Unintended Consequences of Immune Therapy for Immune-Mediated Diseases: Paradoxical Psoriasis and Dupilumab-Associated Musculoskeletal Syndrome.

Two presentations at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual meeting focused on unintended consequences of immunomodulatory therapy for psoriasis (PsO). Dr. Elizabeth Wallace presented on unintended consequences of tumor necrosis factor inhibitors for treating PsO and other inflammatory disorders. These consequences include paradoxical PsO, which is defined as unexpected new PsO cases or worsening PsO symptoms seemingly induced by treatment. Dr. Bruce Kirkham focused on unintended consequences of dupilumab treatment, which can include a musculoskeletal syndrome similar to psoriatic arthritis.

The Role of Mesenchymal Stem Cells (MSCs) in Veterinary Medicine and Their Use in Musculoskeletal Disorders.

Regenerative medicine is a dynamically developing field of human and veterinary medicine. The animal model was most commonly used for mesenchymal stem cells (MSCs) treatment in experimental and preclinical studies with a satisfactory therapeutic effect. Year by year, the need for alternative treatments in veterinary medicine is increasing, and other applications for promising MSCs and their biological derivatives are constantly being sought. There is also an increase in demand for other methods of treating disease states, of which the classical treatment methods did not bring the desired results. Cell therapy can be a realistic option for treating human and animal diseases in the near future and therefore additional research is needed to optimize cell origins, numbers, or application methods in order to standardize the treatment process and assess its effects. The aim of the following work was to summarize available knowledge about stem cells in veterinary medicine and their possible application in the treatment of chosen musculoskeletal disorders in dogs and horses.

Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab.

We investigated risk factors for immune-related adverse events (irAEs) in patients treated with anti-programmed cell death protein1 antibody pembrolizumab. A retrospective medical record review was performed to identify all patients who received at least one dose of pembrolizumab at Samsung Medical Center, Seoul, Korea between June 2015 and December 2017. Three hundred and ninety-one patients were included in the study. Data were collected on baseline characteristics, treatment details, and adverse events. Univariate and multivariate logistic regression models were used to identify risk factors for irAEs. Sixty-seven (17.1%) patients experienced clinically significant irAEs; most commonly dermatologic disorders, followed by pneumonitis, musculoskeletal disorders, and endocrine disorders. Fourteen patients (3.6%) experienced serious irAEs (grade ≥ 3). Most common serious irAEs were pneumonitis (2.3%). Four deaths were associated with irAEs, all of which were due to pneumonitis. In multivariate regression analysis, a higher body mass index (BMI) and multiple cycles of pembrolizumab were associated with higher risk of irAEs (BMI: odds ratio [OR] 1.08, 95% confidence interval [CI] 1.01-1.16; pembrolizumab cycle: OR 1.15, 95% CI 1.08-1.22). A derived neutrophil-lymphocyte ratio (dNLR) greater than 3 at baseline was correlated with low risk of irAEs (OR 0.37, 95% CI 0.17-0.81). Our study demonstrated that an elevated BMI and higher number of cycles of pembrolizumab were associated with an increased risk of irAEs in patients treated with pembrolizumab. Additionally, increased dNLR at baseline was negatively correlated with the risk of developing irAEs.

Immune-related adverse events following administration of anti-cytotoxic T-lymphocyte-associated protein-4 drugs: a comprehensive systematic review and meta-analysis.

