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.

Reactive Arthritis Provoked by Campylobacter jejuni Enterocolitis Mimicking Prosthetic Joint Infection: A Case Report.

CASE: A 59-year-old man with previously well-functioning partial knee replacement was admitted with a warm, swollen, and painful knee. The clinical presentation was consistent with prosthetic joint infection (PJI), but the synovial fluid analysis was negative for microbial growth. Further discussion revealed earlier Campylobacter jejuni enterocolitis that subsequently provoked reactive arthritis (ReA) mimicking PJI. The patient was treated with oral naproxen and intra-articular injection of triamcinolone and recovered completely without antibiotics or surgery. After 29 months, the knee is functioning normally. CONCLUSION: ReA is rare but should be included in the differential diagnosis of PJI.

Hypertrophic osteoarthropathy mimicking a reactive arthritis: a case report and review of the literature.

BACKGROUND: Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by abnormal proliferation of skin and periosteal tissues of the extremities. It can be a rare hereditary disease (pachydermoperiostosis) or can be secondary to various diseases, though mostly lung malignancies. Here, we report an unusual clinical presentation of HOA. CASE PRESENTATION: A 77-year-old man presented with fever, diarrhea, and an oligoarthritis involving the left knee and the ankles. Since left knee synovial fluid aspiration revealed an aseptic synovitis and Clostridium Difficile toxin was detectable in stool samples, a reactive arthritis secondary to a Clostridium Difficile induced colitis was initially suspected. However, the presence of a worsened digital clubbing and the lack of a good clinical response to steroid therapy led us to perform a radionuclide bone scanning, which revealed HOA. This turned out to be associated with a lepidic predominant lung adenocarcinoma, which was clinically and radiologically difficult to distinguish from a relapse of pneumonia. CONCLUSION: Consistent with the literature, HOA tends to have a variable clinical presentation, mimicking that of various rheumatic diseases. This clinical case shows that HOA can present as a presumptive acute reactive arthritis, and it highlights the importance of patient's follow-up in the differential diagnosis of inflammatory arthritis, especially when a worsened digital clubbing is present.

Reiter's syndrome postintravesical Bacillus Calmette-Guérin instillations.

Intravesical Bacillus Calmette-Guérin (BCG) has been a proven and effective immunotherapy treatment for superficial transitional cell carcinoma (TCC) of the bladder, especially for high-grade tumors and carcinoma in situ. Nevertheless, significant side effects are associated with BCG instillations, including fever, myalgia, malaise, dysuria, hematuria, and irritable lower urinary tract symptoms. We herein report the case of a patient who developed Reiter's syndrome following intravesical BCG instillations. A 39-year-old Chinese man presented with a 3-week history of dysuria, suprapubic pain, and pain at the tip of the penis postmicturition. Initial investigations revealed that he had microhematuria, and an ultrasound with computed tomography scan of the abdomen showed a bladder mass. Transurethral resection of the bladder tumor was performed and the patient received a single dose of intravesical mitomycin postoperatively. Results of histopathological examination revealed high-grade bladder TCC (G3pT1), and the patient was managed with intravesical BCG for 2 weeks following the surgery. Four weekly cycles of BCG were administered uneventfully; however, before the fifth instillation, the patient complained of urethral discharge, bilateral conjunctivitis, and low back pain. Reiter's syndrome was diagnosed as a rare but known complication of BCG instillation and the BCG immunotherapy was withheld. The patient was treated with nonsteroidal antiinflammatory drugs (for back pain) and eye ointment (for conjunctivitis) and his condition improved. This case report of Reiter's syndrome should be highlighted as a rare but significant complication of BCG immunotherapy and urologists should have a high index of suspicion to diagnose this rare complication.

Spondyloarthropathies: new directions in etiopathogenesis, diagnosis and treatment.

The spondyloarthropathies (SpA) are a group of inflammatory rheumatic diseases affecting the spine, peripheral joints and nonarticular structures. Often referred to as "seronegative" due to the absence of rheumatoid factor, SpA include ankylosing spondylitis (AS), reactive arthritis (ReA), enteropathic (IBD) associated arthritis, psoriatic arthritis (PsA), as well as undifferentiated, and juvenile SpA. A broad and overlapping spectrum of disease presentations creates difficulties in determining an initial diagnosis. In the last 10 years treatment options have expanded.

