Discerning “the Imitator” From its Imitators: Sifting Through Gout, Pseudo-Gout, Other Arthropathies
There is much discussion surrounding the mechanisms and pathogenesis of microcrystalline arthropathies and gout. Specifically, calcium pyrophosphate deposition disease can have a range of gout-like symptoms that may present like polyarthritis among other conditions. Clinicians have investigated specific components of these crystalline arthropathies, including fibrocartilage, hyaline cartilage, tendons and synovial fluid, for information about how they may be managed. The body of knowledge is growing but remains incomplete.
One such area is diagnosis, where a lack of randomized, blinded, controlled studies exists. Synovial fluid centrifugation is the gold standard but is infrequently utilized, according to Brian F. Mandell MD, PhD, professor and chairman of academic medicine at the Cleveland Clinic Lerner College of Medicine, and the department of rheumatic and immunologic disease, vasculitis care and research. Beyond this, musculoskeletal ultrasound, Raman spectroscopy, CT and MRI, along with conventional crystal analysis as a standard-of-care diagnostic approach, have all been examined, with no clear conclusions about the next wave of methodology. For Mandell, simply gaining an understanding of the diagnostic arena is a good place to start in understanding these diseases.
“While there are clinical algorithms proposed to diagnose gout without obtaining a synovial fluid analysis, none are likely to be able to distinguish gout from calcium pyrophosphate arthritis, or pseudo-gout,” he told Healio Rheumatology in an interview. “Since the appropriate long-term management —which should be a cure — of gout requires lifelong therapy, the gold standard for diagnosis remains synovial fluid analysis with recognition of [monosodium urate] crystals. It is clear that the use of serum urate levels alone is an inadequate approach and should be eschewed.”
Regarding treatment, data sets addressed therapies for gout and a number of crystalline arthritidies and found that various approaches to urate lowering may be useful in addition to pegloticase when these approaches achieve less than optimal results. NSAIDs, colchicine and corticosteroids remain the bedrock of first-line therapy, while other data sets have explored adrenocorticotropic hormone (ACTH) as a primary treatment for acute calcium pyrophosphate crystal arthritis. Patient education, particularly in terms of the importance of treatment adherence, is a critical component that must also be considered.
Understanding the Basics
In the European Journal of Geriatrics, Schlee and colleagues recently wrote a comprehensive, two-part paper about gout and calcium pyrophosphate deposition disease (CPPD or pseudo-gout). They suggested that an important pathophysiological difference between the two conditions is that gout carries associations with both metabolic syndrome and cardiovascular mortality. Another factor is that polyarticular manifestations in gout make it challenging for clinicians to differentiate between it and either RA or CPPD — an imbalance in the formation and elimination of uric acid lies at the heart of these conditions.
“The degradation of the purine bases adenine and guanosine to uric acid is catalyzed by xanthine oxidase and genetic polymorphisms and mutations play an important role in absorption and excretion processes,” they wrote. They added that these processes may be impacted by carrier proteins URAT-1 and OAT-4. Crystallization of urate, in turn, produces inflammatory conditions at both the molecular and cellular levels.
Inorganic pyrophosphate is critical in forming calcium pyrophosphate crystals, Schlee and colleagues wrote. In terms of epidemiology, asymptomatic hyperuricemia may occur in 10% to 20% of adults, according to their data. They added that approximately 7% of individuals aged 65 years or older may have clinically detectable gout, while 30% of individuals aged 80 years or older may demonstrate calcium pyrophosphate dehydrate in the cartilage.
CPPD most frequently impacts the knee, followed by the wrist and ankle. While both gout and CPPD involve crystal deposits in the joints, the crystals differ between the two diseases. Schlee and colleagues also suggested that CPPD is more likely to be asymptomatic, yet pain, swelling, and warm or hot joints may occur in both gout and CPPD, with both conditions more frequently impacting older individuals.
