Mimickers of Immune Checkpoint Inhibitor-induced Inflammatory Arthritis.

The differential diagnosis of inflammatory arthritis as an immune-related adverse event can be challenging as patients with cancer can present with musculoskeletal symptoms that can mimic arthritis because of localized or generalized joint pain. In addition, immune checkpoint inhibitors can exacerbate joint conditions such as crystal-induced arthritis or osteoarthritis, or induce systemic disease that can affect the joints such as sarcoidosis. This distinction is important as the treatment of these conditions can be different from that of immune-related inflammatory arthritis.

[Diagnostic approach and differential diagnosis of mon- and oligoarthritis]. / Wichtige Differenzialdiagnosen von Mon- und Oligoarthritiden.

Reasons of mon- and oligoarthritis are heterogeneous. The diagnostic approach includes a detailed medical anamnesis, physical examination and imaging (conventional X-ray, sonography, MRI and, CT). Analysis of the synovial fluid is required in suspected septic arthritis and frequently helps in diagnosis and differential diagnosis of crystal arthropathies. Dual-energy-CT (DECT) detects sodium urate crystals and can replace joint puncture in some cases. In addition to crystal arthropathies and septic arthritis, differential diagnosis of mon-/oligoarthritis includes reactive arthritis, arthrosis and monarthritic courses of SpA/PsA. A rheumatologist should be consulted particularly in the case of persistent monarthritides, in order to initiate a specific therapy to prevent secondary damage.

Clinical implications of synovial fluid specimen handling for crystal associated arthritides: A systematic review.

AIM: To identify the appropriate methods of synovial fluid (SF) specimen storage, manipulation and handling for crystal associated arthritides (CAA) diagnosis. METHOD: A systematic literature review was conducted using 5 medical databases to identify diagnostic studies assessing SF specimen handling for calcium pyrophosphate (CPP) and monosodium urate (MSU) crystals identification. All included studies were rated for quality using the Quality Assessment of Diagnostic Accuracy Studies 2. RESULTS: Fifteen studies, including 2 non-English language manuscripts, were included. Eight studies examined both types of crystals, while 3 studies examined CPP and 4 studies examined MSU crystals only. Overall, MSU crystals were more stable over time compared to CPP crystals. MSU stability was generally independent of time, preservative and temperature. CPP crystals deteriorated with time and were more stable if refrigerated. Ethylenediaminetetraacetic acid (EDTA) was a suitable preservative. Re-examining an initially negative SF sample at 24 hours facilitated detection of additional cases. Very few studies had an overall low risk of bias and applicability. CONCLUSION: Monosodium urate crystals remain stable over time independent of storage time, temperature and preservative. CPP crystals are mostly stable for 24-48 hours but can deteriorate with time. Overall, SF crystal examination should ideally be done within 24-48 hours. They may be stored at room temperature without any preservative. Otherwise, refrigeration (4°C/39°F) and EDTA preservation is reasonable. Stored SF re-examination, at 24 hours, helps identify a small number of additional MSU and CPP cases. Centrifugation techniques allow better and easier crystal identification, particularly CPP. Most studies were of unclear or low quality.

Synovial fluid presepsin as a novel biomarker for the rapid differential diagnosis of native joint septic arthritis from crystal arthritis.

OBJECTIVE: To investigate whether presepsin can be used as a novel biomarker to differentiate between native joint septic arthritis (NJSA) and crystal arthritis (CA). METHODS: This study included 75 patients diagnosed with either NJSA (n = 21) or CA (n = 54). Presepsin in synovial fluid and blood, C-reactive protein, and procalcitonin were measured and compared between the NJSA and CA groups. Receiver operating characteristic (ROC) curve analyses were performed to differentiate between the two groups. RESULTS: Synovial fluid and blood presepsin were significantly higher in the NJSA group than in the CA group (p < 0.0001 and p < 0.01, respectively). The area under the ROC curve for synovial fluid presepsin in the NJSA group compared with the CA group was 0.93 (sensitivity 85.7%, specificity 85.2%, positive predictive value 69.2%, negative predictive value 93.9%, positive likelihood ratio 5.79, negative likelihood ratio 0.17). Among the tests, synovial fluid presepsin was the most accurate. CONCLUSIONS: Measurement of synovial fluid presepsin is reliable for the early diagnosis of NJSA, and synovial fluid presepsin could be used as a novel biomarker for differentiating between NJSA and CA.

