose of no more than 7.5 mg per day and standard maintenance doses of immunosuppressive treatments.¹

Specific ways to measure success in treating lupus nephritis include improvement in glomerular filtration rate (GFR) and proteinuria, and Dr. Ardoin cited the guidelines published by the ACR in 2024 as a particularly helpful resource for clinicians.² Significant innovations from these guidelines were the concept of using triple therapy at time of diagnosis of lupus nephritis and using such factors as the International Society of Nephrology/Renal Pathology Society (ISN/RPS) class of nephritis, GFR, degree of proteinuria and presence or absence of significant hypertension to guide selection of therapy. She noted that the FDA’s approval of obinutuzumab for the treatment of adults with active lupus nephritis came after publication of these guidelines, thus updates may be needed to the guidelines with respect to this medication; recommendations from the European Alliance of Associations for Rheumatology, however, do include obinutuzumab.³

For non-renal manifestations of disease, Dr. Ardoin explained that this is a bit of the Wild West in that more variability in practice patterns exists even among experts in the field, although this should improve with the publication of guidelines for the management of SLE presented at this year’s Convergence. When a patient has possible neuropsychiatric lupus (NPSLE), Dr. Ardoin noted that it is important to first ask a few questions: Could this be something else, like infection, malignancy or a toxic exposure? Why is the patient flaring now, and is it related to medication adherence? Is the patient pregnant or planning to become pregnant? If NPSLE does appear to be the correct diagnosis, then the clinician must consider if the driving issue is ischemia, in which case anticoagulation is important, or inflammation, which would require consideration of glucocorticoids, cyclophosphamide and anti-CD20 directed therapies. Symptomatic treatments, such as antipsychotics and antidepressants, may also have a role to play, and Dr. Ardoin recommended shared decision making with patients around treatment strategies whenever this is possible. For cutaneous disease, Dr. Ardoin stressed the importance of checking for medication adherence and the use of topical therapies and photoprotection, and stressed highly encouraging patients who smoke to quit as this may have dramatic effects on improving their skin disease. Options for medical management include dapsone, quinacrine, anifrolumab, anti-CD20 therapy and lenalidomide. For articular disease, Dr. Ardoin has had more success with methotrexate and leflunomide than with mycophenolate mofetil and azathioprine, and she sometimes borrows from treatment strategies for juvenile idiopathic arthritis and rheumatoid arthritis (RA) in considering treatment with tocilizumab, abatacept or Janus kinase inhibitors, although the latter may have concerns in patients with risk factors for thrombotic or cardiovascular disease.

Dr. Ardoin noted considerations that are particular to pediatric vs. adult patients with SLE that clinicians must keep in mind. Pediatric patients often present with more severe disease and may have monogenic forms of lupus, such as that seen with C1q deficiency, and given their earlier age of onset they have more potential years to be exposed to the effects of high disease activity or to incur the effects of years of drug exposure. Adults, meanwhile, often have more comorbidities and, thus, a greater degree of polypharmacy. Both pediatric and adult patients may face challenges with medication adherence, social impacts on their families, struggles with mental health, absences from work or school and impacts on their reproductive health/family planning.

Dr. Ardoin also discussed the situation in which a patient’s laboratory studies and physical exam look good, but they feel poorly. In such cases, she recommended that the rheumatologist consider different etiologies of the patient’s not feeling well, including medication side effects, fibromyalgia/amplified musculoskeletal pain syndrome, depression, adrenal insufficiency, other medical conditions that may arise secondary to the effects of SLE and life stressors.

Inflammatory Brain Diseases

Dr. Muscal

The next talk was delivered by Eyal Muscal, MD, MS, division chief, pediatric rheumatology, Pawelek Endowed Chair of Pediatric Rheumatology, Texas Children’s Hospital, Houston, and the topic was inflammatory brain diseases. Dr. Muscal provided a systematic approach to the evaluation of these patients, and he noted four tools at the disposal of clinicians.

