Perioperative management of patients with inflammatory rheumatic diseases : Updated recommendations of the German Society for Rheumatology.

BACKGROUND: Prior to surgical interventions physicians and patients with inflammatory rheumatic diseases remain concerned about interrupting or continuing anti-inflammatory medication. For this reason, the German Society for Rheumatology has updated its recommendations from 2014. METHODS: After a systematic literature search including publications up to 31 August 2021, the recommendations on the use of of glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics (bDMARDs) were revised and recommendations on newer drugs and targeted synthetic (ts)DMARDs were added. RESULTS: The glucocorticoid dose should be reduced to as low as possible 2-3 months before elective surgery (in any case <10 mg/day) but should be kept stable 1-2 weeks before and on the day of surgery. In many cases csDMARDs can be continued, exceptions being a reduction of high methotrexate doses to ≤15 mg/week and wash-out of leflunomide if there is a high risk of infection. Azathioprine, mycophenolate and ciclosporin should be paused 1-2 days prior to surgery. Under bDMARDs surgery can be scheduled for the end of each treatment interval. For major interventions Janus kinase (JAK) inhibitors should be paused for 3-4 days. Apremilast can be continued. If interruption is necessary, treatment should be restarted as soon as possible for all substances, depending on wound healing. CONCLUSION: Whether bDMARDs increase the perioperative risk of infection and the benefits and risks of discontinuation remain unclear based on the currently available evidence. To minimize the risk of a disease relapse under longer treatment pauses, in the updated recommendations the perioperative interruption of bDMARDs was reduced from at least two half-lives to one treatment interval.

Therapeutic consequences in patients with both inflammatory rheumatic diseases and multiple sclerosis.

Dealing with patients with both multiple sclerosis (MS) and inflammatory rheumatic disorders (IRDs) is not uncommon for a rheumatologist, as there is a statistical association between SpA and MS. As several CNS demyelinating events have been reported in patients treated with TNF inhibitor (TNFi), the pre-existing demyelinating disease was considered a contraindication for TNFi. However, this contraindication is mainly based on a randomized controlled trial in MS and not on large epidemiological studies. According to the last epidemiological studies, TNFi might not be an inducer of MS. Moreover, there are no clear recommendations on the use of the other DMARDs in patients suffering from an IRD and MS. In this review, we summarize the link between MS and IRDs and the impact of DMARDs on MS, especially TNFi. We also look at the impact of disease-modifying drugs for adults with MS and IRDs.

[Management of inflammatory rheumatic diseases during and after malignancies]. / Management von entzündlich rheumatischen Erkrankungen während und nach Malignomen.

The management of inflammatory rheumatic diseases in patients with a simultaneous or previous malignant disease is associated with complex questions. Difficulties and possible solutions in the interpretation of meaningful studies are presented. Recommendations in guidelines on this topic are discussed. National registries and health insurance databases were examined with respect to the risk of tumor recurrence under disease-modifying antirheumatic drugs; however, these analyses mainly refer to tumor necrosis factor (TNF) inhibitors and rituximab. Data on tumor incidence and, if available, risk of tumor recurrence are summarized for commonly used disease-modifying antirheumatic drugs. Finally, an attempt is made to formulate proposals for rheumatological treatment in patients with a history of malignancy.

[Diagnostic issues of Whipple's disease during chronic inflammatory rheumatism: About three cases]. / Difficultés diagnostiques de la maladie de Whipple au cours des rhumatismes inflammatoires chroniques : trois observations.

INTRODUCTION: Whipple's disease (WD) can mimic chronic inflammatory rheumatism leading to incorrect prescription of tumor necrosis factor inhibitors (TNFI). Several complicated cases of WD have been reported during TNFI treatment which is strongly suspected to modify the host-pathogen relationship. Tropheryma whipplei asymptomatic carriage is high in the general population, making the diagnosis of WD more difficult face to unexplained arthritis. OBSERVATIONS: We report three observations that illustrate situations for which the detection of T. whipplei might be valuable to investigate the differential diagnosis of inflammatory rheumatism. CONCLUSION: The decision to check for T. whipplei infection should rely on individual clinical assessment. It should be considered in the absence of clinical response or in case of worsening of an inflammatory rheumatism under TNFI treatment, especially in front of atypical features. A systematic screening for T. whipplei before anti-TNF treatment seems unjustified since asymptomatic carriers are frequent.