Synovial Biopsy in the Diagnosis of Crystal-Associated Arthropathies.

BACKGROUND/ OBJECTIVE: This study seeks to assess the utility of synovial biopsy in the diagnosis of crystal-associated arthropathies (CAAs) in a clinical setting. METHODS: In this retrospective study, we reviewed biopsy reports involving synovial tissue between 1988 and 2015. We then reviewed the records of patients where the biopsy was performed for a clinical suspicion of CAA-the clinical group-and calculated the frequency of a positive diagnosis. The t test, Mann-Whitney-Wilcoxon test, and Fisher test were used to compare clinical characteristics of patients with and without a tissue diagnosis of CAA. We also reviewed cases of unexpected detection of crystalline disease involving synovial tissue-the incidental group. RESULTS: Among 2786 biopsies involving the synovium, we identified 65 cases in the clinical group and 33 cases in the incidental group. In the clinical group, a relevant diagnosis was obtained from synovial tissue in 36.9%, and a CAA was diagnosed in 20%. Restricting analysis to clinical biopsies performed for a primary suspicion of CAA, a relevant diagnosis was obtained in 61.3%, and a CAA was diagnosed in 38.7%. The incidental group comprised 1.2% of all synovial biopsies and included 7 mass lesions. Basic calcium phosphate was not reported on any biopsy in the study period. CONCLUSIONS: Synovial biopsy is a diagnostic option when suspected CAA is resistant to conventional modes of diagnosis. Crystalline diseases should be considered in the differential diagnosis of musculoskeletal mass lesions mimicking neoplasms.

Prevalence and incidence of non-gout crystal arthropathy in southern Sweden.

OBJECTIVE: To estimate the prevalence and incidence of non-gout crystal arthropathy in relation to socioeconomic factors in southern Sweden. METHODS: All patients (age ≥ 18 years) with at least one visit to a physician with the diagnosis of interest in the Skåne region (population of 1.3 million) in 1998-2014 were identified. Non-gout crystal arthropathy (ICD-10 codes M11.0-M11.9) was subclassified in four different groups: calcium pyrophosphate crystal deposition related arthropathy (CPPD), unspecified non-gout arthropathies, chondrocalcinosis, and hydroxyapatite crystal deposition disease. The crude and age-adjusted point prevalence on December 31, 2014, and the cumulative incidence during 2014 were calculated for all non-gout crystal arthropathies, CPPD, and other unspecified non-gout arthropathies overall and in relation to occupation, income, and level of education. RESULTS: The crude 2014 point prevalence (95% CI) and 2014 cumulative incidence (95% CI) of all non-gout crystal arthropathies were 0.23% (0.23-0.24) and 21.5 (19-25) cases/100,000 persons. Mean age (range) among all prevalent cases in 2014 was 71 (20-102) years and 56% were males. The point prevalence and cumulative incidence of CPPD were 0.09% (0.08-0.09) and 8 (7-10)/100,000 persons, respectively. The corresponding data for unspecified non-gout crystal deposition disease was 0.16% (0.16-0.17) and 15.6 (13-18)/100,000 persons, respectively. The prevalence and incidence of CPPD and unspecified non-gout crystal arthropathies were slightly higher in men and increased with age irrespective of gender. Unspecified non-gout crystal arthropathy but not CPPD was less prevalent in persons with ≥ 15 years of education, whereas there were no clear associations with occupation and income. CONCLUSION: The prevalence of all diagnosed non-gout crystal arthropathies was 0.23%, thus considerably less prevalent than gout in southern Sweden. CPPD and other unspecified non-gout crystal arthropathies are the predominant diagnoses, increasing with age and in men. With the exception for unspecified non-gout crystal arthropathies being inversely correlated to a higher level of education, no convincing association with the socioeconomic factors was found.

