EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.

BACKGROUND: Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management. METHODS: First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed. RESULTS: The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies. CONCLUSION: These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.

Giant cell arteritis: is the clinical spectrum of the disease changing?

BACKGROUND: Giant cell arteritis is a vasculitis of large and middle-sized arteries that affects patients aged over 50 years. It can show a typical clinical picture consisting of cranial manifestations but sometimes nonspecific symptoms and large-vessel involvement prevail. Prompt diagnosis and treatment is essential to avoid irreversible damage. DISCUSSION: There has been an increasing knowledge on the occurrence of the disease without the typical cranial symptoms and its close relationship and overlap with polymyalgia rheumatica, and this may contribute to reduce the number of underdiagnosed patients. Although temporal artery biopsy is still the gold-standard and temporal artery ultrasonography is being widely used, newer imaging techniques (FDG-PET/TAC, MRI, CT) can be of valuable help to identify giant cell arteritis, in particular in those cases with a predominance of extracranial large-vessel manifestations. CONCLUSIONS: Giant cell arteritis is a more heterogeneous condition than previously thought. Awareness of all the potential clinical manifestations and judicious use of diagnostic tests may be an aid to avoid delayed detection and consequently ominous complications.

Incidence of rheumatoid arthritis, psoriatic arthritis and polymyalgia rheumatica in an inland area of central Italy: results of the CAMPO-RHE study.

OBJECTIVE: The aim of the CAMPO-RHE study was to determine the incidence of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and polymyalgia rheumatica (PMR) in patients attending a rheumatologic outpatient's clinic of a new institution in Campobasso, Italy. METHODS: Campobasso is a small town of approximately 50,000 inhabitants located in the inland territory of central Italy (Molise), and Public Health is managed from a single health authority. In Italy, all citizens are registered with a National Health System of General Practitioner (GP) Physicians. Between the 1st of June 2014 and the 31st of May 2016, all consecutive adult patients, sent by a GP, of Campobasso with any diagnosis of musculoskeletal symptoms/signs/complaints were evaluated in a single rheumatology outpatient clinic of our Academic Unit. The clinic represents the first and unique reference for GPs about rheumatic diseases in the territory. Subjects were classified using the 2010 EULAR criteria for RA, the CASPAR criteria for PsA and the 2012 ACR classification criteria for PMR. RESULTS: 1003 adult patients, sent by GPs, with articular or musculoskeletal complaints visited our clinic. Of these, 409 inhabitants of the municipality of Campobasso were evaluated for the study. During the 2-year study period we diagnosed 18, 19 and 12 new cases of RA, PsA and PMR respectively, with a new incident cases rate of 21.4, 22.59 and 27.43/100,000/year on the population at risk. CONCLUSION: The results of our study could contribute to better define the incidence of these rheumatic diseases classified with the new classification criteria.

[Polymyalgia rheumatica: diagnostic and therapeutic issues of an apparently straightforward disease.] / La polimialgia reumatica: difficoltà diagnostiche e terapeutiche per una malattia apparentemente "banale".

Polymyalgia rheumatica (PMR) is an inflammatory disease characterized by aching and stiffness in the girdles, which affects typically people over 50 years old and could overlap with giant cell arteritis (GCA) in about 15-20% of cases. Although the diagnosis of PMR is usually considered straightforward, clinicians facing this disease should be aware of its atypical manifestations, which can hamper the correct identification of PMR and, conversely, should be aware of other diseases which may present with polymyalgic features. The aim of this review is to synthetize current knowledge about clinical presentations of PMR, the differential diagnoses, the relationship with cancer, the clues to the presence of a concomitant GCA, the role of ultrasonography at the onset and in the follow-up and, finally, treatment approaches. Besides evidence from the literature, this review will highlight some "tips&tricks" useful in everyday clinical practice. The awareness of the different presentations and pitfalls of PMR could improve patients' management and avoid complications consequent upon unrecognized diseases or, conversely, overtreatment.

Polymyalgia Rheumatica and Giant Cell Arteritis: A Systematic Review.

