Let’s Discuss Part 2: More Insights from the ACR Convergence 2025 Review Course

CHICAGO—Each year at ACR Convergence, the Review Course sessions provide timely and relevant information with speakers who are skilled at distilling complex topics down to their essence. The talks of the first four speakers at this year’s Review Course, on pediatric and adult systemic lupus erythematosus (SLE), inflammatory brain diseases, drug management and mimics of inflammatory myopathies, are summarized here. The talks of the final four speakers are presented below.

Cutaneous Manifestations of Rheumatic Diseases

Katharina Shaw, MD, FAAD, director of rheumatology-dermatology at Children’s Hospital of Philadelphia, discussed the cutaneous manifestations of rheumatic diseases. Using a case-based approach, Dr. Shaw very skillfully illustrated that, even in this era of artificial intelligence, a detailed physical exam is often still key to making the correct diagnosis. She provided images of a patient with eosinophilic fasciitis, a condition that is often mistaken for systemic sclerosis, and pointed out specific findings, such as the groove sign, which refers to linear depressions that appear along the course of superficial veins in the affected area, and a cinching of the skin at the waist that she called the corset sign. These help to identify the condition.

Dr. Shaw noted that textbooks indicate the prayer sign, in which inflammatory involvement of the fascia leads to reduced joint mobility and results in an inability to fully extend the fingers at the joints, can be seen in either eosinophilic fasciitis or systemic sclerosis, but clinicians must examine the distal fingers to evaluate for skin laxity, which will be normal in eosinophilic fasciitis and abnormal in systemic sclerosis. As for treatment, pulse therapy with glucocorticoids can be given in severe cases of eosinophilic fasciitis whereas glucocorticoids are generally avoided in patients with systemic sclerosis given the risk of scleroderma renal crisis. Glucocorticoid-sparing treatments for eosinophilic fasciitis can include mycophenolate mofetil, methotrexate, intravenous immunoglobulin and mepolizumab, and patients also benefit from physical therapy. Dr. Shaw noted that it is important to take photos of patients with eosinophilic fasciitis to more objectively evaluate their improvement with treatment, which occurs very slowly.

For lupus, Dr. Shaw reviewed the categories of cutaneous involvement, namely acute, subacute and chronic cutaneous lupus. One form of chronic cutaneous lupus is lupus panniculitis, a condition that most often involves areas of the body with abundant subcutaneous fat, such as the cheeks and temples, upper arms, shoulders, thighs, buttocks and breasts. Indeed, breast involvement—sometimes referred to as lupus mastitis—can mimic breast cancer and may lead to unnecessary diagnostic testing and delay in diagnosis and treatment. Dr. Shaw also told the audience about subcutaneous panniculitis-like T cell lymphoma, a rare, indolent cutaneous lymphoma that typically presents as painless erythematous nodules or plaques, most often on the extremities or trunk. The disease can often be seen in the context of SLE, and diagnosis requires deep skin biopsy and immunophenotyping. Most patients respond well to immunosuppressive therapy, such as glucocorticoids, cyclosporine and methotrexate, with a five-year survival rate exceeding 80%, although patients whose disease is complicated by hemophagocytic lymphohistiocytosis (HLH) have a five-year survival rate of around 46%.¹

A very instructive case that Dr. Shaw discussed involved a middle-aged woman who presented with erythematous annular and indurated plaques on her face, trunk and extremities and had false-positive syphilis test results during two pregnancies much earlier in life. Testing at the time of presentation showed a high-titer positive rapid plasma reagin (RPR). Although the Poll Everywhere results indicated that the audience thought the positive RPR was a false positive due to anticardiolipin antibodies, Dr. Shaw explained that secondary syphilis was the correct diagnosis as a false positive RPR should be low titer when occurring in the setting of antiphospholipid antibodies. After demonstrating a positive fluorescent treponemal antibody absorption (FTA-ABS) test and with a skin biopsy showing numerous spirochetes, the patient was treated with one dose of intramuscular penicillin G and the patient’s rash was nearly resolved.

Gout

Dr. Gaffo

The next speaker, Angelo Gaffo, MD, MSPH, section chief of rheumatology at the Birmingham VA Medical Center and associate professor of medicine in the Division of Rheumatology at the University of Alabama at Birmingham, lectured on gout, a condition that affects about 5% of the U.S. population.² Although rheumatologists often think of this crystalline arthritis affecting joints, Dr. Gaffo noted that the dorsum of the feet and hands and even the sacroiliac joints can be involved as well. Similarly, although the intercritical periods of gout are typically asymptomatic for patients, individuals with advanced gout may experience pain and stiffness even between true gout flares.

