Azacitidine as a rare cause of reactive arthritis in a patient with acute myeloid leukemia.

INTRODUCTION: Azacitidine (AZA), a demethylating agent, is one of the mainstay treatments for patients with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) who are ineligible for curative allogeneic stem-cell transplantation and is recommended as first-line treatment in multiple countries. While arthralgia and myalgia have been commonly reported as side effects, the incidence of drug-induced reactive arthritis has only been reported twice so far. CASE REPORT: We present a retrospective overview of a clinical case of a 71-year-old patient that developed new cytopenias on a background of Chronic Lymphocytic Leukaemia and was diagnosed with therapy-associated AML. His treatment included an indefinite course of AZA to induce remission and optimise long-term survival which resulted in a satisfactory haematological response. However, after his ninth AZA cycle, he presented to the emergency department with knee swelling and erythema and conjunctivitis. MANAGEMENT AND OUTCOMES: Arthrocentesis of the knee revealed reactive arthritis with no crystal or organism growth. His symptoms were managed effectively with conservative management including NSAIDs, analgesia and temporary immobilization for joint rest. The adverse drug reaction probability score in our study was calculated as six and adverse drug reaction was thus assigned to the "probable" category. CONCLUSION: We report a case that points to AZA as a probable cause of arthritis flares in MDS patients. The current limitation of this study is the lack of available data, future reviews and research will aid in providing stronger evidence of a correlation between arthritis and AZA treatment.

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 following Bacillus Calmette-Guerin Therapy for Bladder Cancer: a Systematic Literature Review.

PURPOSE OF REVIEW: Intravesical BCG therapy (ivBCG) is a treatment for bladder cancer that complements surgery and prevents tumor progression. Reactive arthritis (ReA) is a rare osteoarticular manifestation that can complicate this treatment. An updated systematic literature review has been investigated to identify clinical, biological, and therapeutic data of this pathology. RECENT FINDINGS: A systematic literature was performed on October 2020 to identify papers published from 2000 to 2020. Study eligibility criteria included case reports, case series, cohort studies, systematic reviews, meta-analysis, and letters to the editor, in English and French. Independent extraction of articles was performed by two investigators. Thirteen studies met the search criteria for the systematic review with a good quality assessment. The total number of patients was 107, with an average age of 61.5 [24-80]. The symptoms of ReA appeared after a mean number of 5.71 instillations and 13.9 days. Arthritis was the most common symptom (98.13%) followed by fever (80.76%) and conjunctivitis (64.42%). Human leukocyte antigen (HLAB27) was positive in 28.97% of patients. Therapeutic modalities included non-steroidal anti-inflammatory drugs (NSAIDs) (51.4%), corticosteroids (27.1%), conventional synthetic disease-modifying antirheumatic drugs (3.84%), antitubercular drugs (14.42%), and tocilizumab (0.93%). BCG therapy was discontinued in 29.9% of patients. Remission was achieved in 92.3% of patients and one patient progressed to spondyloarthritis. ReA is a rare complication of BCG therapy. Clinical signs are similar to those of typical ReA and treatment is primarily based on NSAIDs and corticosteroids.

[Reactive Arthritis during the Second Course of Intravesical BCG Therapy Requiring Administration of Methotrexate : A Case Report].

Reactive arthritis, formerly called Reiter's syndrome, is one of the rare complications following intravesical instillation of Bacillus Calmette Guerin (BCG). A 58-year-old man was admitted to our hospital because of fever, hyperemia of conjunctiva, and arthralgia following the second course of intravesical instillation of BCG in the treatment of pT1 and pTis bladder cancer. We diagnosed him with reactive arthritis due to the clinical course. Reactive arthritis is usually well controlled with the discontinuation of instillation and administration of nonsteroidal anti-inflammatory drugs (NSAIDs). However, his symptoms were not improved after administration of NSAIDs, prednisolone, and isoniazid. Following initiation of methotrexate, however, there was remission. He has been free from recurrence of bladder cancer for 20 months.

[REITER'S SYNDROME FOLLOWING INTRAVASICAL BCG THERAPY FOR UROTHELIAL CARCINOMA. SUMMARY OF CASE REPORTS OVER THE PAST 13 YEARS IN JAPAN, INCLUDING OUR CURRENT 6 CASES].