This aspect of both diseases is of particular concern for Mandell. “The treatment of gout in the elderly becomes a bit more challenging due to the common comorbidities such as [chronic kidney disease], [congestive heart failure], diabetes, gastric sensitivity to nonsteroidals and, in some patients, an anticipated shortened lifespan, which may not permit adequate time to dissolve the uric acid deposition that is the soil on which acute gout attacks arise,” he said. “These factors must be considered when treating and prophylaxing against acute gout attacks.”
Joint trauma may increase risk for CPPD, as may genetic factors and increased calcium or iron and/or not enough magnesium in the blood. Both conditions require laboratory and imaging analyses for diagnosis. While X-ray was traditionally the standard imaging analysis, data are emerging on the use of DECT, MRI, musculoskeletal ultrasound and other novel imaging tests. Although NSAIDs, colchicine and corticosteroids may be used to treat gout and CPPD alike, joint drainage is a more involved option in CPPD.
Kenneth G. Saag, MD, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham, put these findings in perspective.
“Gouty arthritis is an interesting entity since we have learned much more about innate immunity and the role of the NALP inflammasomes in causing inflammatory responses to the crystals,” he said.
Regarding pathophysiology, Coiffier and colleagues wrote that a number of factors may impact the development of microcrystals, including uric acid concentrations, temperature and pH, among others. Specifically, crystallization may occur beyond 60 mg/L, according to the authors. They added that these arthropathies involve crystals developing in the fibrocartilage or hyalin cartilage. While presentation may resemble primary osteoarthritis or chronic mono-, oligo-, or polyarthritis, Coiffier and colleagues suggested that the “pathophysiology remains uncompletely understood.”
Boumans and colleagues conducted a prospective trial investigating the added value of synovial fluid centrifugation for microscopic monosodium urate and calcium pyrophosphate crystal detection in a cohort of 98 patients with arthritis undergoing joint arthrocentesis. The final analysis included 87 samples. Investigators examined two smears before and after centrifugation using a microscope. Before centrifugation, the first observer identified monosodium urate crystals in 18.4% of smears and calcium pyrophosphate in 9.2%. After centrifugation, no extra monosodium urate was identified by this observer. However, four additional positive calcium pyrophosphate smears were identified after centrifugation.
For the second observer, monosodium urate crystals were identified in 15.5% of samples before centrifugation, while calcium pyrophosphate were identified in 6.3% both before and after. This observer reported two additional positive monosodium urate smears and four additional positive calcium pyrophosphate smears after centrifugation. The researchers reported that monosodium urate crystals were observed without centrifugation, suggesting that centrifugation had limited value in positive monosodium urate smears.
“However, [calcium pyrophosphate] crystals were identified in a higher number of smears after centrifugation than before,” the researchers concluded. “Therefore, centrifugation may be of additional value in selected patients with suspected [CPPD] and to a lesser extent for gout.”
Mandell addressed these findings. “Centrifugation indeed has no purpose in smear positive synovial fluid,” he said.
Schlee and colleagues similarly addressed diagnostic approaches. “Aspiration of synovial fluid with visualization of urate crystals using compensated polarized light microscopy is the gold standard for diagnosis of acute gout,” they wrote. “Moreover, analysis of synovial fluid enables a distinction from septic arthritis by Gram staining and bacterial culture.”
Saag echoed this point. “Joint aspiration is the gold standard,” he said.
Andrea Di Matteo, MD, of Clinica Reumatologica, Università Politecnica delle Marche, Ospedale “Carlo Urbani,” and colleagues compared musculoskeletal ultrasound with conventional X-ray in assessing wrist triangular fibrocartilage complex in a cohort of 36 patients with definite CPPD against 48 controls. Results indicated sensitivity of 77.8% for musculoskeletal ultrasound and 76.4% for X-ray. Specificity was 90.6% for ultrasound and 96.9% for X-ray. Total agreement between the two imaging procedures was 88.8% for calcifications at the triangular fibrocartilage complex.
“In the recent years, [musculoskeletal ultrasound] has proven to be a reliable imaging tool for the diagnosis of crystal diseases and its use is encouraged in the latest EULAR recommendations for the diagnosis of CPPD,” DiMatteo said. “In particular, [musculoskeletal ultrasound] is especially useful at diagnosing CPPD in the early phase of the disease, allowing the detection of even submillimeter [calcium pyrophosphate] microcrystal aggregates in articular and periarticular structures.”