Tool #1 is the ability of rheumatologists to listen to the stories that patients and their family members tell about their symptoms and tease out if there are clues to a specific process that ought to be considered. The stories may indicate if an infectious or malignant process is at play, or may hint at features of a systemic disease that clinicians can be searching for, such as with manifestations involving the skin, eyes, kidneys, lungs or other organs beyond the nervous system. Dr. Muscal implored clinicians to consider the possibility of an ischemic or focal process, or the possibility of the acute onset of a neurodegenerative disease. He noted that, although rheumatologists are trained to deal with implications of immune dysregulation in the periphery, a variety of cells can break the blood brain barrier and disrupt normal functioning. For example, certain monocytes and macrophages can take the appearance of microglia in the brain and cause issues.

Tool #2 is imaging, namely computed tomography of the head to look for hemorrhage and magnetic resonance imaging (MRI) of the brain and spinal cord to clearly define the anatomy of the patient’s disease process. Before pursuing imaging, the clinician should have a good sense of if the neurologic process is involving the central nervous system (CNS), the peripheral nervous system, or both, but the results of imaging are still very useful. A black blood MRI of the brain uses specialized sequences that suppress the signal from flowing blood, making blood vessels appear dark (black) on images and thus enhancing the visibility of adjacent structures, such as vessel walls, thrombi and parenchymal lesions. This imaging technique can be helpful in looking for certain forms of inflammatory brain disease, such as that which involves the small vessels.

Tool #3 refers to biomarkers of disease, which may be found in the cerebrospinal fluid or serum. These may include specific cytokines and chemokines (interleukin [IL]-6, IL-1β, tumor necrosis factor-alpha (TNF-α), interferon gamma and monocyte chemoattractant protein-1), brain-specific proteins (such as neurofilament light chain that can indicate axonal injury, glial fibrillary acidic protein that reflects astrocytic activation and YKL-40 that is linked to microglial activation and disease progression in multiple sclerosis), and emerging markers, such as sTREM2 (soluble triggering receptor expressed on myeloid cells 2), osteopontin and macrophage migration inhibitory factor, that are being studied for their roles in neuroinflammatory processes.⁴ Dr. Muscal noted that clinicians should look to the serum to evaluate for signs of organ dysfunction that may help inform the differential diagnosis and to think about complement activation as may be involved in conditions like antiphospholipid syndrome, thrombotic microangiopathies and macrophage activation syndrome.

Tool #4 is tissue, which Dr. Muscal says does not always have to be the issue because most inflammatory brain diseases do not require brain biopsy to prove the diagnosis.

Dr. Muscal provided clinical pearls related to several specific rheumatic diseases that can involve the nervous system. For sarcoidosis, neurologic involvement is much less common in children than in adults. Neurosarcoidosis occurs in approximately 5–10% of adult patients with sarcoidosis (most often as part of systemic disease) and only about 6% of adult cases are isolated to the nervous system.^5,6 Although nervous system involvement is seen in fewer than 5% of pediatric patients, children are more likely to present with isolated neurosarcoidosis.^7,8 Behçet’s disease is one of few rheumatic conditions that can involve both the arteries and the veins when involving the CNS. Among systemic vasculitides, CNS involvement is rarer than involvement of other organ systems, but Takayasu arteritis, giant cell arteritis (GCA), polyarteritis nodosa and anti-neutrophil cytoplasmic antibody–associated vasculitis can do so (in a patient age 50 or above with vision changes, clinicians should thoroughly seek to rule out GCA in particular). About 5–10% of patients with IgG4-related disease will have nervous system involvement, and pachymeningitis is a specific manifestation that may be seen.^9,10 Autoinflammatory conditions, such as neonatal-onset multisystem inflammatory disease, tumor necrosis factor receptor-associated periodic syndrome, deficiency of adenosine deaminase 2 (DADA2) and VEXAS (vacuoles E1 enzyme X-linked autoinflammatory somatic syndrome), can all involve the nervous system, and diagnosing these conditions may have significant implications for therapy, such as the indication for TNF inhibitor therapy in cases of DADA2).

