CHICAGO—Held during the 2018 ACR/ARHP Annual Meeting, the ACR Review Course covered a wide range of topics for rheumatologists—from advances in pain and rheumatic disease management to the intersection of rheumatology and neurology. Session speakers shared insights, as well as state-of-the-art approaches to diagnosis, management and treatment.
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Julie J. Paik, MD, MHS, assistant professor of medicine at the Johns Hopkins University School of Medicine, Baltimore, updated the audience on idiopathic inflammatory myopathies, also known as myositis. She began by reviewing the four main types of idiopathic inflammatory myopathies: dermatomyositis, polymyositis, immune-mediated necrotizing myopathy and inclusion body myositis.
Dr. Paik then presented the 2017 EULAR/ACR Classification Criteria for Adult and Juvenile IIM and Their Major Subgroups.1 These criteria represent the first update since the original 1975 classification criteria, which were limited because, although they were sensitive, they were not specific.2 Dr. Paik noted these criteria were old and said, “it was time to move on.”
The process of creating new criteria began in 2004 and included 47 rheumatology, dermatology, neurology and pediatric clinics worldwide. Experts from these clinics reviewed data from 976 idiopathic inflammatory myopathy patients and 624 non-idiopathic inflammatory myopathy patients who had mimicking conditions. The criteria are intended to aid clinicians in distinguishing myositis from myositis mimickers.
Sixteen variables are included the final 2017 EULAR/ACR classification criteria. The criteria note the age of onset is important for distinguishing juvenile from adult cases. They detail the importance of muscle biopsy features, such as endomysial infiltration, perimysial and/or pervascular inflammation, perifasicular atrophy and rimmed vacuoles. And they include a discussion of the anti-Jo-1 antibody, which was the only myositis-specific autoantibody readily available in 2004. Dr. Paik highlighted an online calculator that can be used to input all criteria and determine the probability of myositis.
Dr. Paik then described three challenging myositis cases. The first was a description of transcription intermediary factor-1 gamma-positive dermatomyositis. Although these patients have severe skin disease, they are less likely to have interstitial lung disease (ILD), Raynaud’s or arthritis. Unfortunately, they are at an increased risk of cancer. Their disease tends to be refractory, and they should receive age-appropriate malignancy screening. Dr. Paik also reviewed several ongoing clinical trials in dermatomyositis that show promise, and she highlighted the potential of lenabasum as a successful therapy for these patients.
Knee replacement rates in SLE patients have increased sixfold from 1991–2005. This dramatic increase likely reflects the increased health & survivorship of this patient population.
For the second case, Dr. Paik presented the case of a patient with anti-synthetase syndrome (ASyS) with prominent ILD. Experts now recognize ASyS as a distinct form of myositis, she said, noting that these patients often first present with arthritis. Dr. Paik emphasized the importance of keeping ASyS in the differential when a new patient is evaluated for inflammatory arthritis. ASyS patients commonly progress from inflammatory arthritis to the more recognized triad of myositis, polyarthritis and ILD. Treatment should be directed at the most active organ manifestation.
Last, Dr. Paik discussed inclusion body myositis, noting the gold standard for the diagnosis is the presence of rimmed vacuoles on muscle biopsy associated with the appropriate pattern of muscle weakness. She highlighted the importance of testing for finger flexor weakness and described a newly discovered autoantibody, NT5C1-A, which is commercially available and positive in up to 60% of patients with inclusion body myositis. She also explained that immunosuppression does not work for these patients and may even be harmful.
Susan M. Goodman, MD, director of the Integrative Rheumatology and Orthopedics Center of Excellence at the Hospital for Special Surgery, New York, addressed the perioperative management of patients with rheumatic disease. She began by noting that although the rate of arthroplasty in this patient population remains high, these patients differ from osteoarthritis (OA) patients who seek arthroplasty. The population of rheumatoid arthritis (RA) patients who undergo arthroplasty has become older, while the population of OA patients who seek arthroplasty has become younger. Moreover, when compared with RA patients who do not seek arthroplasty, the RA patients who are at risk for arthroplasty have more erosions, are more likely to have a body mass index of 30 or more, are seropositive, with large joint swelling and may have experienced a delay in methotrexate use.