The value of blocking IL-6 outside of rheumatoid arthritis: current perspective.

PURPOSE OF REVIEW: Interleukin-6 (IL-6) is a multifunctional cytokine that regulates immune response and induces acute phase response. Despite the important physiological activities of IL-6, dysregulated overproduction of IL-6 is pathologically involved in various immune-mediated inflammatory diseases (IMIDs) including rheumatoid arthritis (RA). A series of clinical studies of tocilizumab, a humanized anti-IL-6 receptor (IL-6R) antibody, for patients with RA refractory to conventional therapy or anti-tumor necrosis factor therapy have demonstrated the clinical benefit of IL-6 blockade in RA. On the other hand, there is now accumulating evidence that tocilizumab is therapeutically effective for patients with a number of IMIDs other than RA. This review focuses on the perspective of IL-6 blockade therapy for such IL-6-related IMIDs outside of RA. RECENT FINDINGS: A considerable number of case reports and preclinical studies have shown the benefit of IL-6 blockade therapy in various IMIDs such as systemic lupus erythematosus, adult-onset Still disease, Takayasu arthritis, polyarteritis nodosa, systemic sclerosis, reactive arthritis, dermatomyositis, and polymyositis. SUMMARY: Blocking IL-6 with tocilizumab can be a therapeutic option for patients with various IMIDs in which overproduction of IL-6 plays a pathological role. Future clinical studies investigating the safety and efficacy will elucidate the clinical benefits of IL-6 blockade therapy for such diseases.

Health care utilization in patients with spondyloarthropathies.

OBJECTIVE: To study health care utilization in veterans with SpAs. METHODS: In a postal survey of 70,508 veterans in Veterans Integrated Service Network (VISN)-13 from 1 October 1996 to 31 March 1998, demographics, smoking status and performance of activities of daily living (ADLs) were queried. Databases provided ICD-9 codes for AS, PsA and ReA; comorbidities; demographics; and health care utilization post-survey in respondents. Multivariable linear/logistic regression compared out- and inpatient health care utilization in SpA vs non-SpA, and its predictors in SpA. RESULTS: A total of 1001 veteran respondents had diagnoses of SpA: AS, n = 154; PsA, n = 814; ReA, n = 33. Veterans with AS, PsA and ReA, respectively, had significantly higher adjusted annual medical specialty (2.8, 3.6 and 3 vs 1.5; P < 0.0001), surgical care (3.3, 2.7 and 3.2 vs 1.9; P < 0.0001) and primary care visits (3.4, 3.0 and 2.3 vs 2.7, P = 0.024). Multivariable-adjusted analyses showed that more ADL limitations and higher comorbidity were associated with higher in- and outpatient health care utilization in PsA and none of the predictors were significantly associated with utilization in AS. CONCLUSIONS: After adjustment for differences in demographics and comorbidities, more outpatient health resource utilization was observed in SpA patients. Further studies should focus on what leads to this increase in utilization, and whether any modifiable factors can be introduced to reduce health care utilization in PsA patients.

[Radon alpha-applicator in therapy of reactive and inflammatory arthropathies].

The article presents the results of treatment of 42 patients with reactive and inflammatory arthropathy of the knee and ankle joints. Nineteen patients were exposed to EHF (460 MHz) electromagnetic field, 23 patients received local cutaneous alpha therapy with radon applicator. Radon concentration was 7.4 Bq/l (0.2 nCi/l), the exposure was 90 minutes. Local alpha-therapy by radon applicator proved highly active as shown by attenuation of inflammation, excudative and proliferative disorders in the joints.

Successful treatment of postvenereal reactive arthritis with synovectomy and 3 months' azithromycin.