Objective: Administration of drugs targeting anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is often associated with serious immune-related adverse events (irAEs). Here, we performed a comprehensive analysis of organ-specific irAEs and treatment-related hematologic abnormalities and musculoskeletal disorders resulting from anti-CTLA-4 treatment. Materials and methods: PubMed, the Cochrane library, Web of Science, and ClinicalTrials.gov were searched for studies between January 1990 and March 2018 reporting AEs associated with anti-CTLA-4 therapies. Results: A total of 11 clinical trials with 7,088 patients were included; of these, data were accessible for 10 on ClinicalTrials.gov. Compared with control therapies (placebo, chemotherapy, radiation therapy, or vaccine), anti-CTLA-4 therapies (ipilimumab and tremelimumab) were associated with an increased risk of serious irAEs, predominantly dermatologic (rash: odds ratio [OR] 3.39, P<0.01), gastrointestinal (diarrhea and colitis: OR 6.57 and 14.01, respectively; both P<0.001), endocrine (hypophysitis, hypothyroidism, adrenal insufficiency, and hypopituitarism: OR 4.22, 3.72, 3.77, and 4.73, respectively; all P<0.05), and hepatic (hepatitis, elevated alanine aminotransferase, and elevated aspartate aminotransferase: OR 4.44, 3.28, and 3.12, respectively; all P<0.05). The most common serious organ-specific irAEs were gastrointestinal (diarrhea 9.8% and colitis 5.3%). Although the incidence of selected events was higher in anti-CTLA-4-treated patients, no significant differences were found between anti-CTLA-4 and the control therapies in treatment-related hematologic abnormalities or severe musculoskeletal disorders. Conclusion: Anti-CTLA-4 therapies are associated with an increased risk of serious organ-specific irAEs, most frequently involving the gastrointestinal system; however, no increased risk of hematologic abnormalities or severe musculoskeletal disorders was detected compared with other therapies. These results underscore the need for clinical awareness and prompt and effective management of multi-organ irAEs related to anti-CTLA-4 drugs.

Rheumatic paraneoplastic syndromes - A clinical link between malignancy and autoimmunity.

Paraneoplastic syndromes are rare but can have enormous clinical impact on diagnosis and outcome of neoplastic diseases. The rheumatologist should be familiar with a few typical musculoskeletal manifestations of malignancies to be able to diagnose them early for a timely initiation of anti-tumour therapies. This review describes the characteristic features of various paraneoplastic arthritides and vasculitides, cancer-associated myositis, hypertrophic osteoarthropathy, and tumour-induced osteomalacia. In addition, the current knowledge about underlying pathomechanisms of these syndromes is discussed.

Dendrimers: Breaking the paradigm of current musculoskeletal autoimmune therapies.

The advances achieved by cell-based therapies to treat autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS), despite promising, are still insufficient for the current demands. RA and MS therapeutic approaches follow world guidelines to use disease modifying drugs and biological agents that, regardless of some good results in clinical outcomes, are well known for several systemic secondary side effects. Dendrimers are custom-made nanoparticles with proved clinical potential, displaying proper size, chemistries, immunomodulatory, and anti-inflammatory properties. This has directed their potential use as drug delivery systems for cancer therapy, for instance. This review manuscript discloses the hidden potential behind dendrimers as alternative viable solutions to treat RA and MS, by focusing in the most recent reports describing the use of dendrimers for suppressing inflammation and possibly preventing disease progression. The advantages of their use as compared with current applied therapies is also discussed herein.

Immune-related musculoskeletal toxicities among cancer patients treated with immune checkpoint inhibitors: a systematic review.

AIM: Immune-related musculoskeletal toxicities are uncommon but potentially serious adverse events; and they may accompany the use of immune checkpoint inhibitors (ICIs). The objective of this systematic review is to assess the patterns of these musculoskeletal toxicities. METHODS & RESULTS: PubMed database has been searched till May 2017. Clinical studies and case reports reporting the occurrence of immune-related musculoskeletal toxicities (other than arthralgia and myalgia) in cancer patients treated with ICIs were included. Eight trials with 2263 participants were included. Likewise, nine case reports reporting the outcomes of 12 patients were included. CONCLUSION: Immune-related arthritis and myositis occur uncommonly in cancer patients treated with ICIs. Further studies are required to better describe the pathogenesis as well as the time course of these events.

Modulation of the peripheral immune system after low-dose radon spa therapy: Detailed longitudinal immune monitoring of patients within the RAD-ON01 study.