IMPORTANCE: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are related inflammatory disorders occurring in persons aged 50 years and older. Diagnostic and therapeutic approaches are heterogeneous in clinical practice. OBJECTIVE: To summarize current evidence regarding optimal methods for diagnosing and treating PMR and GCA. EVIDENCE REVIEW: MEDLINE, EMBASE, and Cochrane databases were searched from their inception dates to March 30, 2016. Screening by 2 authors resulted in 6626 abstracts, of which 50 articles met the inclusion criteria. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool or American College of Cardiology Foundation/American Heart Association methodology. FINDINGS: Twenty randomized clinical trials for therapy (n = 1016 participants) and 30 imaging studies for diagnosis and/or assessing response to therapy (n = 2080 participants) were included. The diagnosis of PMR is based on clinical features such as new-onset bilateral shoulder pain, including subdeltoid bursitis, muscle or joint stiffness, and functional impairment. Headache and visual disturbances including loss of vision are characteristic of GCA. Constitutional symptoms and elevated inflammatory markers (>90%) are common in both diseases. Ultrasound imaging enables detection of bilateral subdeltoid bursitis in 69% of PMR patients. In GCA, temporal artery biopsy remains the standard for definitive diagnosis. Ultrasound and magnetic resonance imaging (MRI) of large vessels revealing inflammation-induced wall thickening support the diagnosis of GCA (specificity 78%-100% for ultrasound and 73%-97% for MRI). Glucocorticoids remain the primary treatment, but the optimal initial dose and tapering treatment regimens are unknown. According to consensus-based recommendations, initial therapy for PMR is prednisone, 12.5 to 25 mg/day or equivalent, and 40 to 60 mg/day for GCA, followed by individualized tapering regimens in both diseases. Adjunctive methotrexate may reduce cumulative glucocorticoid dosage by 20% to 44% and relapses by 36% to 54% in both PMR and GCA. Use of tocilizumab as additional treatment with prednisone showed a 2- to 4-fold increase in remission rates of GCA in a randomized clinical trial (N = 30). CONCLUSIONS AND RELEVANCE: Diagnosis of PMR/GCA is made by clinical features and elevated inflammatory markers. In PMR, ultrasound imaging may improve diagnostic accuracy. In GCA, temporal artery biopsy may not be required in patients with typical disease features accompanied by characteristic ultrasound or MRI findings. Consensus-based recommendations suggest glucocorticoids as the most effective therapy for PMR/GCA. Methotrexate may be added to glucocorticoids in patients at risk for relapse and in those with glucocorticoid-related adverse effects or need for prolonged glucocorticoid therapy.

Recent advances in the diagnosis and treatment of polymyalgia rheumatica.

INTRODUCTION: Polymyalgia rheumatica is one of the most common rheumatic inflammatory disorders in people older than 50 years characterized by aching and prolonged morning stiffness in the shoulder and pelvic girdle and neck.. AREAS COVERED: In this review, we will focus on recent advances on the diagnosis and management of PMR. Expert commentary: Controversy exist whether PMR represent a single entity disease or is an umbrella term that comprises a clinical presentation common to a range of related conditions (polymyalgic syndrome). To date there are no specific diagnostic tests, and the diagnosis remains clinical, although ultrasonography, positron emission tomography scan and the recent ACR/EULAR classification criteria may help to confirm the clinical diagnosis. A step-wise process for the diagnosis of PMR has been proposed. Low-dose steroids are highly effective in the majority of patients and remain the mainstay of treatment, but relapses occur in about 50% of patients and glucocorticoid related adverse event are common. The steroid sparing effects of the immunosuppressive treatment evaluated to date are unclear.

[Polymyalgia rheumatica: What is the current status?]. / Polymyalgia rheumatica : Was ist der aktuelle Stand?

The diagnosis of polymyalgia rheumatica (PMR) is based on the typical clinical symptoms and elevated inflammatory markers in blood; however, both are unspecific and the differential diagnosis of the disease still represents a challenge for clinicians. The new consensus classification criteria of the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) established in 2012 have a high sensitivity (92.6 %) and specificity (91.2 %) and therefore contribute to improved diagnostics. Glucocorticoids are still the standard treatment with methotrexate and as an alternative and possibly anti-interleukin (anti-IL) 6 therapy in the future.