Golimumab improves patient-reported outcomes in daily practice of inflammatory rheumatic diseases in Germany.

Aim: To analyze the quality of life (QoL), work productivity and activity impairment (WPAI) and healthcare resource utilization (HCRU) in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients receiving golimumab under routine clinical settings in Germany. Materials & methods: Prospective observational study, GO-ART, analyzed changes in WPAI, QoL and HCRU during 24 months of golimumab therapy. Results: Seven hundred and forty-eight patients (RA = 250, PsA = 249 and AS = 249) were enrolled. Substantial improvements in WPAI scores presenteeism, activity impairment and total work productivity impairment and QoL were observed at month three and were maintained through month 24. Fewer patients had disease-related hospitalizations and consulted physician at month 24 than at the baseline. Conclusion: Golimumab induces sustained improvements in WPAI and QoL and reduces healthcare resource utilization in RA, PsA and AS.

Mitigation of Rheumatic Arthritis in a Rat Model via Transdermal Delivery of Dapoxetine HCl Amalgamated as a Nanoplatform: In vitro and in vivo Assessment.

PURPOSE: Dapoxetine HCl (DH), a selective serotonin reuptake inhibitor, may be useful for the treatment of rheumatic arthritis (RA). The purpose of this study was to investigate the therapeutic efficacy of transdermal delivery of DH in transethosome nanovesicles (TENVs). This novel delivery of DH may overcome the drawbacks associated with orally administered DH and improve patient compliance. METHODS: DH-TENV formulations were prepared using an injection- sonication method and optimized using a 33 Box-Behnken-design with Design Expert® software. The TENV formulations were assessed for entrapment efficiency (EE-%), vesicle size, zeta potential, in vitro DH release, and skin permeation. The tolerability of the optimized DH-TENV gel was investigated using a rat skin irritation test. A pharmacokinetic analysis of the optimized DH-TENV gel was also conducted in rats. Moreover, the anti-RA activity of the optimized DH-TENV gel was assessed based on the RA-specific marker anti-cyclic cirtullinated peptide antibody (anti-CCP), the cartilage destruction marker cartilage oligomeric matrix protein (COMP) and the inflammatory marker interleukin-6 (IL-6). Level of tissue receptor activator of nuclear factor kappa-Β ligand (RANKL) were also assessed. RESULTS: The optimized DH-TENV formulation involved spherical nanovesicles that had an appropriate EE- % and skin permeation characteristic. The DH-TENV gel was well tolerated by rats. The pharmacokinetics analysis showed that the optimized DH-TENV gel boosted the bioavailability of the DH by 2.42- and 4.16-fold compared to the oral DH solution and the control DH gel, respectively. Moreover, it significantly reduced the serum anti-CCP, COMP and IL-6 levels and decreased the RANKL levels. Furthermore, the DH-TENV gel attenuated histopathological changes by almost normalizing the articular surface and synovial fluid. CONCLUSION: The results indicate that DH-TENVs can improve transdermal delivery of DH and thereby alleviate RA.

Osteoporosis therapy in patients with inflammatory rheumatic diseases and osteonecrosis of the jaw.

BACKGROUND AND OBJECTIVES: The aim of the present study was to assess the prevalence of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients suffering from inflammatory rheumatic diseases, as well as to assess the prevalence of relevant dental, behavioral, and medical risk factors for MRONJ. MATERIALS AND METHODS: A total of 198 patients with inflammatory rheumatic diseases and osteoporosis therapy were recruited from a tertiary rheumatological/immunological referral center between June 2015 and September 2016. They were assessed using a structured interview. A maxillofacial surgeon later examined patients complaining of possible symptoms of osteonecrosis. In cases of osteonecrosis, dental records were obtained and evaluated. Preventive measures taken and dental as well as other clinical risk factors were evaluated. RESULTS: Of the 198 patients, three suffered from osteonecrosis of the jaw, none of whom had any history of malignant disease or radiation therapy, resulting in a prevalence of 1.5%. Of these three patients, only one was given bisphosphonates intravenously (i.v.), whereas all three had been treated orally. All three diagnoses of MRONJ had been previously known to the patients and their maxillofacial surgeons. Two of the patients had rheumatoid arthritis, and one patient suffered from large vessel vasculitis. Long anti-osteoporotic treatment duration, low functional status, and low bone density of the femur were significantly associated with MRONJ development. CONCLUSION: Inflammatory rheumatic diseases constitute a risk factor for MRONJ in patients treated with bisphosphonates for osteoporosis. Patients should be counseled accordingly and should be offered dental screening and regular dental check-ups.