DiMatteo added that musculoskeletal ultrasound carries value in differential diagnosis between CPPD and other crystal-induced arthropathies like gout or calcium basic phosphate disease. “Along with the depiction of crystal aggregates, [musculoskeletal ultrasound] may allow detection of coexistent synovitis and identification of bone erosions and/or tendon structural damage,” he said. “In several studies, [musculoskeletal ultrasound] demonstrated better diagnostic performance than conventional radiography. High sensitivity and good specificity are the main advantages of [musculoskeletal ultrasound]. Operator-dependency is the most important limitation.”
Another advantage of musculoskeletal ultrasound, according to DiMatteo, is that it is able to identify a wide spectrum of pathological findings indicating monosodium urate and/or calcium pyrophosphate crystals deposition at joint and tendon structures. “[Monosodium urate], [ calcium pyrophosphate] and other types of crystals, such as basic calcium phosphate crystals, can reliably be differentiated by [musculoskeletal ultrasound] by virtue of their peculiar shapes and topographic distribution,” he said. “Overall, double contour sign for gout, as well as meniscal and or hyaline cartilage calcification for CPPD, can be considered distinctive features of the above-mentioned diseases.”
Conventional Imaging Techniques
Following an investigation of CT and MRI in crystalline-induced arthropathies, Buckens and colleagues suggested that both modalities offer clinicians the opportunity to view osseous structures, periarticular soft tissue, and tophi with superior spatial resolution, while dual-source CT (DECT) allows for selective identification of crystalline deposits.
DiMatteo addressed these findings. “The low sensitivity of conventional radiography in the early stages of gout and CPPD is the main limitation to its use in the differential diagnosis of crystal diseases,” he said.
In 26 of 111 eligible data sets, ultrasound, DECT, and Raman spectroscopy had been used in the diagnosis of CPPD. Buckens and colleagues reported a sensitivity of >80% for ultrasound in detecting CPPD crystals in peripheral joints, which they suggested was superior to radiography. However, they acknowledged low EULAR evidence levels among the study designs. The analysis also included 35 studies of DECT in gout; however, studies of ultrasound, DECT and Raman spectroscopy carried a study bias risk of approximately 30%, with noncontrolled and nonrandomized trials commonly observed. “We identified major unmet needs, including for randomized, blinded, controlled studies of CPPD diagnostic performance and rigorous analyses of 4T MRI and other emerging modalities,” they wrote.
For Saag, a balance between the traditional and the novel may portend the future of diagnosis of crystalline arthropathies. “Clinical presentation, radiographs and newer imaging modalities such as ultrasound and DECT scans can help,” he said.
In a separate data set involving DECT, Li and colleagues investigated the approach in detecting green-colored voxels in toenails in a cohort of 53 patients with gout and 33 controls. DECT revealed 266 areas of green-colored voxels among patients in the gout group, for a relevance ratio of 50.2%, according to the results. There were 27 areas of green-colored voxels observed among controls, yielding a relevance ratio of just 8.2%. The researchers noted that this difference was statistically significant. The voxels were found in the nail groove of eight DECT patients and just two controls (P < .01). “DECT gout recognition technology can detect green-colored voxels of monosodium urate in the toenails, with a great potential in clinical diagnosis,” the researchers concluded.
Mandell summed up many of the data on imaging in these conditions. “Standard radiographs are insensitive for the diagnosis of early and nondestructive gouty arthritis,” he said. “MRI and CT are not specific. The use of ultrasound and dual energy CT imaging are evolving imaging modalities that seem to have specificity for diagnosing uric acid deposition around tendons and joints. They have as yet not fully defined sensitivity, but clearly the sensitivity is not 100%.”
Additionally, Mandell noted issues of cost and radiation exposure with DECT and issues of operator skill variability with ultrasound. “But in the right clinical setting, classic images obtained with either imaging modality may be acceptable for firm diagnosis,” he said. “However, neither modality is able to detect the presence of coexistent infection or calcium pyrophosphate crystals.”