Reiter's syndrome is one of the rare complications following intravesical bovis Bacillus Calmette-Guerin (BCG) treatment. In this study we have reviewed and discussed 101 cases including our own 6 cases over the past 13 years in Japan (2000-2013). The patients comprised 70 males and 25 females (6 cases were unknown), mean age of 63.1 (range 42 - 91). Arthritis occured 4-5 days after conjunctivitis. Thirty five (55%) of 68 patients needed corticosteroid treatment to control their arthritis. HLA-B27 is known as a risk factor of Reiter's syndrome, however, positive rate was only 2.4% (n = 41).

Reactive arthritis as a rare complication of intravesical bacillus Calmette-Guérin treatment: Report of two cases.

Intravesical bacillus Calmette-Guérin (BCG) immunotherapy is recommended for non-muscle-invasive bladder cancer after transurethral resection. BCG-associated musculoskeletal adverse events are rare. We report two cases of BCG reactive arthritis that were unusually severe and refractory. These describe two male patients who presented with polyarthritis after BCG exposure. Ultrasonography-guided glucocorticoid injections, high-dose systemic glucocorticoids and the institution of sulfasalazine were required for achievement of remission. Bacillus Calmette-Guérin reactive arthritis can present as polyarthritis of small and medium joints or as mono-oligoarthritis of asymmetrical ankles and knees, frequently associated with tenosynovitis and enthesitis. The mechanism by which BCG promotes arthralgia and arthritis is poorly understood. The most well-accepted theory is that the BCG antigens migrate to different peripheral tissues, including the joints. There is also a lack of knowledge regarding risk factors, with possible genetic factors playing a role. As the two presented cases show, BCG-induced reactive arthritis should be considered in the differential diagnosis of arthritis and refractory tenosynovitis in BCG-exposed patients.

Autoimmune disorders caused by intravesical bacillus Calmette-Guerine treatment: A systematic review.

Intravesical bacillus Calmette-Guérin (BCG) is a common and highly effective treatment for non-muscle invasive urothelial carcinoma of the urinary bladder. BCG may cause an autoimmune reaction in some patients. One hundred and fifty-eight papers were analyzed, for a total of hundred and thirty patients with reactive arthritis, sixty patients with ocular manifestations and eighteen patients with other rheumatologic diseases. Among 130 subjects with reactive arthritis, an autoimmune symptom occurred after 5 instillations of intravesical BCG (IQR 4-6), which represents 5 weeks in most cases. Fifty-one patients had concurrent ocular involvement. The resolution of symptoms was achieved in a median of 32.5 days (IQR 14-90). Forty-two men and twenty women had ocular manifestations, most commonly conjunctivitis. Patients with HLA-B27 typing had earlier presentation of ocular symptoms related to the number of instillations (4.5 vs 6 [p < 0.05]. Resolution of symptoms was achieved at a median of 128 days (IQR 21-150). Among patients treated with NSAIDs (either with or without steroids), the duration of the disease was significantly shorter in both the articular and the ocular groups (28 vs. 120 [p < 0.05] and 30 vs.105 [p < 0.05], respectively). Other autoimmune manifestations included general autoimmune diseases, such as vasculitis, psoriasis and myasthenia gravis.

Comparison of immune checkpoint inhibitor-induced arthritis and reactive arthritis to inform therapeutic strategy.

INTRODUCTION: Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) is a relatively new disease entity caused by ICI agents during cancer therapy. Reactive arthritis (ReA) is a well-known disease entity caused by urogenital or gastrointestinal bacterial infection or pneumonia. In this sense, ICI-IA and ReA are both defined by a reaction to a well-specified causal event. As a result, comparing these diseases may help to determine therapeutic strategies. METHODS: We compared ICI-IA and ReA with special focus on pharmacological management. Specifically regarding treatment, we conducted a literature search of studies published in the PubMed database. Inclusion criteria were studies on treatment with non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GC), or disease modifying antirheumatic drugs (DMARDs) in ICI-IA or ReA. During systematic selection, 21 studies evaluating ICI-IA and 14 studies evaluating ReA were included. RESULTS: In ICI-IA, prospective and retrospective studies have shown effects of non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoid (GC), sulfasalazine (SSZ), methotrexate (MTX), hydroxychloroquine (HCQ) and TNFi. In ReA, retrospective studies evaluated NSAIDs and GC. A randomized controlled trial reported the effect of SSZ, and a retrospective study reported the effect of MTX and SSZ in combination with tumor necrosis factor alpha inhibition (TNFi). For both entities, small case reports show treatment effects of interleukin 6 receptor inhibition (IL-6Ri). DISCUSSION: This literature review identified both similarities and differences regarding the pathogenesis and clinical features of ReA and ICI-IA. Studies on treatment reported effectiveness of NSAIDs, GC, MTX, SSZ and TNFi in both diseases. Further, small case reports showed effects of IL-6Ri.