The pain-relieving effects of low-dose radon therapies on patients suffering from chronic painful inflammatory diseases have been described for centuries. Even though it has been suggested that low doses of radiation may attenuate chronic inflammation, the underlying mechanisms remain elusive. Thus, the RAD-ON01 study was initiated to examine the effects of radon spa therapy and its low doses of alpha radiation on the human immune system. In addition to an evaluation of pain parameters, blood was drawn from 100 patients suffering from chronic painful degenerative musculoskeletal diseases before as well as 6, 12, 18, and 30 weeks after the start of therapy. We verified significant long-term pain reduction for the majority of patients which was accompanied by modulations of the peripheral immune cells. Detailed immune monitoring was performed using a multicolor flow cytometry-based whole blood assay. After therapy, the major immune cells were only marginally affected. Nevertheless, a small but long-lasting increase in T cells and monocytes was observed. Moreover, neutrophils, eosinophils and, in particular, dendritic cells were temporarily modulated after therapy. Regarding the immune cell subsets, cytotoxic T and NK cells, in particular, were altered. However, the most prominent effects were identified in a strong reduction of the activation marker CD69 on T, B, and NK cells. Simultaneously, the percentage of HLA-DR+ T cells was elevated after therapy. The RAD-ON01 study showed for the first time a modulation of the peripheral immune cells following standard radon spa therapy. These modulations are in line with attenuation of inflammation.

Musculoskeletal manifestations in inflammatory bowel disease: a revisit in search of immunopathophysiological mechanisms.

Inflammatory bowel diseases are chronic inflammatory disorders of multiple organ systems, primarily involving the gut, with chronic relapsing and remitting course. Musculoskeletal involvement is the most common extraintestinal manifestation. Distinct cell-mediated and humoral immunopathophysiological mechanisms have been identified underlying gut and joint inflammation in patients with inflammatory bowel disease and arthritis. Genetic polymorphisms in genes coding for NOD2 and IL12/IL23 complex lead to impaired antigenic handling in the gut and local immune dysregulation. The gut-synovial axis hypothesis implicates both environmental and host factors acting as triggers to initiate inflammation in genetically predisposed individuals, leading to priming of Th1 and Th17 lymphocytes in the gut and subsequent homing to the synovial tissue. Similar to gut, antibody-dependent cell-mediated cytotoxicity and complement-mediated cell lysis may also contribute to the joint damage. Involvement of peripheral joints occurs in 2 distinct manners, one being oligoarticular asymmetric arthritis associated with active disease and the other being polyarticular symmetric involvement of small joints. The axial involvement may include asymptomatic sacroiliitis, inflammatory back pain, and ankylosing spondylitis, running an independent clinical course. Noninflammatory involvement of the musculoskeletal system may present as osteopenia, osteonecrosis, fibromyalgia, or myopathies, leading to significant impact on quality of life.

Musculoskeletal problems in persons with inhibitors: how do we treat?

Inhibitors are a serious complication, considerably increasing the morbidity, mortality and cost of treatment in this patient group. The challenge of treating people with haemophilia (PWH) with inhibitors can be met by a well-coordinated multidisciplinary team specialized in haemophilia. Each treatment centre must run a screening programme to detect inhibitors within their population and develop protocols to treat these patients. The treatment centre in Buenos Aires developed a screening programme that tests all our patients twice a year, ensuring early detection of inhibitors and early treatment of complications. In 2006, we analysed the quality of life (QOL) of non-inhibitor patients and compared it with inhibitor patients detected by this programme and found no differences in QOL measured by the SF36 questionnaire and no differences in school absenteeism. When diagnosis of the inhibitor does not come from a screening programme, its presence is suspected upon a lack of response to conventional replacement therapy for musculoskeletal bleeding, losing the 'golden moment' of treatment. This complication is much more serious when facing a traumatic bleed. In this situation, the lack of early diagnosis can lead to permanent damage or even death. Due to the cost of bypassing factors and the lack of experience of the medical team in the treatment of patients with inhibitors, many treatments that would improve the QOL of patients are instituted in an insufficient manner. Therefore, patients with haemophilia and inhibitors are often untreated or undertreated in their community. Orthopaedic surgeons and physiotherapists play a key role in the treatment of these patients and should be included in therapeutic decision making and most specifically in the postoperative treatment of patients with haemophilia and inhibitors. It is important that these patients have quick access to a trained therapeutic team in order to obtain an early diagnosis and treatment plan to prevent the evolution of the pathological process. Early treatment is cost-effective in maintaining and improving the QOL of patients. Experience in patients with haemophilia and inhibitors is not very extensive. Today, this situation is changing, with several treatment centres beginning to perform surgeries in these most complex patients, giving them a chance to improve their QOL. This article presents the experience of experts from various fields involved in treating patients with inhibitors from a developed and developing world perspective.