These trends in arthroplasty extend beyond RA. Dr. Goodman explained that, in 1998, 7% of patients with psoriatic arthritis underwent orthopedic surgery.3 By 2016, that number increased to 48%.4 This increase partially reflects the fact that the longer a patient has psoriatic arthritis, the more likely they are to require surgery. Additional risk factors for surgery include inflamed joints and damage visible on X-ray. Patients with systemic lupus erythematosus (SLE) are also increasingly undergoing arthroplasty. Knee replacement rates in SLE patients increased sixfold from 1991–2005.5 Again, this dramatic increase likely reflects the increased health and survivorship of this patient population.
Dr. Goodman also discussed outcomes and adverse events associated with surgery in patients with rheumatic disease. She noted that adverse event information is required by the Centers for Medicare and Medicaid Services to determine hospital reimbursement rates. Generally, RA patients tend to have total knee replacement outcomes similar to OA patients despite having worse pain and function pre-operatively. In contrast, RA patients who receive total hip replacement are four times more likely than OA patients to have a poor functional outcome.6 This poor outcome can be modified with contralateral total hip replacement. Although SLE patients tend to have worse baseline pain and function than OA patients, their post-total hip replacement outcomes appear to be the same as OA patients. Likewise, patients with psoriatic arthritis (PsA), OA and OA plus cutaneous psoriasis do well after total knee replacement.
Patients with inflammatory arthritis are at a 40–80% increase risk of infections relative to those with non-inflammatory arthritis.7 “It is a little hard to figure out what is causing this increase,” added Dr. Goodman. One possibility is patients with inflammatory arthritis who are treated with biologics are more likely to be colonized with S. aureus, which is a risk factor for surgical site infections.
Finally, Dr. Goodman discussed perioperative, disease-modifying anti-rheumatic drugs (DMARDs), biologics and glucocorticoid management. She emphasized that optimal perioperative management requires close collaboration between orthopedists and rheumatologists because the medications used to treat rheumatological disease may contribute to the risk of infection. Although DMARDs, such as methotrexate, hydroxychloroquine and leflunomide, appear to be safe during the perioperative period, biologics should be withheld prior to surgery.
Fibromyalgia & Pain Syndromes
Kristine Phillips, MD, PhD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, introduced the topic of fibromyalgia: “Fibromyalgia is not treated by all rheumatologists, and it is still controversial,” she said. “It has not been adopted by any one specialty … . Those of us who think we don’t see fibromyalgia—maybe—we just aren’t recognizing it.”
By natural extension, if physicians aren’t recognizing fibromyalgia, patients may not be receiving optimal management of their pain symptoms. In many cases, patients with fibromyalgia experience pain even though the stimulus should not cause pain. Although most physicians associate fibromyalgia with this tenderness, sleep quality is also a major component of the disease. Additionally, patients with fibromyalgia are frequently diagnosed with irritable bowel syndrome. Dr. Phillips explained that her growing appreciation of the complexity of the underlying mechanism of disease has extended to the recognition that many fibromyalgia patients have a history of sexual trauma.8
Researchers have identified single-nucleotide polymorphisms associated with abnormal pain sensations in fibromyalgia patients.9 This abnormal pain response appears to be due to an amplification of the pain signals received by the patient, resulting in an altered central sensitization of neurons. Additionally, fibromyalgia patients do not experience the typical reduction in pain upon receiving a second stimulus. This aspect of their distorted pain perception appears to be partially the result of an overlap between the regions of the brain involved in distinguishing pain and affective symptoms.