DiMatteo also weighed in. “To date, conventional radiography is still the reference imaging tool for the diagnosis of CPPD,” he said. “According to the Ryan and McCarty diagnostic criteria, the definite diagnosis of CPPD requires the presence of [calcium pyrophosphate] crystals in the synovial fluid analysis and the detection of the characteristic calcifications on conventional radiography. Other than revealing articular and periarticular calcifications, conventional radiography has the potential to detect joint structures degenerative signs, which are frequently found in CPPD, such as large subchondral cysts or geodes and variable osteophyte formation.”
A benefit of X-ray lies in identifying calcium pyrophosphate crystals in uncommon sites, such as the thoracic joint, according to DiMatteo. “The high specificity is one of the main advantages of X-rays in the diagnosis of CPPD, whereas the low sensitivity is one of the main shortcomings,” he said. “In general, the presence of ionizing radiation makes this imaging tool not always well accepted by patients.”
Filippou and colleagues aimed to quantify and categorize CPPD in specific areas, including fibrocartilage, hyaline cartilage, tendons and synovial fluid. They also aimed to more clearly define ultrasonographic characteristics of calcium pyrophosphate deposits in joints and periarticular tissues with the hope of determining inter- and intra-observer differences in assessment according to OMERACT definitions. Hyaline cartilage yielded the highest inter-observer K value, at 0.73, followed by fibrocartilage, at 0.58. These two sites also carried the highest inter-observer K values for patient-based exercises, at 0.55 for hyaline cartilage and 0.64 for fibrocartilage. These values were 0.28 for tendons and 0.5 for synovial fluid in the static component of the study. Other findings from the patient-based exercise showed K values of 0.09 for the proximal patellar tendon and 0.27 for triangulation fibrocartilage of the wrist.
“The new OMERACT definitions for the US identification of CPPD proved to be reliable at the level of the [hyaline cartilage] and [fibrocartilage] of the knee,” the researchers concluded. “Further studies are needed to better define the ultrasound characteristics of CPPD and optimize the scanning technique in other anatomical sites.”
Loite and colleagues wrote that treatment begins with identifying the roots of hyperuricemia, preventing inflammation attacks through the use of colchinine, NSAIDs or steroids, and establishing clear targets for lowering serum urate to less than 6 mg/dL, ideally. The goal for patients with tophi should be lower than 5 mg/dL. Clinicians should consider lowering urate in both refractory hyperuricemia and chronic tophaceous arthritis. Patients with the latter condition who fail to respond to urate lowering therapy may benefit from pegloticase.
The researchers stressed that controlled trials are lacking for anti-inflammatory approaches to dealing with calcium pyrophosphate and CPPD. They added that no therapies are currently available for dealing with the metabolic disorders associated with CPPD. Beyond the numbers and therapies, the researchers suggested that patient education and adherence are critical to maintaining urate level goals.
“Management of crystal-induced arthropathies depends not only on clinical expression, namely acute attacks or chronic arthropathy, but also on the underlying metabolic disorder,” Loite and colleagues wrote.
Mandell pointed to anakinra (Kineret, Sobi), a short-acting injectable interleukin 1 antagonist, as a possible approach to dealing with flares in this patient population. “Unfortunately, it is not FDA-approved for this indication and thus insurance companies will not pay for it, despite the fact that it is quite effective at resolving attacks and does not have side effects that adversely impact the comorbidities that relate to fluid balance, renal function, diabetes, drug interactions or gastric toxicity,” he said.
For Saag there are two phases of treatment: acute and longer-term prevention. “For acute, we use NSAIDS, colchicine and steroids,” he said. “Longer term, the goal is urate reductions using medications like allopurinol, febuxostat and lesinurad [Zurampic, Ironwood].”
Dimitrios Daoussis, MD, assistant professor of internal medicine/rheumatology at the University of Patras Medical School, and of the department of internal medicine, division of rheumatology, at Patras University Hospital, in Patras, Greece, and colleagues addressed the use of ACTH as first-line therapy for various crystalline arthritides. The treatment, administered as a single intramuscular depot injection of 100 IU, showed a response rate of 77.9%. The researchers added that the clinical benefit was evident the day following ACTH injection.