The process from symptom onset to rheumatology clinic in polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is an inflammatory disease of individuals aged over 50 years. Because of the concomitant malignancy possibility and the high prevalence of constitutional symptoms seen in this condition, patients with classical clinical picture often experience delay in diagnosis and treatment and are exposed to a wide list of laboratory and imaging procedures. In this study, we aimed to explore the adventure these patients experience from symptom onset to rheumatology clinic. A total of 106 PMR patients (84 women, 22 men) mean age 70.1 ± 8 were analyzed retrospectively. The time period from the onset of symptoms and referral to rheumatology specialists was explored. Diagnostic methods applied to these patients, antibiotic use and hospitalization during this period were recorded. The interval between the onset of the symptoms and admission to rheumatology unit was 13 ± 13 months. In this period, abdominal computed tomography (29.2 %), chest computed tomography (21.7 %), cranial magnetic resonance imaging (18.9 %) and whole-body scintigraphy (3.8 %) were applied to the patients. About 30 % of the patients were hospitalized for a mean period of 7 ± 3 days before referral to rheumatology unit, and 30 % of the patients were given antibiotics. In order to reduce the delay in the diagnosis of PMR and prevent unnecessary and expensive diagnostic methods, education of clinicians about the diagnosis of PMR may be beneficial.

A case of apoplectic lymphocytic hypophysitis complicated by polymyalgia rheumatica.

A case of apoplectic lymphocytic hypophysitis complicated by polymyalgia rheumatica (PMA) is described. A 72-year-old man was admitted to our hospital due to severe headache. Two months prior to admission, the patients had exhibited recent-onset stiffness and myalgia of shoulder and pelvic girdle that was compatible with PMR. Magnetic resonance imaging revealed a mass lesion in the pituitary fossa with focal hemorrhage. Endocrinologic studies demonstrated hypopituitarism. The headache and myalgia were improving with corticosteroid treatment; however, a trans-sphenoidal surgery was performed due to visual field loss. A white-colored mass was resected, and histologic examination showed diffuse infiltration of lymphocytes and plasma cells consistent with lymphocytic hypophysitis. Post-operatively, the headache and visual field loss resolved completely. This is the first documented case of apoplectic lymphocytic hypophysitis complicating PMR, and a possible mechanism for this rare association was discussed.

Our approach to the diagnosis and treatment of polymyalgia rheumatica and giant cell (temporal) arteritis.

We believe there is a strong case for formalised collaborative care between GPs and rheumatologists in the management of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), which can be difficult conditions to diagnose and manage. Our rapid access diagnostic care pathways allow early referral of patients who appear to have PMR or GCA, before glucocorticoids are prescribed. Using set referral criteria, we identify patients with PMR who can follow our slow-reduction glucocorticoid regimen without recurrence or exacerbation in about 80% of cases, a much lower relapse rate than that reported using more rapid reduction regimens. We have a low threshold for performing a temporal artery biopsy in GCA and where possible defer treatment until this is done. Using this approach, we can establish a secure diagnosis in the vast majority of patients and refer them back to primary care for our standardised treatment regimens.

Current understanding and management of giant cell arteritis and polymyalgia rheumatica.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are linked conditions that occur in the elderly. GCA is a vasculitis of large- and medium-sized vessels causing critical ischemia. It is a medical emergency owing to the high incidence of neuro-ophthalmic complications. PMR is an inflammatory disease characterized by abrupt-onset pain and stiffness of the shoulder and pelvic girdle muscles. Both conditions are associated with a systemic inflammatory response and constitutional symptoms. The pathogeneses are unclear. The initiating step may be the recognition of an infectious agent by activated dendritic cells. The key cell type involved is CD4(+) T cells and the key cytokines are IFN-γ (implicated in granuloma formation) and IL-6 (key to the systemic response). The pathogenesis of PMR may be similar to that of GCA, however, PMR exhibits less clinical vascular involvement. The mainstay of therapy is corticosteroids, and disease-modifying therapy is indicated in relapsing disease. This article reviews recent guidelines on early recognition, investigations and management of these diseases, as well as advances in imaging.