Next, Dr. Phillips described her approach to managing fibromyalgia patients, explaining that she treats pain in a multi-factorial fashion. She begins by determining which of the patient’s symptoms are related to fibromyalgia and which may be related to something else. For Dr. Phillips, an important part of caring for the patient is helping them understand this distinction. Most fibromyalgia patients respond well to cognitive behavioral therapy and may not require other treatment. Unfortunately, in some regions of the country, especially rural areas, patients may not have access to cognitive behavioral therapy.
Dr. Phillips discourages her patients from seeking disability status. She believes working offers many benefits, especially if the patient finds work personally fulfilling. However, she does complete Family and Medical Leave Act paperwork requesting reasonable accommodations for her patients. She also encourages her patients to maintain an exercise program, even if it’s just going for a walk.
She concluded her presentation by explaining that fibromyalgia consumes a large amount of healthcare dollars and efforts should be made to train an army of nurse practitioners and primary care teams to appropriately diagnose and treat these patients. Healthcare providers should listen carefully to the patient and validate their symptoms, thereby building a good patient-physician relationship. Primary care providers can partner with psychiatrists, who are best suited to manage any concomitant psychiatric illness.
Osteoporosis Update 2018: New Issues & Challenges
Felicia Cosman, MD, professor of medicine at Columbia University, New York, talked about the current challenges in treating osteoporosis. The first challenge, she said, is that healthcare providers are not focusing on the highest risk patients, adding, “Many patients who have fractures are not in the osteoporosis range with regard to BMD [bone mineral density].” Moreover, fewer than 25% of patients with new fractures are treated for osteoporosis.
The second challenge: When healthcare providers do treat osteoporosis, they tend to prescribe long-term, anti-resorptive treatments, such as bisphosphonates, which are associated with rare adverse events and have unproven anti-fracture efficacy. The problem is compounded by the fact that little evidence exists to help guide long-term treatment strategies and sequences. Moreover, whatever guidelines do exist are highly inconsistent across medical specialties. Above all, physicians tend not to recognize the role of anabolic therapy.
Dr. Cosman then focused her talk on fractures. She noted that fracture represents the highest risk factor for osteoporosis and is more important than BMD. Unfortunately, healthcare providers often overlook fractures, especially in the spine. Because most spinal fractures don’t come to clinical attention at the time of the event, proactive targeted spine imaging is the only way to identify these at-risk patients. “These fractures are important, and they are also quite common,” said Dr. Cosman.
The prevalence of spinal fractures increases with age. Thus, Dr. Cosman suggests vertebral fracture assessment for women over age 70 and men over age 80 if their BMD T score is -1.0 or less in the spine, total hip or femoral neck. If the BMD T score is -1.5 or less, then women 65–69 years old and men 70–79 years old should have a vertebral fracture assessment. Vertebral fracture assessment should also be performed on postmenopausal women and men age 50 and older with certain risk factors. These risk factors include low trauma fracture during adulthood, historical height loss of 1.5 inches or more, prospective height loss of 0.8 inches or more, and/or recent or ongoing long-term glucocorticoid treatment. If bone density testing is not available, then vertebral imaging may be considered based on age alone.
After a patient has had a first fracture, the risk of subsequent fracture is not linear over time. Instead, the patient is at very high, imminent risk. This risk translates into the need for a therapy that works quickly. Unfortunately, anti-resorptive agents require three years before they begin to reduce risk. In contrast, teriparatide works more quickly and has a greater degree of efficacy. Likewise, abaloparatide, a 34-amino acid osteoanabolic peptide that is a synthetic analog of parathyroid (PTH)-related peptide, interacts with the PTH1 receptor to stimulate bone formation with limited calcium mobilization and bone resorption. It has been shown in preclinical and clinical studies to improve BMD, bone microarchitecture and bone strength.