Safety profile information showed no significant adverse events, according to Daoussis. “We found that it is highly effective and associates with minimal side effects,” he said in an interview. “If the efficacy and safety profile of ACTH is verified in a randomized controlled trial, the use of ACTH for the treatment of gout in the hospital setting will be strongly supported. Taking into account that hospitalized patients are the most difficult-to-treat patients, this may lead to wider use of ACTH in the treatment of gout in the community as well.”
“Treatment of gout can be either simple and straightforward in many cases, or extremely problematic in others,” Daoussis continued. “Current guidelines recommend the use of NSAIDs and colchicine as first-line treatment. However, patients with gout typically have multiple comorbidities such as cardiovascular disease or renal failure that often preclude the use of these drugs. Steroids are considered an alternative therapeutic option especially for difficult-to-treat patients, but they associate with immunosuppression and metabolic side effects and therefore their use may be problematic as well.”
Historically speaking, ACTH has long been used in gout, Daoussis noted. “The interest in ACTH was revived in the mid-1990s when several studies showed that ACTH is equally effective and in most cases faster acting than NSAIDs or steroids while exhibiting an excellent safety profile,” he said. “It was previously thought that the anti-inflammatory action of ACTH was steroid-related. If this was the case, then one could argue that treatment with ACTH would have no advantage over the systemic administration of steroids. However, experimental evidence challenges this view; it has been shown that ACTH mainly acts in a steroid independent manner.”
Daoussis described ACTH as a member of the melanocortin family of proteins, with the ability to bind and activate melanocortin receptors on many different cell types. “ACTH seems to have a steroid-independent anti-inflammatory effect by stimulating melanocortin receptors on immune cells such as macrophages and may therefore have a broad immunomodulatory effect beyond steroid release,” he said. “It is impressive that in mouse models of gout, ACTH is effective even in adrenalectomized animals, indicating that its effect is completely steroid independent.”
ACTH has been a first-line treatment for hospitalized patients since 1995 in the center where Daoussis works. “ACTH can be considered an attractive therapeutic option for patients with gout and multiple comorbidities that cannot receive standard treatment,” he said. – by Rob Volansky
Of note, and not a subject of this conversation, is the importance of delivering cost-effective care. When we speak of treating gout, historical treatments such as NSAIDS, colchicine and glucocorticoids are cheap while modern therapies, such as anakinra, are expensive. ACTH gel in its currently available preparation is also very expensive; thus, it is incumbent on gout investigators to design trials that weigh effectiveness, toxicity and cost in order to engage our patients in decisions that affect both their health and finances.
— Leonard H. Calabrese, DO
Chief Medical Editor, Healio Rheumatology
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- For more information:
- Dimitrios Daoussis, MD, can be reached at the University of Patras Medical School, Patras University Hospital, Department of Internal Medicine, Division of Rheumatology, 26504, Greece; email: firstname.lastname@example.org.
- Andrea Di Matteo, MD, can be reached at Via Aldo Moro 25, 60035 Jesi, Ancona, Italy; email: email@example.com
- Brian F. Mandell, MD, PhD, can be reached at 9500 Euclid Avenue A50, Cleveland Clinic, Cleveland Ohio 44195; email: MANDELB@ccf.org.
- Kenneth G. Saag, MD, can be reached at Faculty Office Tower (FOT), Room 820D, 510 20th Street South, 35294-3408; email: firstname.lastname@example.org.
Disclosures: Daoussis reports receiving speaking fees from Mallinckrodt, the manufacturer of Synachten (ACTH). DiMatteo reports no relevant financial disclosures. Mandell reports consulting for Horizon and Ironwood pharmaceuticals; being a clinical investigator for Horizon; and being the editor of rheumatology and immunology for The Merck Manual (no product association). Saag reports receiving grants and personal fees from Amgen, grants and personal fees from Merck and personal fees from Radius.