Update on rheumatology: part 1.

There are many rheumatic diseases. Part 1 of this 2 part series on rheumatology presented a few of those most commonly seen in the community. Home health clinicians can be helpful in managing these diseases and preventing progression by watching for new symptoms or acute attacks of pain or disability, ensuring that patients take their medications appropriately, reminding patients to see their rheumatology providers and have their lab work done regularly, and reporting adverse effects to medications promptly. Additionally, as with most home health patients, an interdisciplinary approach that includes physical and occupational therapy, social work, nursing, nutrition, and other disciplines as needed should be implemented so that all patient needs are met and the patient is discharged at the highest level of self-care that is possible. Part 2 of this series will discuss the care of the patient with rheumatic disease at home and will provide a more in-depth look at lab diagnosis of rheumatic diseases.

Giant cell arteritis and polymyalgia rheumatica: role of cytokines in the pathogenesis and implications for treatment.

OBJECTIVE: To summarize the contribution of cytokines to pathogenesis, clinical manifestations and prognosis of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). METHODS: MEDLINE database search for studies published between 1980 and April 2008. RESULTS: PMR and GCA are characterized by a hyperproduction of IL-6. The role of other circulating cytokines in their pathogenesis remains unclear. Cytokine mRNA in the arterial wall of GCA can distinguish different clinical subgroups of patients. The profile of T cell-derived cytokines in GCA suggests that it is a Th1-driven disease. The scarce number of studies makes difficult to evaluate the exact contribution of cytokine polymorphisms to their pathogenesis. Small studies have suggested the utility of TNF antagonists in patients with refractory PMR and GCA. However, these data have not been confirmed in controlled studies in patients with recent onset disease. CONCLUSION: Further studies are needed to evaluate the role of circulating cytokines in PMR and GCA. The study of tissue cytokines has provided important insights into the mechanisms implicated in the local inflammatory response that occurs in GCA. The important advance in the knowledge of the role of cytokines in PMR and GCA will have clear implications for treatment.

[Polymyalgia rheumatica and giant cell arteritis: recent data and current situation]. / Polymyalgia rheumatica et artérite giganto-cellttulaire: données actuellttes.

Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are two frequently linked inflammatory diseases of the elderly. The diagnosis of GCA is based on temporal artery biopsy, but results must not delay steroid therapy because of the potential sudden ocular and neurologic ischemic complications. PET-scan and MRI angiography can be helpful in difficult cases. The diagnosis of PMR is essentially clinical, centred on subacute onset of morning aching and stiffness in the shoulder and hip girdles. The treatment of both entities is still based on glucocorticoids (10-20 mg/j of prednisone for PMR, and 40-60 for GCA). Methotrexate, though, now appears a sometimes-useful corticosteroid-sparing agent, both in PMR and GCA. There also appears to be a role for low dose aspirin to decrease ischemic events in GCA.

Vasculitis in the geriatric population.

Vasculitis represents an uncommon but important group of disease entities that may affect older patients. The most common vasculitic disease in humans in giant cell arteritis, a disease process seen almost exclusively in patients older than 50 years in age. Vasculitic disease in geriatric patients presents unique challenges with regard to diagnosis and treatment. A thorough understanding of the vasculitic disease entities that may affect older patients as well as their diagnosis and management is essential in minimizing disease and treatment-related morbidity and mortality.

Polymyalgia rheumatica: diagnosis and treatment.