Dr. Cosman concluded by reiterating that most high-risk patients are not being identified and treated. Spine imaging can help identify these patients, and they should be treated with active anabolic therapies that can be followed by sequential monotherapy. This approach will minimize the duration of exposure to pharmacology while maximizing benefits to strength and BMD.
Neurology for the Rheumatologist
Julius Birnbaum, MD, MHS, associate director of the Johns Hopkins Jerome L. Greene Sjögren’s Syndrome Center, Baltimore, gave an overview of neurology for the rheumatologist. He began by describing how neurological examination can be a powerful tool in distinguishing between myelopathies, radiculopathies and neuropathies. He emphasized that distinguishing between a radiculopathy and a neuropathy does not require the memorization of a web of neuroanatomy. He encouraged rheumatologists to forget about most of the cross wiring between the spinal cord and peripheral nerves. Instead, he told the audience they should remember that radiculopathy has more diffuse sensory and motor features, while neuropathy has more focal sensory and motor features.
Dr. Birnbaum talked through an example of a patient who presented with wrist drop, explaining that all the healthcare provider has to do is check the number of affected muscle groups. If the patient has neuropathy, it’s likely only one or a few muscle groups are affected. In contrast, if the patient has weakness in three or more muscle groups, radiculopathy is more likely. Dr. Birnbaum explained the approach to diagnosing foot drop is similar. If the patient has an insidious onset of less severe, but diffuse sensory and motor features, then it’s likely they have L5 radiculopathy. In contrast, the patient who presents with acute severe localized symptoms likely has peroneal neuropathy.
Small fiber neuropathies can present as neuropathic pain in patients with systemic rheumatic diseases. They target thinly myelinated A-delta or unmyelinated C-fiber nerves, and the resulting pain is burning, paroxysmal and allodynic. Patients may even complain of pain when bed sheets graze their toes at night. They often have vivid and remarkable descriptions of neuropathic pain. “It is really amazing, the lyricism,” said Dr. Birnbaum.
For example, he discussed a patient who said, “I feel like my legs are being electrocuted at night.” Physical examination of patients with small fiber neuropathies often reveals small fiber deficits (i.e., decreased pinprick and cold sensation) even though electrodiagnostic studies are normal. Unfortunately, because small fiber neuropathy can be associated with a seronegative profile, it may be difficult for these patients to receive an accurate diagnosis. A delayed diagnosis can contribute to a more widespread and treatment-refractory, centrally sensitized pain state that results from central amplification.
The differential diagnosis of potential small fiber neuropathies includes vasculitis, infection and autoimmune/inflammatory disorders. Metabolic disorders are also important in the differential because impaired glucose tolerance can cause a reversible small fiber neuropathy. It is also important to exclude neoplastic disorders or structural mimics, such as syringomyelia and myeloradiculopathies. A punch skin biopsy will not only be diagnostic for small fiber neuropathy, but may also help identify which part of the peripheral nervous system is being targeted. Patients with vasculitic neuropathies can be treated with immunosuppressive therapy. Painful neuropathies can initially be treated with symptomatic therapies.
Treatment of Lupus Nephritis
Gerald Appel, MD, director of the Center for Glomerular Diseases at Columbia University College of Physicians and Surgeons, New York, discussed how he treats lupus nephritis. He began by describing what he looks for in the biopsy of a patient with lupus nephritis and emphasized the importance of reading the pathology report. He highlighted five important pieces of information to glean from the report:
First, to allow for an accurate interpretation, the biopsy must have at least seven glomeruli and, ideally, 20–25 glomeruli. The next important information is the International Society of Nephrology (ISN) class. Dr. Appel only gives “vigorous treatment” to patients with Class III + V or Class IV + V lupus nephritis. Additionally, he focuses treatment on patients with active or active and chronic lupus nephritis. He explained that he typically does not treat patients who have only chronic lupus nephritis because the more chronicity in the biopsy, the less likely the patient will benefit from treatment. This factor is especially the case for patients with interstitial fibrosis. He then explained the importance of determining if the deposits are extensive, especially as visualized by electron microscope. Finally, he emphasized that fibrinoid necrosis of glomerular caps and an abundance of crescents, while bad, is treatable.