BACKGROUND: The effects of antibiotic therapy on the course of postvenereal reactive arthritis have not yet been elucidated. OBJECTIVE: The objective of this study was to observe the clinical course and outcome of synovectomy and 3 months of azithromycin therapy in patients with reactive arthritis and previously diagnosed triggering bacteria. METHODS: We performed an open, prospective study on 20 (14 male/6 female) patients with postvenereal reactive knee arthritis, aged 36.7 +/- 14.8 years, and with 16.5 +/- 20.4 months' duration of the disease. Detection of bacteria triggers was done by polymerase chain reaction, isolation and identification, and electron microscopy. Synovectomy was performed in all patients at entry into the study. Azithromycin was given at a dose of 500 mg per day for 5 days, and then 500 mg twice a week, during a 3-month period. Patients without remission were treated with combined antibiotic therapy using a macrolide, quinolone, and tetracycline for the next 4 months. Outcome evaluations of therapeutic efficacy and azithromycin safety were done after 1 and 3 months and 2 years of follow up. RESULTS: Remission, defined by the absence of joint swelling and tenderness, and extraarticular signs, was reached after 3 months in 15 of 20 (75.0%) patients (P = 0.025). Of 5 patients with persistent knee arthritis, remission was achieved with combined antibiotic therapy in 4. Visual analog scale scores (P < 0.01), the number of patients (P = 0.002), and the number of samples (P = 0.01) with a positive finding of bacteria or their DNA were significantly lower after 3 months of therapy. During the azithromycin therapy, there were no significant adverse effects. CONCLUSIONS: These patients with reactive arthritis did extremely well on the regimen described. In our study group, the number of patients and the number of samples with positive findings of bacteria or their DNA were lower after the antibiotic treatment combined with surgery, although not all bacteria were eradicated. Adverse effects of prolonged azithromycin administration were insignificant. This open treatment approach is recommended but does need a study with controls.

Reactive arthritis. A clinical approach.

What do conjunctivitis, urethritis/cervicitis, and arthritis have in common? These are all clues to the diagnosis of reactive arthritis. It takes a keen eye, a thorough history, a good physical examination, and a broad differential diagnosis to pull together the picture when sorting through seemingly unrelated clinical symptoms. Often a team approach is used when caring for patients with reactive arthritis. This article presents the diagnosis and treatment of reactive arthritis.

Spondyloarthropathies.

The spondyloarthropathies include ankylosing spondylitis, reactive arthritis (including Reiter's syndrome), psoriatic arthritis, inflammatory bowel disease-associated spondyloarthropathy, and undifferentiated spondyloarthropathy. These diseases are linked by their association with the HLA-B27 gene and by the presence of enthesitis as the basic pathologic lesion. Additional clinical features include inflammatory back pain, dactylitis, and extra-articular manifestations such as uveitis and skin rash. The history and physical examination are the major diagnostic tools, although radiographic evidence of sacroiliitis is helpful. Therapeutic options include nonsteroidal anti-inflammatory drugs, sulfasalazine, methotrexate, and tumor necrosis factor-alpha inhibitors. Early recognition and appropriate treatment can help to limit disability.

Degenerative sternoclavicular arthritis and hyperostosis.

Symptomatic arthritic involvement of the sternoclavicular joint is relatively uncommon and can be a result of distant trauma, infection, and sternocostoclavicular hyperostosis, post-menopausal arthritis, condensing osteitis of the proximal clavicle, or secondary to an underlying arthropathy. Patients with degenerative osteoarthritis due to trauma most commonly have had either an anterior or posterior dislocation, subluxation, or periarticular fracture. Medical claviculectomy with or without ligamentous stabilization is indicated only in situations of painful primary and secondary rheumatoid arthritis, or in patients with neoplastic lesions. Numerous authors have recommended surgical reconstruction but few have reported series larger than two or three cases. This article reviews a few specific arthropathy conditions about the sternoclavicular joint and discusses their nonoperative and operative management.

Defective Fas ligand-mediated apoptosis predisposes to development of a chronic erosive arthritis subsequent to Mycoplasma pulmonis infection.