Coexistencia de artritis séptica y microcristalina: un reto diagnóstico. A propósito de 25 casos / Coexistence of septic and crystal-induced arthritis: a diagnostic challenge. A report of 25 cases

OBJETIVO: La artritis séptica es una urgencia médica y la artritis microcristalina es un factor de riesgo para su aparición. Si ambas cursan de forma simultánea, la identificación de microcristales puede enmascarar el diagnóstico de la infección y causar un retraso en la instauración del tratamiento antibiótico. MÉTODO: Análisis retrospectivo de pacientes con coexistencia de artritis séptica y microcristalina. Se incluye únicamente a los enfermos con aislamiento del germen en líquido articular y/o hemocultivo e identificación de cristales en el líquido articular. RESULTADOS: Se identificaron un total de 25 pacientes (17 varones y 8 mujeres) con una media de edad de 67 años. La articulación que se afectó con mayor frecuencia fue la rodilla. Los cristales de urato monosódico fueron los que con mayor frecuencia se identificaron en el estudio citológico del líquido sinovial. Los factores de riesgo más frecuentes fueron la diabetes mellitus y la insuficiencia renal crónica. El germen aislado con mayor frecuencia fue el Staphylococcus aureus sensible a meticilina (48%), seguido del Staphylococcus aureus resistente a meticilina (12%) y Mycobacterium tuberculosis (12%). El 36% de los pacientes precisaron desbridamiento quirúrgico (excluyendo los causados por M. tuberculosis). La evolución fue favorable en el 56% de los pacientes, aunque la presencia de complicaciones intercurrentes fue habitual (40%). La mortalidad fue del 8%. CONCLUSIONES: La coexistencia de artritis séptica y microcristalina representa un reto diagnóstico y requiere un alto índice de sospecha. La artropatía por cristales de urato monosódico es la más prevalente y S. aureus el germen causal más frecuente, con una tasa elevada de infección por S. aureus resistente a meticilina. Si se instaura de forma precoz el tratamiento adecuado, la evolución suele ser favorable, por lo que el estudio microbiológico del líquido sinovial es imperativo

OBJECTIVE: Septic arthritis is a medical emergency and crystal-induced arthritis is a risk factor for its development. If both occur simultaneously, crystal-induced arthritis may mask the diagnosis of infection and delay antibiotic therapy. METHOD: Retrospective analysis of patients with coexistence of septic and crystal-induced arthritis. We included only patients with isolation of crystals in synovial fluid analysis and positive culture of synovial fluid and/or blood culture. RESULTS: A total of 25 patients (17 men and 8 women) with a mean age of 67 years. The most commonly affected joint was the knee. In synovial fluid cytological studies, the most frequently identified crystals were monosodium urate. Risk factors included diabetes and chronic renal failure. The most frequently isolated germs were methicillin-sensitive S. aureus (48%), methicillin-resistant S. aureus (12%) and Mycobacterium tuberculosis (12%). In all, 36% of subjects required surgical drainage (excluding those caused by M. tuberculosis). Clinical outcome was favorable in 56%, although intercurrent complications were usual (40%). Mortality was 8%. CONCLUSIONS: Coexistence of septic and crystal-induced arthritis represents a diagnostic challenge and requires a high index of suspicion. Gout was the most prevalent crystal-induced arthritis. S. aureus was the most commonly causative pathogen, with a high rate of methicillin-resistant S. aureus infection. If treated early, the outcome is usually favorable, making synovial fluid microbiological study imperative

[Crystal arthropathies]. / Kristallarthritiden.

Crystals are one of the commonest reasons for acute joint inflammation. The most relevant types of crystals are those of monosodium urate (MSU) and calcium pyrophosphates (CPP). To get proven diagnosis of a crystal arthropathy the microscopic identification of those crystals in synovial fluid is still recommended by the actual guidelines. Whenever arthrocentesis is not feasible, ultrasound or dual-energy-computed tomography might help to visualize specific changes induced especially by MSU crystals. Both types of crystals act as danger signals inducing flares of immediate inflammatory response via activation of the innate immune system. Therefore crystal arthropathies could be seen as an auto-inflammatory condition. As neutrophils, monocytes and macrophages are the key cells and Interleukin 1ß is one of the dominant cytokines the way of blocking inflammation by colchicine and override IL-1ß are specific options in treating inflammation due to the crystals. For gout, causal treatment with urate lowering therapy can result in clearance of urate crystals. Unfortunately, to date there is no causal therapy for CPPD available. The present article summarises the recent knowledge highlighting the news regarding the crystal arthropathies gout and CPPD.