Serious musculoskeletal infections in children receiving anti-tumor necrosis factor-alpha therapy: a case series.

Anti-tumor necrosis factor-alpha (anti-TNF-alpha) agents are widely used to treat children with juvenile idiopathic arthritis (JIA) whose disease is resistant to conventional therapy. Although generally well tolerated, use of these agents has been associated with an increased risk of infection. In particular, in patients treated with anti-TNF-alpha agents, there is an increased susceptibility to infection by intracellular organisms such as tuberculosis, and common infections may present atypically or be more severe. We report four cases of serious musculoskeletal infections among 31 children with JIA being treated with anti-TNF-alpha agents, two of which were secondary to group A beta-hemolytic Streptococcus.

Rheumatic manifestations of endocrine diseases.

PURPOSE OF REVIEW: Musculoskeletal complaints accompanying or as a result of endocrine disorders are common and have been well described. This review re-examines these associations in light of newer information on biology and genetics. RECENT FINDINGS: In this article, we describe the recent studies on pathophysiology of the muscular skeletal complaints in endocrine disease. In addition we report on population as well as genetic studies, which address the relationship between endocrine and rheumatologic disease, both of which are autoimmune. SUMMARY: Very often, the presentation of rheumatic manifestations is the initial presentation of endocrine disease. Being aware of the presentation as well as the unique physiology of these complaints will help alert the clinician to an early diagnosis of endocrine disease. In addition understanding whether certain endocrine disease occurs more often in rheumatologic illness will enable the clinician to investigate their occurrence early, leading to earlier intervention and resulting in decreased morbidity from these concomitant illnesses.

Rheumatic manifestations of sleep disorders.

PURPOSE OF REVIEW: We have long assumed that rheumatic pain causes sleep problems, fatigue, and functional disability. This paper reviews the accumulating evidence from human and animal experimental research studies that show a bidirectional relationship of disordered sleep to pain and fatigue. RECENT FINDINGS: The studies demonstrate that both disturbances of sleep and sleep restriction result in increased sensitivity to noxious stimuli and musculoskeletal pain symptoms. The notion of central nervous system hypersensitivity affecting widespread pain in patients with fibromyalgia syndrome is the result of a reduction in neurophysiologic inhibition of perception of noxious stimuli that is provoked by disordered sleep. Clinical and epidemiological studies show that sleep disturbances directly influence musculoskeletal pain, fatigue, mood, and overall well-being. Indeed, the interrelationships of the sleeping/waking brain with cytokine and cellular immune functions have important implications for the understanding of rheumatic disease pathology and management with disease-modifying antirheumatic drugs. SUMMARY: The determination of how disordered sleep affects musculoskeletal pain, fatigue, mood, and behavior is important in the assessment and management of patients with rheumatic illness. The high prevalence of obstructive sleep apnea and restless legs syndromes requires more research to determine whether treatments of these sleep disorders will benefit the symptoms of rheumatic diseases.

CD146+ T lymphocytes are increased in both the peripheral circulation and in the synovial effusions of patients with various musculoskeletal diseases and display pro-inflammatory gene profiles.