OBJECTIVE: To determine whether defective T cell apoptosis is associated with the development of a chronic arthritis subsequent to mycoplasma infection, and to determine whether deletion of T cells can prevent the development of this arthritis. METHODS: B6 wild-type (B6-+/+), B6-lpr/lpr, and B6-gld/gld mice were infected with Mycoplasma pulmonis. The severity of lymphocytic infiltration and joint damage was evaluated, and the degree of recovery of viable mycoplasma from the spleen and joints was determined. Antigen-presenting cells derived from Fas mutant lpr mice (lpr-APC) were transfected ex vivo with an adenovirus (Ad) vector to yield lpr-APC expressing high levels of Fas ligand (lpr-APC-AdFasL), which in turn were transferred intraperitoneally into M pulmonis-infected B6-gld/gld mice. The development of arthritis subsequent to M pulmonis infection and the induction of apoptosis of cells within the synovial tissue and lymph nodes of lpr-APC-AdFasL-treated B6-gld/gld mice were determined. RESULTS: Infection of B6-lpr/lpr and B6-gld/gld mice with M pulmonis resulted in an acute-phase inflammation of the synovium that later developed into a chronic erosive arthritis. Similar infection of B6-+/+ mice resulted only in an acute joint inflammatory response that resolved. Chronic arthritis in B6-gld/gld mice and B6-lpr/lpr was not due to persistent infection, since there were no differences in the rates of clearance of M pulmonis from the joints of B6-gld/gld or B6-lpr/lpr mice compared with B6-+/+ mice. Treatment of infected B6-gld/gld mice with lpr-APC-AdFasL resulted in a significantly decreased incidence of chronic arthritis that was associated with a decrease in lymph node T cells, but not with apoptosis of synovial T cells or fibroblasts. CONCLUSION: Defective Fas/FasL-mediated apoptosis of T cells is an important factor that rendered arthritis-resistant B6 mice susceptible to the development of a chronic erosive arthritis subsequent to mycoplasma infection. In vivo lpr-APC-AdFasL cell-gene therapy is a safe and effective method for inhibiting the development of this arthritis.

Hepatitis C-associated arthritis.

Rheumatologic complications of hepatitis C virus (HCV) infection are common and include mixed cryoglobulinemia, vasculitis, sicca symptoms, myalgia, arthritis, and fibromyalgia. The prevalence of cryoglobulinemia in Sweden and Germany is much lower compared with data from southern Europe. Viral, genetic, or environmental factors may be responsible for such a difference in prevalence. There is no single clinical picture of arthritis in patients with HCV infection. There is a well-defined picture of arthritis associated with the presence of mixed cryoglobulinemia that consists of an intermittent mono- or oligoarticular, nondestructive arthritis affecting large and medium-size joints. Involvement of salivary and lacrimal glands is common in HCV-infected subjects, but HCV antigens are not detected in affected glands. HCV-infected subjects express a high prevalence of a variety of autoantibodies, usually in low titers. The clinical significance of most of these autoantibodies is not clear. The prevalence and titer of these autoantibodies are unaffected by interferon-alpha therapy. Several studies have attempted to assess whether HCV infection may be involved in the etiopathogenesis of rheumatic and autoimmune diseases. The results of most of these studies do not support the idea that HCV infection may play a pathogenic role in the development of systemic lupus erythematosus, antiphospholipid syndrome, or leukocytoclastic vasculitis. Experience treating patients with HCV-associated arthritis is limited and treatment remains controversial. No major therapeutic trials in HCV-associated arthritis were reported in the past 2 years.

Sindrome de Reiter e infeccao pelo virus da imunodeficiencia humana / Reiter's syndrome and human immunodeficiency virus infection

Tem sido observado aumento da prevalencia de manifestacoes reumatologicas em infectados pelo HIV, com destaque especial para a Sindrome de Reiter. A despeito de fatores de risco para infeccao pelo HIV serem importantes para surgimento de manifestacoes reumatologicas por outros agentes, a imunodeficiencia intensa para ter papel fundamental no desenvolvimento de doenca articular, por predispor a presenca de microorganismos artritogenicos. Sao considerados para entendimento da patogenese da Sindrome de Reiter associada ao HIV; queda de linfocitos TCD4, niveis elevados de linfocitos TCD8 e alteracoes na regulacao imune. O tratamento da Sindrome de Reiter no paciente infectado pelo HIV e dificil, nao havendo resposta ao emprego de terapeutica antiinflamatoria nao esteroide