Dr. Gaffo implored clinicians not to be fooled by a seemingly normal or low serum uric acid level during an acute flare, when the active inflammatory process can cause a uricosuric effect and result in this misleadingly low urate level. Although radiographs continue to be helpful in diagnosis, especially if the classic rat bite erosions or tophi are visualized, other imaging modalities are of great help as well. Ultrasound of a joint that has been affected by gout can reveal the double contour sign, an echogenic line on the outer surface of the joint cartilage running parallel to the subchondral bone; this occurs secondary to deposition of monosodium urate (MSU) crystals on the surface of hyaline articular cartilage. Dr. Gaffo is a proponent of dual-energy computed tomography (DECT) scans in cases where a crystal-proven diagnosis has not been obtained and where diagnostic uncertainty exists. DECT scans are fast, do not require contrast and can detect MSU deposition even in intercritical periods of the disease, although Dr. Gaffo warned that DECT scans may be less helpful early in the disease course when less MSU deposition has occurred.

For treatment, Dr. Gaffo noted that the Gout Education Society’s website, gouteducation.org, has excellent resources for patients and caregivers who are dealing with this chronic disease that is clearly impacted by diet and lifestyle. For pharmacologic treatment, treat-to-target remains the most evidence-based approach, and clinicians should seek to help patients get to and maintain a serum uric acid level of <6 mg/dL. Allopurinol remains the first-line urate-lowering therapy and, in a study from O’Dell et al., allopurinol was noninferior to febuxostat in controlling flares, and similar outcomes were noted in participants with stage 3 chronic kidney disease.³ Flare prophylaxis also remains a necessary part of management when initiating urate lowering therapy, and the ACR recommends colchicine as first-line prophylaxis when starting urate-lowering therapy for gout, with continuation for three to six months to minimize flare risk.⁴

For severe cases of chronic tophaceous gout, pegloticase can be employed, and it is ideal to prescribe either methotrexate or mycophenolate mofetil along with this therapy to increase response rates and reduce the risk of infusion reactions. Based on work showing that sodium-glucose cotransporter-2 inhibitors promote uricosuria and lower serum urate concentrations, Dr. Gaffo predicted that these medications may be recommended in the future for patients with gout, particularly for those with comorbid diabetes, renal disease or cardiovascular disease.⁵

Macrophage Activation Syndrome

Dr. Schulert

The penultimate speaker, Grant Schulert, MD, PhD, associate professor of pediatrics in the Division of Rheumatology, Cincinnati Children’s Hospital Medical Center and the Department of Pediatrics, University of Cincinnati College of Medicine, Ohio, discussed macrophage activation syndrome (MAS). Dr. Schulert provided an extremely helpful discussion of the different terminology employed by rheumatologists and oncologists around this topic. MAS, hemophagocytic lymphohistiocytosis, cytokine storm and cytokine release syndrome (CRS) are overlapping but distinct hyperinflammatory syndromes, each defined by specific clinical contexts and triggers.

HLH is a life-threatening syndrome of uncontrolled immune activation, characterized by fever, cytopenias, hepatosplenomegaly, hyperferritinemia and multiorgan dysfunction. It is classified as primary (genetic, often in children) or secondary (acquired, triggered by infection, malignancy or autoimmune disease), and when HLH is associated with rheumatic disease, it is termed MAS. MAS is, therefore, a subtype of secondary HLH, most commonly seen in systemic juvenile idiopathic arthritis, adult-onset Still’s disease (AOSD) or SLE, and shares clinical features with HLH but is specifically linked to autoimmune triggers.

Cytokine storm is a broader umbrella term describing any syndrome with excessive cytokine release, systemic inflammation and organ dysfunction, including HLH, MAS and CRS. It is defined by elevated circulating cytokines, acute systemic symptoms and secondary organ dysfunction beyond a normal immune response. CRS refers specifically to cytokine storm syndromes triggered by immunotherapies, such as CAR T–cell therapy, and it presents with fever, hypotension, hypoxemia and multiorgan dysfunction; it is most often seen in the context of hematologic malignancy treatment.