Reactive arthritis following treatment with intravesical Bacillus Calmette-Guerin for papillary carcinoma of bladder.

A man in his 60s developed reactive arthritis following treatment with intravesical Bacillus Calmette-Guerin (iBCG) for papillary carcinoma of bladder. Evaluation revealed leucocytosis and raised inflammatory markers. HLA B27 was positive. Based on the temporal relationship, it was attributed to BCG-related reactive arthritis. iBCG was stopped. Treatment with non-steroidal anti-inflammatory drugs (NSAIDS) and glucocorticoids were ineffective. Prolonged course of disease-modifying antirheumatic drugs (DMARDS) was required which aided in alleviation of symptoms and sustained remission. Intravesical BCG therapy is a treatment for bladder cancer. It is rarely associated with reactive arthritis, which responds to discontinuation of iBCG and treatment with NSAIDS and/or short-term glucocorticoids. iBCG-related reactive arthritis commonly has an acute/subacute course. Chronic arthritis as observed in our case requiring prolonged treatment with DMARDS is rare.

Reactive arthritis after COVID-19 vaccination.

The severe acute respiratory syndrome coronavirus 2-induced coronavirus disease 2019 (COVID-19) has had a global spread. Vaccines play an essential role in preventing the spread. However, almost all types of vaccines have been reported to be associated with adverse events. Reactive arthritis (ReA) after vaccination has been reported; however, ReA after COVID-19 vaccination has not been reported. We reported a 23-year-old woman who suffered from an acute ReA on her left knee joint after COVID-19 vaccination and discussed the etiology and preventive strategy. She presented with swollen, painful left knee joint for 18 d. She had been inoculated 0.5 ml CoronaVac vaccine on 0 d and the 14th day with deltoid intramuscular injection. Finally, she was diagnosed as ReA after CoronaVac vaccination and was administered a single intra-articular injection of 1 ml compound betamethasone. The swelling and pain nearly disappeared after 2 d. On 1month follow-up, her condition was normal. ReA after COVID-19 vaccination is rare. The benefits of vaccination far outweigh its potential risks and vaccination should be administered according to the current recommendations. Further attentions should be put to determine which individual is at higher risk for developing autoimmune diseases after COVID-19 vaccination. More versatile and safer vaccines should be explored.

Intrathecally injected tramadol reduces articular incapacitation and edema in a rat model of lipopolysaccharide (LPS)-induced reactive arthritis.

AIMS: Intrathecal injection of morphine presents analgesic and antiedematogenic effects in rats. However, it is unknown whether tramadol, which possess a mixed mechanism of action, can also produce analgesic and antiedematogenic effects similarly. MAIN METHODS: Male Wistar rats received carrageenan and LPS in the right knee joint. Tramadol (10 µg) was injected intrathecally 20 min before articular LPS injection. Incapacitation and articular edema were measured 5 h after LPS stimulation. Synovial fluid was collected for leukocyte counting and western blot analysis. Whole joint and lumbar spinal cord were also collected for histology and immunohistochemistry, respectively. Intrathecal pretreatments groups were with the NKCC1 blocker bumetanide, TRPV1 agonist resiniferatoxin, µ-opioid receptor antagonist CTOP and serotonergic neurotoxin 5,7-DHT, all previously to tramadol. KEY FINDINGS: Tramadol treatment caused the reduction of incapacitation and edema. It also reduced c-Fos protein expression in the spinal cord dorsal horn and slightly reduced TNF-α levels in synovial fluid, but neither reduced cell migration nor tissue damage. Bumetanide and resiniferatoxin prevented the analgesic and antiedematogenic effects of tramadol. CTOP prevented the analgesic and the antiedematogenic effects, but 5,7-DHT prevented only tramadol-induced analgesia. SIGNIFICANCE: Spinal NKCC1 cotransporter and peptidergic peripheral afferents seem to be important for the analgesic and antiedematogenic effects of tramadol, as well as µ-opioid receptor. However, the monoamine uptake inhibition effect of tramadol seems to be important only to the analgesic effect.