Clinic factors associated with better delivery of secondary prophylaxis in acute rheumatic fever management.

BACKGROUND AND OBJECTIVES: Acute rheumatic fever (ARF) is a complication of infection with group A streptococcus. ARF is treated with a long-term regimen of antibiotic secondary prophylaxis. Recent data have shown that only 36% of clients receive >80% of their regimen. The aim of this study was to determine clinic-level factors independently associated with the performance of primary healthcare clinics in delivering secondary prophylaxis to patients with ARF. METHOD: Cross-sectional de-identified data from clinics agreeing to data retention through the Audit and Best Practice for Chronic Disease National Research Partnership were accessed to calculate secondary prophylaxis performance scores and clinic-level factors associated with secondary prophylaxis performance using regression analysis. RESULTS: Thirty-six clinics and 496 client records met eligibility criteria for analysis. Clinic secondary prophylaxis performance was significantly associated with 'systematic processes of follow-up'. Every one unit increase in 'systematic approach to follow-up' increased the median level of secondary prophylaxis performance by 30% (95% confidence interval: 2, 66). Clinic accreditation status, location or workforce were not associated with secondary prophylaxis performance. DISCUSSION: General practitioners as clinical leaders are well placed to support managers to critically review follow-up and electronic reminder systems for secondary prophylaxis delivery at clinic level.

Report: Metformin potential in predisposing arthralgia, type II cross reactivity secondary to group A streptococcus infection & other comorbidities in treating PCOS.

One of the most common endocrinological disorder affecting women in adolescence is Polycystic Ovarian Syndrome (PCOS). Women suffering from PCOS diagnosed with follicles in ovaries show enlarged reproductive organs with small filled follicles. Unusual bleeding, prolonged menstruation, unwanted hair growth, accumulation of fat and acne are the most common problems experienced by adolescents with PCOS. Nowadays, PCOS is treated successfully with the oral antidiabetic drug, metformin and hormone replacement therapy. Its off-label use is still controversial with unknown mechanisms due to patient risk versus benefit hypothesis by practitioners as they successfully treat PCOS in adolescents with metformin. But in few reported cases metformin has potential to induce back pain and swollen joints less frequently with rare cases of behavior alteration. Penicillin belongs to the beta-lactam antibiotics and is most commonly used to treat rheumatic fever although it has potential to cause allergic reactions affecting 10% of patients who exhibit IgE-mediated immunological reactions. Here, we present a case of a female diagnosed with PCOS who after treatment with metformin for more than two years, reported with hyperuricemia, migraine, neurological pain, severe joint and knee pains on shoulders and legs, and rheumatic fever. After treatment with benzathine benzyl penicillin for rheumatic fever, the patient also exhibited Type IV delayed hypersensitivity reaction.

Case Report: Diffuse Cutaneous Leishmaniasis by Leishmania infantum in a Patient Undergoing Immunosuppressive Therapy: Risk Status in an Endemic Mediterranean Area.

This case report highlights the risk of severe cutaneous leishmaniasis (CL) by Leishmania infantum in patients undergoing immunosuppressant therapy who either live in an endemic area or are visiting in the transmission season. The case patient, resident in Majorca (Balearic Islands), presented 12 disseminated erythematous skin lesions, 1-6 cm in diameter, located on the scalp, cheek, umbilical region, and lower extremities 8 years after undergoing anti-tumor necrosis factor (TNF) therapy. Parasite presence in peripheral blood and high levels of specific antibodies were also observed, indicating a possible risk of CL shifting toward a visceral infection. However, once CL was diagnosed, anti-TNF therapy was discontinued and liposomal amphotericin B was administered, resulting in a complete healing of lesions, no Leishmania DNA detection in blood, and an important serological decrease in antibodies. The lack of data on the supposed epidemiological association between leishmaniasis and immunosuppressive therapy highlights the importance of implementing surveillance systems in endemic areas. No obvious relationship was found based on the data provided by the Balearic Islands Epidemiological System, in contrast with data reported in nearby endemic areas. This indicates that if the suspected association is to be clarified, greater efforts are needed to report information about concomitant diseases and therapies in leishmaniasis patients.