Twenty-eight synovial effusions (SE) were obtained from 24 patients, paired samples of peripheral blood (PB) from 10 of these patients, and PB from 36 healthy individuals for analysis of CD146 on T-lymphocytes by flow cytometry. CD146+ or CD146- T-lymphocytes were sorted from three SE to study gene expression profiles and selected genes revalidated using QPCR assays. We found more CD3+CD146+ and CD4+CD146+ T-lymphocytes in PB from patients compared with PB of healthy individuals (4.71% +/- 2.48% vs. 2.53% +/- 1.08%, P = 0.028) and (6.29% +/- 2.74% vs. 2.41% +/- 0.96%, P = 0.0017), respectively, whereas CD8+CD146+ T-lymphocytes were not significantly different (2.55% +/- 1.65% vs. 3.18% +/- 2.59%, P = 0.5008). SE displayed CD146 staining on 16.32% +/- 6.06% of CD3+ cells. This expression was skewed toward CD4+ T-lymphocytes, with CD146 present on 24.06% +/- 8.20% of the CD4+ T-lymphocytes compared with 6.19% +/- 5.22% of the CD8+ T-lymphocytes. CD146 on CD3+, CD4+ and CD8+ T-lymphocytes in SE was significantly higher compared with PB in patients (P < 0.0001, P < 0.0001 and P = 0.0036, respectively). Gene expression profiles of sorted CD146+CD4+CD3+ vs. CD146-CD4+CD3+ T-lymphocytes (n = 2) and CD2+CD146+ vs. CD2+CD 146- (n = 1) from SE, displayed increased CD146, LAIR2, CXCL13, CD109, IL6ST, IL6R, TNFRsf18, and TNFRsf4 genes, whereas decreased CCR7, CCL5, and cytotoxicity-associated genes including granzymes b, h, and k, perforin were found with the CD146- T-lymphocytes. By QPCR higher mRNA expression of CXCL13, CD146 and CD109 was also noted in the CD146+ subset, compared with the CD146- subset, in PB of healthy individuals and in PB and SE from patients. Our study establishes increased CD146+ T-lymphocytes in diseases with joint effusions, and demonstrates pro-inflammatory gene profiles in these cells.

Major orthopaedic surgeries for haemophilia with inhibitors using rFVIIa.

SUMMARY: Between 2000 and 2008, 11 major orthopaedic surgeries for 7 congenital haemophilia patients with inhibitors were performed by the first author as the primary doctor using recombinant activated factor VII (rFVIIa). Orthopaedic surgical treatments were performed for six surgeries for four high-responder haemophilia A patients, three surgeries for two high-responder haemophilia B patients and two surgeries for one low-responder haemophilia B patient. This low-responder patient is allergic to factor IX products, so he usually uses rFVIIa as a haemostatic agent. All of the surgeries were major, such as joint arthroplasty, arthroscopic synovectomy, and a combination of both, and excellent surgical results were achieved. Seven cases were controlled by bolus infusion of rFVIIa, and the other four cases were controlled by combined bolus and continuous infusion of rFVIIa. An anti-fibrolytic agent was used for all cases. There were no thrombogenic adverse effects, only two bleeding episodes. As for haemostatic control, nine surgeries were excellent, one was good and one was fair. This report is the largest clinical report on major orthopaedic surgeries at a single institute. We have concluded that the combination of bolus and continuous infusion of rFVIIa is safe and effective, and more convenient to administer than simple bolus infusion therapy to achieve haemostasis at peri-operative periods. In addition, our data also concurs with the data of several previous reports which showed that orthopaedic surgery for haemophilia patients with inhibitors by means of rFVIIa is safe and effective.

[Current treatment of systemic sclerosis. Part I. Immunosuppressive treatment]. / Wspólczesne metody leczenia twardziny ukladowej. Czsc I. Leczenie immunosupresyjne.

Systemic sclerosis (scleroderma) has a complex pathogenesis. Thus, management of systemic sclerosis remains a challenge. Currently, treatment in systemic sclerosis is targeted at reducing 1) abnormal immune activation, 2) microvascular abnormalities and 3) fibrosis. Therapy should be adjusted individually, depending on disease subtype and activity. Immunosuppressive agents, such as cyclophosphamide or mycophenolate mofetil and occasionally methotrexate or cyclosporine A are indicated in rapidly progressing systemic sclerosis. Low or moderate doses of corticosteroids may be used in patients with musculoskeletal involvement. Reports of effective biological therapy with rituximab or infliximab are available. In cases of rapidly progressing systemic sclerosis high dose immunosuppressive or cytostatic agents with subsequent autologous bone marrow transplantation may be indicated. Novel therapies have the potential of significantly modifying disease process and improving overall clinical outcome in patients with systemic sclerosis.

The prevalence of generalized soft tissue rheumatic conditions in Turkish medical students.