Reiter's syndrome during intravesical BCG therapy for bladder carcinoma.

A 50-year-old male with superficial bladder carcinoma developed fever, conjunctivitis, cystitis, and arthritis of the ankles and metatarsophalangeal and sacroiliac joints after the fourth course of intravesical Bacillus Calmette-Guerin (BCG) therapy. Reiter's syndrome in the context of BCG therapy was diagnosed, and intravesical immunotherapy was discontinued. Treatment with indomethacin was started with partial response, while a significant clinical improvement was noted when prednisolone 30 mg daily was started. One month later, the patient was on full clinical and laboratory remission, and steroid treatment was gradually tapered. Clinicians should be aware of this rare complication of BCG therapy because early diagnosis may lead to early management.

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.

Poncet's disease after the intravesical instillation of Bacillus Calmette-Guérin (BCG): a case report.

BACKGROUND: Poncet's disease is a rare syndrome characterized by articular impairment in a form of rare tuberculid. One of the theories of its cause involves an autoimmune response induced by the intravesical administration of the Calmette-Guerin Bacillus or the treatment of bladder carcinoma. Furthermore, there may be an appearance of oligoarticular or polyarticular arthritis, beginning 1-3 months after the start of therapy. Few physicians know the disease and the literature related to that syndrome is scarce and restricted to case reports, which contributes to its under diagnosis. CASE PRESENTATION: Female patient, 64 years old, Caucasian, in whom was noticed firstly dark urine, without haematuria or dysuria. Later felt also colic pain in the hypogastric region. Microscopically, the conclusive diagnosis was a high grade non-invasive papillary urothelial carcinoma. Thereupon, the treatment of the tumour began with transurethral resection technique and intravesical instillation of Calmette-Guérin Bacillus as adjuvant treatment. Eight months after the beginning of treatment, the lingering presence of the carcinoma was identified. Nevertheless, arthritis was identified through radiographs, after an increase in the clavicle capitation, right knee and left ankle in bone scintigraphy. Coinciding with the joint manifestations, the patient developed fever and purulent urethral discharge (culture was negative). Therefore, trying to investigate the cause of the arthritis, Purified Protein Derivate was taken, with reactive results. An increase of acute phase reactants was found, with other tests resulting normal: blood chemistry, Complete Blood Count, immunology and serology. Human Leukocyte Antigen typing by polymerase chain reaction revealed the presence of A24/AX, B44, B27, BW4/BW4, DQ7 and DQ5. Consequently, Poncet's disease was the diagnostic conclusion. The treatment with intravesical Calmette-Guérin Bacillus was immediately discontinued. The patient received corticosteroids associated with etoricoxib and isoniazid for 4 months, achieving disappearance of the inflammatory joint signs in 3 months. After 6 months, no joint pain recurrence or other manifestations suggesting active disease had been seen. CONCLUSIONS: Therefore, such diagnosis should be considered when confronted with an osteoarticular clinical picture in patients treated with intravesical Calmette-Guérin Bacillus, especially patients with HLA-B27 (+) and B7 (+), as Poncet's disease is a reactive arthritis.

Articular nociception induced by endothelin-1, carrageenan and LPS in naive and previously inflamed knee-joints in the rat: inhibition by endothelin receptor antagonists.