Safety and efficacy of etanercept-methotrexate combination therapy in patients with rhupus: an observational study of non-glucocorticoid treatment for rheumatic diseases.

OBJECTIVES: To evaluate the safety and efficacy of etanercept (ETN) plus methotrexate (MTX) in patients with rhupus without using corticosteroids. METHODS: Twenty rhupus patients [meeting the criteria for both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)] who had never been treated with corticosteroids, DMARDs, or biological agents with a 28-joint Disease Activity Score (DAS28) >3.2 and lupus nephritis determined from histopathological specimens were enrolled. All patients were treated with MTX plus ETN, and monitored for 24 weeks of treatment. Clinical efficacy was evaluated using the DAS28 and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). Demographic characteristics, clinical parameters, and treatment data were analyzed at baseline (BL) and after 4, 8, 16, and 24 weeks of treatment. The incidence of adverse events (AEs) was evaluated. RESULTS: The 20 patients had a mean age of 44.3±8 years and a disease duration of 5.4±3.1 years. At week 24, treatment with ETN plus MTX resulted in a significant improvement in DAS28 (3.3±0.1 vs. 6.0±0.1 /BL; p<0.001), tender joint count (2.9±0.2 vs. 10.75±0.8/BL; p<0.001), swollen joint count (2.7±0.2 vs. 8.5±0.5/BL; p<0.001), Visual Analog Scale for pain (27.0±2.6 mm vs. 66.5±3.1 mm/BL; p<0.001), and SLEDAI-2K (6.30±0.36 vs. 13.7±0.48/BL; p<0.001). During the study, the most frequent AEs were upper respiratory tract infections (10%), injection site reactions (10%), and cutaneous rashes (5%); there were no serious AEs. No deaths, malignancies, or tuberculosis or other serious infections were reported. CONCLUSION: Without corticosteroids, combination therapy of ETN plus MTX was relatively safe and effective in rhupus patients, which indicates efficacy of non-corticosteroid treatment for rhupus.

A 2018 Approach to Combating Methotrexate Toxicity Folic Acid and Beyond.

Methotrexate (MTX) is the cornerstone to management across a variety of rheumatic diseases. Effective use and adherence to MTX treatment is dependent on toxicity prevention and management. The major deterrents to patient tolerability and adherence can include GI upset, hepatic transaminase elevation, stomatitis, hair loss, and CNS toxicity. Many rheumatologists are familiar with employing supplementation of folic acid and folinic acid, as well as a change from oral to subcutaneous (SC) MTX, to help combat MTX toxicity. There are, however, more potential strategies in a rheumatologist's armamentarium to ameliorate side effects and improve adherence, including vitamin A supplementation and dextromethorphan. Herein, we will provide a review of the literature (both rheumatologic and oncologic) and expert opinion in terms of managing methotrexate toxicity and improving adherence in rheumatic diseases.

Pulse therapy combined with oral corticosteroids in the management of severe rheumatic carditis and rebound.