OBJECTIVE: To assess the prevalence of generalized soft tissue rheumatism (GSTR) in medical students in Izmir, Turkey. METHODS: Medical students from each grade of Medical School of Ege University, Izmir, Turkey, were evaluated by a survey and physical examination for GSTR including fibromyalgia (FM) syndrome, myofascial pain syndrome (MPS), benign joint hypermobility syndrome (BJHS), and chronic fatigue syndrome. FM Impact Questionnaire was assessed in FM diagnosed students. Short Form-36 (SF-36) was obtained from each student to determine the quality of life. RESULTS: Among the participants (n = 306), 191 were women (62.4%) and 115 were men (37.6%) and mean age was 20.23 +/- 1.56. Fifty-eight students (19%) were diagnosed with a GSTR. The distributions of the diagnoses were: 6 (2%) FM, 21 (6.9%) MPS, 28 (9.2%) BJHS, 1 (0.3%) chronic fatigue syndrome, and 2 students (0.7%) had both BJHS and MPS. Fifty-three (27.7%) women and 5 (4.3%) men were diagnosed with a GSTR (P < 0.01). Mean FM Impact Questionnaire score was 50.8 in FM diagnosed students. Physical role, vitality, and mental subscores of SF-36 were significantly lower in the students having a GSTR (P < 0.05). CONCLUSION: This is the first study performed in medical students to find out the prevalence of generalized soft tissue rheumatic conditions. Although medical students are under high stress due to hard training, the prevalence of GSTR in medical students was found similar to previous reports in the general population.

Musculoskeletal syndromes associated with malignancy (excluding hypertrophic osteoarthropathy).

PURPOSE OF REVIEW: To examine recent data about the association between rheumatic disorders and cancer. This article focuses on paraneoplastic rheumatic disorders, which usually precede by a short period of time the diagnosis of malignancy, and on malignant transformation, which occurs late in the course of rheumatic disorders. Evidence of causality between malignancies and rheumatic disorders was reviewed based on statistical indicators (standardized incidence ratios and odds ratios) and by applying Bradford Hill's criteria of causality. RECENT FINDINGS: Firm epidemiological evidence was found attesting that dermatomyositis and polymyostis may present as paraneoplastic syndromes. Several other musculoskeletal disorders may be present akin to paraneoplastic syndrome, based on clinicians' impressions, but with scarce epidemiological evidence supporting a causal determinism. In contrast, robust evidence has accumulated on the role of longstanding rheumatoid arthritis, Sjögren's syndrome and systemic sclerosis as premalignant conditions. Evidence that systemic lupus erythematosus may evolve into lymphoma is equivocal. SUMMARY: The link between malignancies and rheumatic disorders may impact on clinical practice. First, paraneoplastic rheumatic syndromes can provide the clinician with hints for earlier diagnosis of occult cancer. Second, the risk of malignant transformation during the course of rheumatic disorders may motivate the search for strategies aimed at prevention.

Recombinant activated factor VII for haemophilia patients with inhibitors undergoing orthopaedic surgery: a review of the literature.

Arthropathy is prevalent in patients with haemophilia and inhibitors and is a major source of pain and disability, significantly reducing quality of life. Recombinant activated factor VII (rFVIIa; NovoSeven is one of the treatments available for acute life-threatening bleeding episodes in haemophilia patients with inhibitors. It has also been used successfully in a range of orthopaedic surgical procedures in these patients. This is a review of published data on elective orthopaedic procedures in haemophilia patients with inhibitors under cover of rFVIIa from January 2002 to November 2006. Articles were retrieved from MEDLINE using specified search parameters. Twelve articles covering a total of 80 orthopaedic procedures were identified. In the vast majority of cases, rFVIIa provided safe and effective haemostatic cover during orthopaedic surgery with no bleeding complications. There was variation in the administered dose, although the majority of patients were treated with 90 mug kg(-1) bolus followed by either continuous infusion or bolus infusion. Of those cases reporting bleeding complications, most were considered to be related to an inadequate amount of rFVIIa. The cumulative experience presented here suggests that rFVIIa is safe and effective for providing adequate haemostatic cover for haemophilia patients with inhibitors undergoing orthopaedic surgery. The optimal dosing regimen and mode of administration has yet to be identified. Further controlled trials are needed to confirm these experiences.