A key takeaway from Dr. Muscal’s talk was the need for collaboration between rheumatologist and neurologists in caring for patients with inflammatory brain diseases, and understanding each other’s thought processes. For the neurologist, the MRI of the brain is a significant branch point in how they think about the most likely underlying condition. Myelin oligodendrocyte glycoprotein antibody disease and neuromyelitis optica may not immediately find their way onto the rheumatologist’s differential when evaluating patients, but neurologists commonly consider these conditions. Conversely, it may be up to the rheumatologist to do a thorough evaluation for SLE in a patient presenting with transverse myelitis given that this can be a manifestation of lupus-spectrum disorders. Dr. Muscal presented a particularly challenging case of encephalitis in a young woman that initially looked like it could be SLE, but was actually the result of N-methyl-D-aspartate (NMDA) receptor encephalitis, driving home the point that keeping an open diagnostic mind is essential when evaluating these types of patients.

Drug Management of Rheumatic Diseases

Dr. Chung

The third talk was given by Cecilia Chung, MD, MPH, professor of medicine and chief in the Division of Rheumatology of the Department of Medicine at University of Miami, Fla., who discussed pearls in drug management of rheumatic disease. Her talk was broken down into three sections with illustrative case examples. Pearl #1 was to employ the effects of drug pleiotropism to maximize the benefit provided by any single medication. This applies to losartan, which not only is an effective antihypertensive but also has uricosuric and promotes uricosuria. This is not a class effect among all angiotensin-receptor blockers (ARBs) and, in actuality, other ARBs may actually increase the risk for gout.¹¹ Pleiotropism is also relevant to statins, which are used for hyperlipidemia but may also have anti-inflammatory properties relevant to patients with conditions like RA. In a seminal paper from Ridker et al. involving healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein (hsCRP) levels, rosuvastatin significantly reduced the incidence of major cardiovascular events as compared with placebo.¹² Meta-analyses of randomized, controlled trials have been able to demonstrate that statins—atorvastatin in particular—can reduce DAS28 scores, CRP, erythrocyte sedimentation rate, tender and swollen joint counts, and circulating inflammatory cytokines in patients with RA, and this effect is most pronounced in patients with higher baseline disease activity.¹³ Dr. Chung also referred to work indicating that glucagon-like peptide-1 (GLP-1) receptor agonists may be able to improve pain in patients with osteoarthritis not only through helping these patients lose weight, but also through anti-inflammatory mechanisms that are still being explored.¹⁴

Pearl #2 was to bear in mind that many immunosuppressive medications may need to be renally dosed in patients with impaired renal function. Dr. Chung pointed out that more than 600 drugs have a high risk for toxicity in patients with impaired renal function, and rheumatologists should bear in mind that baricitinib, tofacitinib, methotrexate, leflunomide, cyclophosphamide and sulfasalazine may have specific issues arise in patients with reduced GFR. In a study from Muanda et al., adults with chronic kidney disease who started low-dose methotrexate (5–35 mg per week) had a higher 90-day risk of serious adverse events, such as a hospital visit with myelosuppression, sepsis, pneumotoxic effects or hepatotoxic effects, compared with those who started hydroxychloroquine (200–400 mg per day).¹⁵

Pearl #3 was that clinicians must not ignore the possible injurious effects of drug interactions. Dr. Chung provided a case example of a patient on tizanidine, a medication that is extensively metabolized in the liver by the cytochrome P450 1A2 (CYP1A2) enzyme. When CYP1A2 activity is reduced, as is the case with patients taking strong CYP1A2 inhibitors like fluvoxamine or ciprofloxacin, the metabolism and clearance of tizanidine are markedly decreased. This can result in substantially higher serum concentrations of the drug and increased risk of adverse effects like hypotension and excessive sedation. Similarly, rheumatologists must remember that for patients on allopurinol co-administration of azathioprine is dangerous as a highly significant interaction between the drugs can cause life-threatening bone marrow suppression.