Coexistence of septic and crystal-induced arthritis: A diagnostic challenge. A report of 25 cases. / Coexistencia de artritis séptica y microcristalina: un reto diagnóstico. A propósito de 25 casos.

OBJECTIVE: Septic arthritis is a medical emergency and crystal-induced arthritis is a risk factor for its development. If both occur simultaneously, crystal-induced arthritis may mask the diagnosis of infection and delay antibiotic therapy. METHOD: Retrospective analysis of patients with coexistence of septic and crystal-induced arthritis. We included only patients with isolation of crystals in synovial fluid analysis and positive culture of synovial fluid and/or blood culture. RESULTS: A total of 25 patients (17 men and 8 women) with a mean age of 67 years. The most commonly affected joint was the knee. In synovial fluid cytological studies, the most frequently identified crystals were monosodium urate. Risk factors included diabetes and chronic renal failure. The most frequently isolated germs were methicillin-sensitive S. aureus (48%), methicillin-resistant S. aureus (12%) and Mycobacterium tuberculosis (12%). In all, 36% of subjects required surgical drainage (excluding those caused by M. tuberculosis). Clinical outcome was favorable in 56%, although intercurrent complications were usual (40%). Mortality was 8%. CONCLUSIONS: Coexistence of septic and crystal-induced arthritis represents a diagnostic challenge and requires a high index of suspicion. Gout was the most prevalent crystal-induced arthritis. S. aureus was the most commonly causative pathogen, with a high rate of methicillin-resistant S. aureus infection. If treated early, the outcome is usually favorable, making synovial fluid microbiological study imperative.

Gout, Hyperuricemia, and Crystal-Associated Disease Network Consensus Statement Regarding Labels and Definitions for Disease Elements in Gout.

OBJECTIVE: The language currently used to describe gout lacks standardization. The aim of this project was to develop a consensus statement on the labels and definitions used to describe the basic disease elements of gout. METHODS: Experts in gout (n = 130) were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach consensus on the labeling and definitions for the basic disease elements of gout. Disease elements and labels in current use were derived from a content analysis of the contemporary medical literature, and the results of this analysis were used for item selection in the Delphi exercise and face-to-face consensus meeting. RESULTS: There were 51 respondents to the Delphi exercise and 30 attendees at the face-to-face meeting. Consensus agreement (≥80%) was achieved for the labels of 8 disease elements through the Delphi exercise; the remaining 3 labels reached consensus agreement through the face-to-face consensus meeting. The agreed labels were monosodium urate crystals, urate, hyperuric(a)emia, tophus, subcutaneous tophus, gout flare, intercritical gout, chronic gouty arthritis, imaging evidence of monosodium urate crystal deposition, gouty bone erosion, and podagra. Participants at the face-to-face meeting achieved consensus agreement for the definitions of all 11 elements and a recommendation that the label "chronic gout" should not be used. CONCLUSION: Consensus agreement was achieved for the labels and definitions of 11 elements representing the fundamental components of gout etiology, pathophysiology, and clinical presentation. The Gout, Hyperuricemia, and Crystal-Associated Disease Network recommends the use of these labels when describing the basic disease elements of gout.

[Haemochromatosis and Arthropathies]. / Hämochromatose-assoziierte Arthropathien.