OBJECTIVE: The aim of the present study was to describe the clinical course, laboratory tests, and the cardiac involvement in rheumatic carditis patients in functional class III and IV, submitted to pulse therapy combined with oral prednisone. METHODS: A total of 120 patients with severe carditis due to acute rheumatic fever were treatment with three cycles of pulse therapy combined with oral corticosteroids. The patients were followed up from the hospital admission until the end of the treatment and returned after 30, 60, and 90 days to control. The patients were evaluated by clinical, laboratory, and transthoracic echocardiogram. RESULTS: In total, 23 (19.2%) patients at first attack of rheumatic fever and 97 (80.8%) with recurrent carditis were evaluated. Cardiac surgery was performed in 8 (6.6%) patients. The patients showed improved laboratory and radiological parameters (p<0.001) and were discharged, 74 (61.7%) in functional class I and 46 (38.3%) in functional class II. Hospitalisation time ranged from 21 to 176 days, with a mean of 69.1 days. Reduction of left atrium and ventricle diameters was observed, measured by means of transthoracic echocardiography, at hospital admission and discharge (p<0.001). None of the patients experienced rebound. CONCLUSIONS: The pulse therapy was effective in controlling severe rheumatic carditis and the oral corticosteroid prevented rebound episodes. Prolonged hospital stay was required for the clinical stabilisation of patients and to avoid the interruption of medication.

Phosphoinositide-3-kinases as the Novel Therapeutic Targets for the Inflammatory Diseases: Current and Future Perspectives.

OBJECTIVE: To review the role of PI3K/AKT/mTOR signalling pathway, and the current and future prospects of targeting PI3Ks for various diseases, like malignant, autoimmune, inflammatory, cardiovascular, neurological disorders etc., laying special emphasis on the inflammatory diseases and associated cellular responses. BACKGROUND: Recent findings have publicized phosphoinositide-3-kinases (PI3Ks) as novel therapeutic targets, which are also purported to be involved in the complex pathophysiology of inflammatory and various other diseases. They are recognized to participate in the inflammatory cellular responses by modulating the growth, development and proliferation of various immune cells and hence, affect the release of various cytokines and other inflammatory mediators involved in these manifestations. The recent literature relating this pathway with these diseases is highlighted, with a hope, which remains for the progression of PI3K inhibitors in the market as a treatment option. RESULT: With Idelalisib entering the market for cancer, PI3K/AKT signalling has also gained significance as an investigational target for various diseases, particularly for inflammation. Based on the pharmacological, genetic, and clinical data available, PI3K/AKT signalling can be designated as an outstanding target for their treatment. CONCLUSION: Further exploration of this pathway may also uncover its involvement in these disorders, which may further contribute to developing the new treatments and can turn out to be an innovative brainwave in the field of experimental and clinical pharmacology in future.

Fructose 1,6-bisphosphate, a high-energy intermediate of glycolysis, attenuates experimental arthritis by activating anti-inflammatory adenosinergic pathway.

Fructose 1,6-bisphosphate (FBP) is an endogenous intermediate of the glycolytic pathway. Exogenous administration of FBP has been shown to exert protective effects in a variety of ischemic injury models, which are attributed to its ability to sustain glycolysis and increase ATP production. Here, we demonstrated that a single treatment with FBP markedly attenuated arthritis, assessed by reduction of articular hyperalgesia, joint swelling, neutrophil infiltration and production of inflammatory cytokines, TNF and IL-6, while enhancing IL-10 production in two mouse models of arthritis. Our mechanistic studies showed that FBP reduces joint inflammation through the systemic generation of extracellular adenosine and subsequent activation of adenosine receptor A2a (A2aR). Moreover, we showed that FBP-induced adenosine generation requires hydrolysis of extracellular ATP through the activity of the ectonucleosides triphosphate diphosphohydrolase-1 (ENTPD1, also known as CD39) and ecto-5'-nucleotidase (E5NT, also known as CD73). In accordance, inhibition of CD39 and CD73 abolished anti-arthritic effects of FBP. Taken together, our findings provide a new insight into the molecular mechanism underlying the anti-inflammatory effect of FBP, showing that it effectively attenuates experimental arthritis by activating the anti-inflammatory adenosinergic pathway. Therefore, FBP may represent a new therapeutic strategy for treatment of rheumatoid arthritis (RA).

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis.