Potential Mimics of Inflammatory Myopathies

The fourth talk of the session was from Jens Schmidt, MD, FEAN, FAAN, chair of the Department of Neurology and Pain Treatment, Immanuel Klinik Rüdersdorf, University Hospital of the Brandenburg Medical School Theodor Fontane in Rüdersdorf/Berlin, Germany, who described the potential mimics of the inflammatory myopathies. Dr. Schmidt provided the audience with an excellent online resource from the Neuromuscular Disease Center at Washington University in St. Louis; he noted that this site is continually updated and, thus, quite helpful to clinicians.¹⁶ Dr. Schmidt explained that a fundamental issue in the field is the confusing terminology in myositis that is not uniform across the world or even among professional societies. Given the diversity of terms and acronyms to describe the forms of these conditions, it can be hard for clinicians to speak the same language with one another. For example, some feel that the term polymyositis should be discarded into the wastebasket of history, but Dr. Schmidt explained it may still be needed to describe certain patients whose muscle disease cannot be described by an alternative diagnosis. Some have argued that scleromyositis should be recognized within both the systemic sclerosis and the autoimmune myositis spectrum of diseases, but this is not a universally accepted term.¹⁷

Dr. Schmidt broke down his talk into several categories of mimics of inflammatory myopathies. For clinical mimics, this refers to patients presenting with myalgias (muscle pain). The long list of potential causes of myalgias includes toxins like alcohol, such drugs as statins, thyroid disease, myopathies (i.e., metabolic, mitochondrial or muscular dystrophies), polymyalgia rheumatica, fibromyalgia and neuropathic processes. Dr. Schmidt noted that Becker muscular dystrophy can present with a proximal paresis and onset can range anywhere from 10 to 60 years of age. These patients can demonstrate a creatine kinase (CK) elevation of up to 10 times the upper limit of normal. Clinicians should look for hypertrophy of the calf muscles in evaluating for this condition. Chronic inflammatory demyelinating polyneuropathy is a condition with a subacute onset and typically affects patients ages 40–60 years (more men than women), and forms of the condition can present with a pure motor deficit without a concurrent sensory deficit. CK can be elevated to two to five times the upper limit of normal, and nerves may appear thickened when imaged with ultrasound. Myasthenia gravis is a disease that presents with fatigable weakness, often involving the arms and legs, with a bimodal distribution of disease onset (one peak is between ages 20–40, the other at 70 years and older). Clinicians should be on the lookout for patients describing double vision, drooping eyelids, impaired chewing and swallowing, or slurred speech. Dr. Schmidt also warned clinicians not to be fooled into thinking that amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that affects the motor neurons in the brain and spinal cord, is actually inclusion body myositis (IBM); he noted that one can be fooled by the pattern of weakness in the hands, which can be strikingly similar-appearing in both conditions. Detection of myopathic motor unit potentials (MUPs) in flexor digitorum profundus muscles may argue more strongly for ALS, though neurogenic MUPs can be seen in IBM as well.

For laboratory mimics of myositis, Dr. Schmidt noted two important concepts: 1) it is possible to find both false positive and false negative myositis-specific antibodies in the general population and 2) a normal CK does not rule out myositis. With an acute elevation in CK, clinicians should consider rhabdomyolysis, particularly with a history of toxin exposure, intense physical activity, trauma or seizures. With a more chronic elevation in CK, it is important to consider the possibility of muscular dystrophies and metabolic myopathies, and to ask about family history of muscle disease that may imply the need for genetic testing. Dr. Schmidt informed the audience that, in evaluating patients with elevated CK, muscle ultrasound is a relatively newer, emerging modality that is being used, especially in cases of suspected IBM.

For imaging mimics of myositis, it is important to consider the possibility of even rare entities, such as acute myonecrosis in diabetes (diabetic myonecrosis), a rare, spontaneous muscle infarction that causes sudden pain, swelling and tenderness, most often in the thigh. Muscle biopsies can be very helpful, such as for teasing apart immune-mediated necrotizing myopathies from antisynthetase syndrome, but reading pathologists can disagree, even when they are looking at the same slides. Myofibrillar myopathy can mimic IBM on muscle biopsy as both share similar features, such as rimmed vacuoles. Dysferlinopathy refers to a group of rare muscular dystrophies caused by recessive mutations in the DYSF gene, and these patients have muscle biopsies with inflammation that can be confused with that of polymyositis. Thus, every muscle biopsy should be evaluated within the clinical context, especially with attention paid to pattern of weakness, degree of CK elevation, presence or absence of myositis-specific antibodies and electromyography/nerve conduction study findings.

Jason Liebowitz, MD, FACR, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.

References

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