Arthropathy is the most common and often the earliest clinical manifestation of hereditary hemochromatosis (HH). It is difficult to treat and there is a high risk for early endoprosthetic joint replacement. Research done during the last decade shows that it is a joint disease in its own right. Clinically, there are degenerative articular changes with an atypical pattern of distribution, a crystal arthropathy (CPPD) with congenital joint swelling and synovitis like in RA. The X-ray image shows typical but not exclusive findings. In MRI, groundbreaking subchondral findings are found, especially in the large joints, and ultrasound shows inflammatory lesions in non-arthropathy patients as well. In animal experiments and pathomorphological studies of the synovial membrane, the arthropathy can be differentiated from osteoarthrits and RA. The pathophysiological significance of iron overload can be distinguished from immunohistochemical and cytogenetic investigations in chronic degenerative HH arthropathy and inflammatory-destructive arthropathy in hemophilia. By elucidating the pathophysiology, new therapeutic approaches can be formulated. In addition to colchicine, the IL-1 receptor antagonist anakinra is available for activation of the NLRP3 inflammasome by CPPD crystals and subsequent induction of IL-1ß overproduction. Other manifestations include symptomatic pain therapy and intensive physiotherapy and occupational therapy. To promote further research into hemochromatosis arthropathy, the Hemochromatosis Arthropathy Research Initiative (HARI) was established in 2016.

The Limitations of Gram-stain Microscopy of Synovial Fluid in Concomitant Septic and Crystal Arthritis.

BACKGROUND: Rapid diagnosis of septic arthritis from Gram-stain microscopy is limited by an inherent false-negative rate of 25-78%. The presence of concomitant crystal arthritis in 5% of cases represents a particular diagnostic challenge. OBJECTIVES: This study aims to investigate the effects that a concomitant crystal arthropathy has on the ability of Gram-stain microscopy of synovial fluid to diagnose a septic arthritis. METHODS: This is a 22-year retrospective cohort study. Inclusion criteria were a positive synovial fluid culture result with a positive clinical diagnosis of septic arthritis. Results were correlated with the presence or absence of urate and calcium pyrophosphate crystals, and Gram-stain result. During this time our collection and analysis methods remained unchanged. All samples were collected in Lithium Heparin containers. Chi-squared test with a p value < 0.05 was considered significant. RESULTS: 602 synovial fluid samples were included. 162 cases of concomitant crystal arthritis were identified (27%). Of these, 16 (10%) had an initial negative Gram-stain. Out of the 440 samples with no crystals detected, 18 (4%) had an initial negative Gram-stain microscopy result (p < 0.05). CONCLUSION: The incidence of concurrent septic and crystal arthritis may be higher than previously thought. Synovial fluid samples in concomitant septic and crystal arthritis are significantly less likely to have a positive Gram-stain at microscopy than in cases of an isolated septic arthritis. We would advise the clinician to maintain a high index of suspicion for septic arthritis in these patients.

Discordant American College of Physicians and international rheumatology guidelines for gout management: consensus statement of the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN).

In November 2016, the American College of Physicians (ACP) published a clinical practice guideline on the management of acute and recurrent gout. This guideline differs substantially from the latest guidelines generated by the American College of Rheumatology (ACR), European League Against Rheumatism (EULAR) and 3e (Evidence, Expertise, Exchange) Initiative, despite reviewing largely the same body of evidence. The Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) convened an expert panel to review the methodology and conclusions of these four sets of guidelines and examine possible reasons for discordance between them. The G-CAN position, presented here, is that the fundamental pathophysiological knowledge underlying gout care, and evidence from clinical experience and clinical trials, supports a treat-to-target approach for gout aimed at lowering serum urate levels to below the saturation threshold at which monosodium urate crystals form. This practice, which is truly evidence-based and promotes the steady reduction in tissue urate crystal deposits, is promoted by the ACR, EULAR and 3e Initiative recommendations. By contrast, the ACP does not provide a clear recommendation for urate-lowering therapy (ULT) for patients with frequent, recurrent flares or those with tophi, nor does it recommend monitoring serum urate levels of patients prescribed ULT. Results from emerging clinical trials that have gout symptoms as the primary end point are expected to resolve this debate for all clinicians in the near term future.

Crystal-Induced Arthropathy in Elderly Patients Hospitalized for Acute Conditions.