Monoclonal antibodies (mAbs) are increasingly used to treat rheumatoid arthritis (RA). At present, anti-tumor necrosis factor-α drugs (infliximab, adalimumab, certolizumab pegol, and golimumab), rituximab, and tocilizumab are approved for RA treatment. This review focuses on the pharmacokinetics and pharmacodynamics of mAbs approved in RA. Being large proteins, mAbs exhibit complex pharmacokinetic and pharmacodynamic properties. In particular, owing to the interactions of mAbs with their antigenic targets, the pharmacokinetics of mAbs depends on target turnover and exhibits non-specific (linear) and target-mediated (often nonlinear) clearances. Their volume of distribution is low (3-4 L) and their elimination half-life usually ranges from 2 to 3 weeks. The inter-individual pharmacokinetic variability of mAbs is usually large and is partly explained by differences in antigenic burden or by anti-drug antibodies, which accelerate mAb elimination. The inter-individual variability of clinical response is large and influenced by the pharmacokinetics. The analysis of mAbs concentration-effect relationship relies more and more often on pharmacokinetic-pharmacodynamic modeling; these models being suitable for dosing optimization. Even if adverse effects of mAbs used in RA are well known, the relationship between mAb concentration and adverse effects is poorly documented, especially for anti-tumor necrosis factor-α mAbs. Overall, RA patients treated with mAbs should benefit from individualized dosing strategies. Because of the complexity of their pharmacokinetics and mechanisms of action, the current dosing strategy of mAbs is not based on sound knowledge. New studies are needed to assess individual dosing regimen, adjusted notably to disease activity.

Whipple's disease diagnosed during anti-tumor necrosis factor alpha treatment: two case reports and review of the literature.

INTRODUCTION: Whipple's disease is a rare infectious disease caused by Tropheryma whipplei with protean clinical manifestations. This infection may mimic chronic inflammatory rheumatisms. CASE PRESENTATION: We report two cases of Whipple's disease diagnosed in the context of an inflammatory disease with anti-tumor necrosis factor alpha failure. The first patient was a 58-year-old white man with psoriatic spondylarthritis, who was treated with adalimumab, etanercept, infliximab, tocilizumab and golimumab. The second was a 73-year-old white man with rheumatoid arthritis, who received treatment with infliximab, then etanercept and rituximab. CONCLUSIONS: Whipple's disease should be suspected in all patients diagnosed with chronic inflammatory rheumatism, partially controlled or not controlled by treatment with tumor necrosis factor alpha blockers, whose condition worsens after treatment.

Rapidly Fatal Internal Carotid Artery Mycotic Aneurysm Rupture in a Rheumatoid Patient Taking a TNF-α Inhibitor: Case Report and Literature Review.

OBJECT: Tumor necrosis factor (TNF)-α inhibitors are effective at treating certain inflammatory and autoimmune disorders. They are generally safe; potential adverse events include infections (bacterial, fungal, and viral), congestive heart failure exacerbations, and the potential for demyelinating diseases and possibly certain malignancies. We present the first documented case of fungal internal carotid artery (ICA) mycotic aneurysm in a patient being treated with a TNF-α inhibitor. We also review the literature on infections with TNF-α inhibition and the management of previously reported fungal ICA mycotic aneurysm cases. CASE DESCRIPTION: A 76-year-old woman with rheumatoid arthritis, treated with etanercept and methotrexate, presented with a 2-week history of left temporal headaches. She was treated empirically for giant cell arteritis (GCA) with oral prednisone, which provided no symptom relief. She was subsequently hospitalized for a superficial temporal artery biopsy, which was negative for GCA. She returned 2 weeks later after experiencing a left thromboembolic ischemic stroke. She had an acute neurologic decline, and a head computed tomography scan showed diffuse subarachnoid hemorrhage from a ruptured left fusiform paraclinoid ICA aneurysm. She was taken emergently for a craniotomy for clip-wrapping of the aneurysm, but intraoperative ultrasound revealed poor flow in the left anterior cerebral circulation and a complete infarct of the left-sided anterior circulation. The family withdrew care and the patient died. Postmortem analysis demonstrated fungi consistent with Aspergillus invading the necrotic left ICA. CONCLUSIONS: Although fungal mycotic aneurysms of the ICA are rare, their incidence may increase with the expanded use of immunosuppressive medications. Patients with rheumatoid arthritis who take potent immunosuppression regimens may be prime candidates for mycotic aneurysms because they often have two favoring conditions: atherosclerosis and immunosuppression. These ICA aneurysms carry a high mortality rate, so early diagnosis and aggressive therapy, potentially by endovascular trapping/vessel occlusion coupled with long-term antifungal therapy, is essential.