Polymyalgia rheumatica (PMR) typically manifests as inflammatory pain in the shoulder and/or pelvic girdles in a patient over 50 years of age. This condition was long underrecognized and therefore underdiagnosed. Today, however, overdiagnosis may occur. Physicians must be aware that many conditions may simulate PMR, including diseases that carry a grim prognosis or require urgent treatment. PMR may be the first manifestation of giant cell arteritis, and a painstaking search for other signs is mandatory. PMR may inaugurate other rheumatologic diseases such as rheumatoid arthritis, RS3PE syndrome, spondyloarthropathy, systemic lupus erythematosus (SLE), myopathy, vasculitis, and chondrocalcinosis. Finally, PMR may be the first manifestation of an endocrine disorder, a malignancy, or an infection. Failure to respond to glucocorticoid therapy should suggest giant cell arteritis, malignant disease, or infection. Ultrasonography may assist in the diagnosis by showing bilateral subdeltoid bursitis. Glucocorticoids are the mainstay of the treatment of PMR. Although the optimal starting dosage and tapering schedule are not agreed on, a low starting dosage and slow tapering may decrease the relapse rate. Methotrexate is probably useful when glucocorticoid dependency develops. In contrast, TNF-alpha antagonists are probably ineffective.

Therapy of neurological disorders in systemic vasculitis.

Significant progress has been made in our understanding of the underlying cellular and molecular mechanisms associated with vasculitis. Simultaneous involvement of the nervous system and systemic organs points to shared antigenic targets or immune mechanisms operative at both sites. Although specific immunotherapy is not available, the old and new immunomodulatory therapies have been instrumental in providing effective therapy in most of these chronic autoimmune disorders. The treatment of giant cell arteritis, neurosarcoidosis, Wegener's granulomatosis, systemic lupus erythematosus, polyarteritis, Sjögren's syndrome, and Behcet disease will be reviewed.

Early cancer of the stomach arising after successful treatment of gastric MALT lymphoma in patients with autoimmune disease.

BACKGROUND: Extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma) arises in lymphoid tissue acquired through chronic antigenic stimulation as exemplified by Helicobacter pylori. Secondary development of gastric cancer, however, is thought to be a rare event. The detection of a signet ring cell carcinoma during follow-up endoscopy after successful therapy of MALT lymphoma in a patient with Sjögren's syndrome prompted us to analyse the frequency of subsequent gastric cancer in patients with underlying autoimmune disease (AD). METHODS: Patients with early stage MALT lymphoma and an underlying AD were evaluated for the occurrence of a secondary gastric cancer during the course of follow-up. Data analysed included the type of AD, stage of MALT lymphoma, H. pylori status, treatment for MALT lymphoma and response, follow-up, the presence of a secondary cancer, and time to development of cancer. In all patients, histologic samples were reassessed for the extent of gastritis, presence of intestinal metaplasia or focal atrophy at the time of lymphoma diagnosis. RESULTS: A total of eight patients with overt AD at the time of diagnosis of MALT lymphoma were identified. All patients were women aged between 56 and 77 years; 5 had Sjögren's syndrome, 2 had autoimmune thyroiditis (1 along with psoriasis) and 1 suffered from polymyalgia rheumatica. All patients had early stage MALT lymphoma restricted to the mucosa and submucosa at the time of diagnosis, and the presence of H. pylori was found in all cases. Two of these patients achieved complete remission (CR) of the lymphoma following H. pylori eradication, while six were judged unresponsive and underwent chemotherapy, resulting in CR in all cases. One patient died from stroke while being in CR for 2 months following chemotherapy. Two patients (25%) developed early cancer limited to the gastric mucosa while being in CR from lymphoma for 9 and 27 months, respectively, and underwent partial gastrectomy. Final staging of gastric cancer revealed pT1pN0M0 in both cases. Of the remaining 5 cases, 1 patient had a local lymphoma relapse 18 months after CR and was salvaged with radiotherapy. In the remaining 4 patients, no evidence of lymphoma recurrence or a second malignancy has been found so far by regular follow-up every 3 months for a time-span between 52 and 63 months after initial diagnosis. CONCLUSION: Patients with concurrent MALT lymphoma and an underlying autoimmune condition show not only an impaired response to H. pylori eradication but might also be at increased risk for the development of gastric cancer. In view of this, such patients should be followed closely by regular endoscopies after remission of MALT lymphoma.