Endothelin-1, unlike the selective endothelin ETB receptor agonist sarafotoxin S6c, causes nociception in the rat when injected intraarticularly into the naive knee-joint. By using selective antagonists, the present study further characterizes the receptors underlying the articular nociceptive actions of endothelin-1, as well as the possible contribution of endogenous endothelins towards nociception induced by carrageenan or E. coli lipopolysaccharide (LPS) in this tissue. Nociception was evaluated by placing the animal for 1 min each hour on a revolving (3 rpm) cylinder and measuring the increase in time the hindpaw of the limb affected by the intra-articular (i.a.) injection of the nociceptive agent, failed to touch its metallic surface (i.e. paw elevation time, PET). In naive joints, endothelin-1 (120 pmol) increased the area under the PET curve (AUC 0-6 h, in arbitrary units) from 61+/-3 (control) to 156+/-12. This nociceptive effect was reduced by prior intravenous (i.v.) injection of the mixed ET(A)/ET(B)receptor antagonist bosentan (by 54 and 73% with 10 and 30 mg/kg) or i.a. administration of the selective ETA receptor antagonist BQ-123 (cyclo [D-Asp-Pro-D-Val-Leu]; by approximately/= 45% with 10 or 30 nmol), but was unaffected by the selective ET(B) receptor antagonist BQ-788 (N-cis-2,6-dimethyl-piperidinocarbonyl-L-gamma-methoxycarbonyl- tryptophanil-D-norleucine; 10 nmol). Prior joint challenge with carrageenan (300 microg) 72 h beforehand (i.e. priming) rendered the joint more sensitive to nociception induced by either endothelin-1 or sarafotoxin S6c (15, 30 and 60 pmol). Responses elicited by endothelin (30 pmol) in the primed joint were sensitive to inhibition by either BQ-123 or BQ-788 (each causing approximately/= 80% inhibition at 10 nmol). Priming also enhanced PET responses to carrageenan itself and to LPS (1 microg) markedly and persistently, increasing the area under the curve (AUC 0-12 h, in arbitrary units) from 241+/-19 to 409+/-50 and from 312+/-40 to 466+/-25, respectively (P < 0.05), without changing that measured following vehicle injection (from 121+/-3 to 117+/-4). Bosentan (up to 30 mg/kg, i.v.) failed to modify nociception caused by carrageenan or LPS in naive joints, by carrageenan in the primed joint, or control PET responses. LPS-induced nociception in the primed joint, however, was inhibited by 52 to 56% by bosentan (3 or 10 mg/kg) or 59% by local injection of the selective endothelin ET(B) receptor antagonist BQ-788 (10 nmol, i.a.), but was unaffected by the selective endothelin ETA receptor antagonist BQ-123. Thus, nociception induced by endothelin-1 in the naive joint is mediated largely via endothelin ETA receptors, whereas both ET(A)and ET(B) receptors contribute to its action in the carrageenan-primed joint. Furthermore, LPS-induced nociception in the primed joint is mediated to a large extent via endothelin release and activation of ET(B) receptors within the joint itself. These findings may be relevant to the etiology of pain underlying chronic arthritic disease in humans.

Reactive arthritis associated with typhoid vaccination in travelers: report of two cases with negative HLA-B27.

As international travel to developing countries increases, more people seek medical advice concerning food and water-borne diseases, including typhoid fever. Prevention of typhoid fever in high-risk groups (travelers to endemic areas, laboratory workers and household contacts of typhoid carriers) should rely primarily on prevention of exposure. However, immunization is an important adjunct. The decision to immunize against typhoid fever should be individualized, taking into account the benefits versus the risk of possible adverse reactions. Cases of reactive arthritis have been associated with the heat-phenol inactivated 'whole cell' parenteral vaccine, but to our knowledge reactive arthritis has not been previously reported with the oral form (Ty21a). This is a report of HLA-B27 negative reactive arthritis occurring in two travelers after the administration of oral Ty21a typhoid vaccine.

[Formaldehyde in the occupational environment. A possible cause of chemically induced reactive arthritis]. / Formaldehyd i arbejdsmiljøet. En mulig årsag til kemisk induceret reaktiv arthritis.

A case is presented of a farmer aged 33 years who developed polyarthritis four to five days after having used formaldehyde for fumigation of his piggery. The farmer was admitted to the General Hospital in Herning for treatment. The course of the treatment was several months. Furthermore, two farm assistants and a bricklayer were exposed to formaldehyde in the piggery. They developed acute intoxication symptoms and, a few days after the exposure, arthralgia. There was no other collective exposure. Apart from the formaldehyde, there was a great amount of water in the piggery, leading to the conclusion that the exposure was due to the formaldehyde being absorbed in the water with following evaporation. In conclusion, a relationship between these particular circumstances of formaldehyde exposure and reactive arthritis is found to be likely.

[Reiter's syndrome exacerbated by indomethacin]. / Síndrome de Reiter exacerbado por indometacina.

A 26-year-old man, with a personal history of drug abuse and positive serology for HIV, had Reiter's syndrome for six years. He experienced progressive worsening of his cutaneous lesions after initiation of indomethacin therapy. The skin lesions were almost completely resolved after the discontinuance of the drug and its reintroduction resulted in a similar deterioration. To our knowledge, indomethacin has not been reported to aggravate Reiter's syndrome. This case study documents anti-inflammatory drugs as possible causal factors for triggering Reiter's syndrome. Possible implicated mechanisms are also discussed.