Dr. Appel then introduced the Kidney Disease Improving Global Outcomes (KDIGO) Treatment Guideline and explained that patients with serious lupus nephritis should be treated with mycophenolate mofetil and steroids or cyclophosphamide plus steroids. The guideline, which is supported by several clinical trials that combine expertise in rheumatology and nephrology, includes a flowchart that describes these two different regimens.
Dr. Appel also reviewed the relevant clinical trials for this treatment approach, beginning with a 2005 multi-center trial published in the New England Journal of Medicine that compared mycophenolate mofetil to intravenous cyclophosphamide as an induction therapy for severe lupus nephritis.10 Although Dr. Appel acknowledged the many flaws in the trial, the study found patients treated with mycophenolate mofetil had better outcomes than those treated with cyclophosphamide.
The second relevant clinical trial was the Aspreva Lupus Management Study (ALMS) trial, during which a blinded clinical endpoint committee judged patient response based on a decrease of proteinuria by less than 3 g if baseline nephrotic or by greater than 50% in patients with subnephrotic proteinuria.11 The committee also judged response based on the stabilization—or improvement—of serum creatinine levels. The ALMS trial revealed no significant difference between mycophenolate mofetil and intravenous cyclophosphamide.
Finally, the Euro-Lupus Nephritis Trial was a multi-center, prospective trial of 90 patients with proliferative lupus nephritis.12 The study included an initial follow-up of 41 months and subsequent 10-year follow-up. Patients received monthly high doses of intravenous cyclophosphamide or low doses of intravenous cyclophosphamide. The Euro-Lupus Nephritis Trial documented identical outcomes in the two groups.
The results from all three clinical trials suggest it may be possible to treat patients with lupus nephritis without using cyclophosphamide. This alternative is worth considering because cyclophosphamide is associated with multiple side effects. Dr. Appel concluded the most important thing is individualized therapy, saying, “You have a lot more choices than you had a few years ago.”
Andrea Kalus, MD, associate professor of dermatology at the University of Washington, Seattle, began her talk by reviewing the cutaneous manifestations of lupus. She explained that skin involvement occurs in the majority (72–85%) of SLE patients and is the first sign of disease in around a quarter of SLE patients. Most patients with cutaneous lupus erythematosus (CLE) are young women, but the disease can occur in both sexes at any age. In all cases, ultraviolet light is a dependable and controllable trigger for skin symptoms.
Dr. Kalus manages CLE by first encouraging all patients to reduce sun exposure and stop smoking. She will treat patients who have limited disease with topical steroids, intralesional steroids, topical calcineurn inhibitors and hydroxychloroquine. In contrast, for patients with extensive disease, she prescribes methotrexate and/or mycophenolate, and low-dose steroids when needed. If the patient has refractory disease, she turns to lenalidomide or thalidomide, belimumab and/or retinoids.
The type of CLE also informs the treatment decision. Lupus can present in the skin in several ways, all of which have distinct clinical features and are associated with different risks of systemic disease. Chronic CLE includes discoid lupus erythematosus, lupus panniculitis and tumid lupus. Subacute CLE presents with rings and semicircles on the upper body, while the face is typically bare. The final subtype is acute CLE, which is present in 40–50% of patients at the diagnosis of acute systemic lupus. Although histology can help diagnose lupus, it does not differentiate between the subtypes of cutaneous lupus. Instead, diagnosis relies on the combination of clinical, histologic and laboratory features.