Dr. Schulert explained that interleukin-18 (IL-18) is markedly elevated in patients with AOSD who develop MAS, and it is thought to be a key driver of MAS. IL-18 is produced by activated monocytes/macrophages via inflammasome-dependent processing, and its pathogenic role in MAS is mediated by the induction of interferon-γ and amplification of Th1-type immune responses, which lead to hyperinflammation and tissue damage. Recent studies have shown that chronic elevation of free, bioactive IL-18 is strongly associated with the risk and severity of MAS in patients with AOSD and, clinically, serum IL-18 levels can serve as a biomarker for disease activity.⁶

Vasculitis

Dr. Stone

At the final talk of the session, John Stone, MD, MPH, professor of medicine at Harvard Medical School, Boston, and the Edward A. Fox Chair in Medicine at Massachusetts General Hospital, Boston, provided an update on vasculitis. Dr. Stone began by discussing IgG4-related disease (IgG4-RD), which he said might strike some audience members as odd for a talk on vasculitis. However, he explained that IgG4-RD can be described as a vasculitis in that histopathology demonstrates obliterative phlebitis, which is evidence of small vessel vasculitic involvement, and patients can manifest with aortitis, tender temporal arteries or coronary artery aneurysms. Dr. Stone provided the clinical pearl that, in a patient with giant coronary artery aneurysms and no history of Kawasaki disease, IgG4-RD should be high on the differential. Although glucocorticoids are often used to treat IgG4-RD, these should be thought of as an induction rather than maintenance therapy because patients often have pancreatic involvement, which can be further complicated by the effects of prolonged steroid use. Inebilizumab, a monoclonal antibody targeting CD19⁺ B cells, was recently evaluated in a 52-week randomized, double-blind, placebo-controlled phase 3 trial. Among 135 participants with IgG4-RD, only 10% of those receiving inebilizumab experienced a treated disease flare compared with 60% in the placebo group. Secondary end points also favored inebilizumab, with markedly lower annualized flare rates and significantly higher odds of achieving flare-free, treatment-free or glucocorticoid-free remission.⁷ Based on these results, inebilizumab became the first U.S. Food & Drug Administration (FDA) approved treatment for IgG4-RD earlier this year.

On the subject of giant cell arteritis (GCA), Dr. Stone discussed the significant role that tocilizumab now plays in the management of most patients, who he advised should be started on this therapy at the time of diagnosis. A recent phase 3 trial evaluated upadacitinib, a selective Janus kinase inhibitor, combined with a 26-week glucocorticoid taper vs. placebo with a 52-week taper. Among the randomized patients (n=209 receiving 15 mg, n=107 receiving 7.5 mg and n=112 receiving placebo), approximately 70% had new-onset disease. Sustained remission at week 52 was achieved in about 46% of those on 15 mg of upadacitinib compared with 29.0% on placebo; the 7.5 mg dose did not show significant benefit. In addition, secondary outcomes, including reduced flare rates, lower glucocorticoid exposure and improved patient-reported measures, favored the 15 mg dose, and overall safety over 52 weeks was comparable between treatment and placebo groups.⁸ On the basis of this data, earlier this year upadacitinib became the second FDA approved treatment for GCA.

Finally, Dr. Stone discussed eosinophilic granulomatosis with polyangiitis (EGPA), a condition that, among other things, can cause devastating vasculitic neuropathy. IL-5 inhibition has been a mainstay of treatment in recent years, and this can be done with either mepolizumab or benralizumab. For severe cases of EGPA, such as with neuropathy or cardiomyopathy, patients are typically treated with high-dose glucocorticoids and rituximab; cyclophosphamide is also a consideration. Looking to the future, Dr. Stone was bullish on the concept that CAR T cell therapy can be applied to patients with vasculitis and expressed the hope that this may obviate the need for ongoing treatment with medications like rituximab, which he views as problematic when it is used every six months for indefinite periods of time.

All told, the Review Course was a masterful display of clinical and basic science insights. The audience left much the wiser and excited to apply the lessons learned to the care of their patients, both across the country and around the world.

Dr. Jason Liebowitz

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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6. Baggio C, Bindoli S, Guidea I, et al. IL-18 in autoinflammatory diseases: Focus on adult onset still disease and macrophages activation syndrome. Int J Mol Sci. 2023 Jul 5;24(13):11125.
7. Stone JH, Khosroshahi A, Zhang W, et al. Inebilizumab for treatment of IgG4-related disease. N Engl J Med. 2025 Mar 27;392(12):1168–1177.
8. Blockmans D, Penn SK, Setty AR, et al. A phase 3 trial of upadacitinib for giant-cell arteritis. N Engl J Med. 2025 May 29;392(20):2013–2024.