BACKGROUND: Arthritis and arthralgia are painful symptoms experienced by many elderly patients during hospitalization. Crystal-induced arthritis (CIA) is one of the most common causes of arthritis worldwide and represents the most common cause of acute arthritis in the elderly. OBJECTIVES: To determine the incidence of both acute new onset or acute exacerbation of CIA among elderly patients hospitalized due to an acute medical illness. METHODS: This study comprised 85 patients. Patients aged 70 years and older who complained of any articular pain were included in the study. Exclusion criteria were signs of septic arthritis, chronic use of steroids or non-steroidal anti-inflammatory drugs, or admission to the hospital due to an acute attack of CIA. RESULTS: RSynovial aspiration was performed in 76 patients (89%). Joint aspiration yielded a diagnosis in 67 of them (79%). The predominant type of crystal was calcium pyrophosphate dehydrate (68%) followed by monosodium urate (20%). The main causes of hospitalization were acute infectious disease (57%) followed by neurologic and cardiac diseases, 14% and 9% respectively, and orthopedic problems (6%). Among patients with acute infectious disease, the main causes were pulmonary (57%) and gastrointestinal (22%) infections. In 9 patients (12%) who underwent synovial aspiration, visible crystals were identified without a definite diagnosis. CONCLUSIONS: Our study showed that hospitalization could be a risk factor for the development of CIA, and the time to diagnose CIA is during hospitalization for other acute illnesses.

Inflammatory Arthritis Prevalence and Health Services Use in the First Nations and Non-First Nations Populations of Alberta, Canada.

OBJECTIVE: To estimate prevalence of rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic disease (PsD), and crystal-related arthritis and health care use for inflammatory arthritis in First Nations and non-First Nations patients in Alberta, Canada. METHODS: Population-based cohorts of adults with RA, AS, PsD, and crystal-related arthritis were defined, with First Nations determination by premium payer status, to estimate prevalence rates. Rates of outpatient primary care, specialist visits, and hospitalizations (all-cause, inflammatory-arthritis specific) were estimated. RESULTS: RA affected 3 times as many First Nations residents compared to non-First Nations residents (standardized rate ratio [SRR] 3.2, 95% confidence interval [95% CI] 2.9-3.4). AS and PsD were more prevalent in First Nations (AS 0.6 per 100 residents; SRR 2.7, 95% CI 2.3-3.2 and PsD 0.3 per 100 residents; SRR 1.5, 95% CI 1.3-1.9), whereas crystal-related arthritis was less prevalent (SRR 0.7, 95% CI 0.6-0.7). First Nations patients were more likely to have primary care visits (SRR 1.7, 95% CI 1.6-1.8) and less likely to have specialist visits (SRR 0.6, 95% CI 0.6-0.7) for RA relative to non-First Nations individuals. In PsD and crystal-related arthritis, First Nations people had higher rates of cause-specific hospitalizations. CONCLUSION: The estimated prevalence of RA, AS, and PsD was higher in the First Nations population, while crystal-related arthritis was less prevalent compared to the non-First Nations population. First Nations people were more likely to see primary care physicians and were less likely to see specialists for inflammatory arthritis care.

Use of Ultrasound by Internists to Improve Diagnostic Small Joint Aspiration.

BACKGROUND: Primary care internists are often the first to see patients with an initial episode of crystalline arthritis. Timely aspiration of the affected joint for definitive diagnosis and treatment in the office is desirable but can be difficult, especially if the joint is small, surrounded by soft tissue swelling distorting landmarks, and is very painful to move or palpate. METHODS: We compared the likelihood of successful aspiration of the great toe metatarsophalangeal joint by primary care internists for the diagnosis of potential crystalline arthritis by either landmark identification of the joint space or by employing ultrasound to identify the joint space. RESULTS: Aspiration was performed by one of 2 primary care internists using landmarks and palpation to identify the joint space in 27 patients with suspected crystalline arthritis affecting the first metatarsophalangeal joint. A sample adequate for diagnosis by polarized light microscopic crystal analysis was obtained in 14 of the 27 aspirations (52%) when landmarks alone were used to locate the joint space. In an additional 27 patients with suspected crystalline arthritis affecting the first metatarsophalangeal joint, ultrasound was used to identify the joint space and resulted in a significant increase in the success of obtaining an adequate diagnostic sample, which was obtained in 25 of the 27 aspirations (93%). CONCLUSIONS: The primary care internist can easily provide quality and timely small joint diagnostic aspiration when ultrasound is used to identify the location of the joint space.