Discoid lupus presents with red papules, primarily on the head and neck, which gradually expand into a plaque and then scar. The scars can be disfiguring, with scarring alopecia. Dr. Kalus notes the conchal bowl of the ear of patients with discoid lupus often contains scarring alopecia. Discoid lupus is the most frequent skin manifestation of lupus and, although high potency topical steroids aren’t often used on facial skin, they are the appropriate treatment for this condition. Other options to prevent scarring include intralesional steroids and hydroxychloroquine, which can help prevent future lesions.
Subacute CLE presents as erythematous polycyclic or ring-shaped macules and papules with some scale that are predominantly located on the upper chest and back. Patients, especially those with more skin pigment, tend to have hyperpigmentation as they heal. It can take six months to a year for the hyperpigmentation to clear. Patients also have marked photosensitivity, and approximately 70% have anti-Sjögren’s-syndrome-related antigen A (anti-SSA/anti-Ro) antibodies and, thus, may meet the criteria for SLE. Patients with subacute CLE typically have a benign clinical course and, although pigment changes may occur, there is no scarring.
Dr. Kalus suggested the first thing a physician should do when presented with a patient newly diagnosed with subacute CLE is to review the medication list. Approximately 40 different medications have been reported to cause subacute CLE. These include hydrochlorothiazide, calcium channel blockers, angiotensin-converting enzyme inhibitors and terbinafine. If a patient is taking any of these drugs, the drugs should be discontinued and the subacute CLE may resolve without any treatment.
Acute CLE presents as a malar erythema that can also be more generalized rash on the forehead, chest and body. The rashes worsen with sun exposure and systemic disease flares. Dr. Kalus encourages patients to reduce sun exposure and encourages vitamin D supplementation at a minimum of 400 international units daily. Dr. Kalus also emphasized that although tumid lupus has historically been classified as a form of cutaneous lupus and is very photosensitive, it’s never associated with systemic lupus and, therefore, does not need to be considered a form of cutaneous lupus.
PsA: 2018 Update
Iaian B. McInnes, MD, PhD, Muirhead professor of medicine at the University of Glasgow, U.K., finished the day’s presentations with a talk on PsA. He began by describing the clinical and radiographic heterogeneity of PsA, which includes synovitis, enthesitis, osteitis and skin/nail disease. He noted that although many different types of rashes exist, they are all called psoriasis.
However, Dr. McInnes emphasized that PsA is not RA with a rash. “It is a clinical catastrophe for the many young people who it afflicts,” he explained. The disease extends beyond the classical manifestations to eye disease, psychiatric disease, gastrointestinal disease and more. “Cytokines and brain function are intimately related to each other,” explained Dr. McInnes, adding, “Depression is a part of the inflammatory syndrome and not a consequence of failing to deal with the disease.” Patients find it helpful to learn depression may be a manifestation of PsA.
Approximately half of patients with PsA have microscopic gut inflammation. Over five years, 20% of PsA patients will develop chronic inflammation and 6% will develop Crohn’s disease. Patients with PsA and psoriasis are also at increased risk of cardiovascular morbidity.
Even in patients who do not report musculoskeletal disease, psoriasis may extend beyond cutaneous disease. Moreover, many patients who appear to have only cutaneous symptoms also have subclinical synovitis, which suggests the arthritis probably starts much earlier than traditionally believed. Debate still exists over whether aggressive treatment of cutaneous psoriasis can prevent musculoskeletal disease. Research does suggest that, when it comes to treatment, time matters. Early recognition of disease matters, because even a six-month delay in diagnosis means the patient is more likely to experience functional disability and less likely to experience remission.
Dr. McInnes concluded his presentation by calling on members of the audience to “make the diagnosis early and treat aggressively and according to guidelines and recommendations. … Please treat the psychological impact. If you can do that, your patients will be infinitely better.”
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
For your information …
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- Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005 Nov;353:2219–2228.
- Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009 May;20(5):1103–1112.
- Houssiau FA, Vasconcelos C, D’Cruz D, et al. Immunosuppressive therapy in lupus nephritis: The Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002 Aug;46(8):2121–2131.