Therapy insight: how the gut talks to the joints--inflammatory bowel disease and the spondyloarthropathies

Axial and peripheral arthritis can occur in up to 30% of patients with inflammatory bowel disease. Likewise, the presence of gut inflammation in primary spondyloarthropathies is underappreciated, with subclinical gut inflammation documented in up to two-thirds of patients with this group of inflammatory disorders. Common genetic and immunologic mechanisms underlie the coincidence of inflammation in the joints and the intestine. New research highlights the critical role of innate and adaptive immune responses directed against components of the enteric microbial flora in driving gut and articular inflammation. Indeed, elucidation of genetic and serological immune markers will define clinically important subgroups of patients with these heterogeneous diseases. The treatment of inflammatory articular manifestations of inflammatory bowel disease is similar to the treatment of primary spondyloarthropathies. A notable exception is the use of NSAIDs, which can precipitate flares of inflammatory bowel disease and should be used with caution. Agents that target tumor necrosis factor have been a major advance in the treatment of both gut and joint inflammation in inflammatory bowel disease.     

Valor diagnóstico del HLA-B27 en las espondiloartropatías

Spondyloarthropathies are chronic inflammatory diseases that share a wide range of clinical features, including spondylitis, sacroiliitis, pauciarticular peripheral arthritis, and enthesopathy. The pathogenesis is not well known, although all these diseases (ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis in patients with inflammatory bowel disease, some forms of juvenile idiopathic arthritis, and undifferentiated spondyloarthropathies) seem to have common genetic bases. In the last few years, several theories on the pathogenesis of these diseases have been postulated. Many of these theories have implicated HLAB27, a molecule of the major histocompatibility complex, as a predisposing genetic factor. However, because some B27-positive individuals are disease-free while some B27 negative individuals develop one of these diseases, the pathogenic role of HLA-B27 remains unclear. To date, the diagnosis of spondyloarthropathies has mainly been based on clinical and radiographic criteria (New York modified criteria, European Study Group criteria, Bernard Amor criteria). The present review aims to describe current knowledge on the value of HLA-B27 in the diagnosis of spondyloarthropathies.     

Clinical features and epidemiology of spondyloarthritides associated with inflammatory bowel disease

Inflammation of axial and/or peripheral joints is one of the most frequent extra-intestinal manifestations complicating the clinical course and therapeutic approach in inflammatory bowel diseases （IBD）. The frequency of these complications seems to be similar for both diseases, Crohn＇s disease and ulcerative colitis. Arthritis associated with IBD belongs to the category of spondyloarthropathies. Axial involvement ranges from isolated inflammatory back pain to ankylosing spondylitis, whereas peripheral arthritis is noted in pauciarticular and in polyarticular disease. Asymptomatic radiological involvement of the sacroiliac joints is reported to occur in up to 50% of patients. Other musculoskeletal manifestations such as buttock pain, dactylitis, calcaneal enthesitis, and thoracic pain are frequently underdiagnosed and, consequently, are not treated appropriately. Several diagnostic approaches and criteria have been proposed over the past 40 years in an attempt to correctly classify and diagnose such manifestations. The correct recognition of spondylarthropathies needs an integrated multidisciplinary approach in order to identify common therapeutic strategies, especially in the era of the new biologic therapies.     

The joint–gut axis in inflammatory bowel diseases

Inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are associated with a variety of extraintestinal manifestations. The most common extraintestinal manifestation, articular involvement, occurs in 16% to 33% of inflammatory bowel disease patients. These arthropathies may increase morbidity, resulting in a worse quality of life compared with inflammatory bowel disease patients without arthropathies. Thus, arthropathies in inflammatory bowel diseases represent a major medical problem in these patients. Arthritis associated with inflammatory bowel diseases is one of the diseases captured under the umbrella of spondyloarthritis. Spondyloarthritis is a group of inflammatory diseases with overlapping features and is linked to Human Leukocyte Antigen-B27. Arthropathy in inflammatory bowel diseases is clinically divided into peripheral and axial involvement. Peripheral arthritis often flares with relapses of bowel disease resulting in a different treatment approach than axial arthritis in which the course is independent of inflammatory bowel disease activity. Definitions, prevalence, pathophysiology and treatment of the arthropathies commonly seen in inflammatory bowel diseases such as peripheral arthritis, dactylitis, enthesitis, arthralgia, sacroiliitis, inflammatory back pain and ankylosing spondylitis are summarized.     

Muscoloskeletal manifestations in inflammatory bowel disease.

Muscoloskeletal manifestations are the most common extraintestinal complications of inflammatory bowel disease. Wide ranges in prevalence have been reported, depending on the criteria used to define spondylarthropathy. In 1991, the European Spondylarthropathy Study Group developed classification criteria that included previously neglected cases of undifferentiated spondylarthropathies, which had been ignored in most of the oldest epidemiological studies on inflammatory bowel disease. The spectrum of muscoloskeletal manifestations in inflammatory bowel disease patients includes all of the clinical features of spondylarthropathies: peripheral arthritis, inflammatory spinal pain, dactylitis, enthesitis (Achilles tendinitis and plantar fasciitis), buttock pain and anterior chest wall pain. Radiological evidence of sacroiliitis is common but not obligatory. The articular manifestations begin either concomitantly or subsequent to the bowel disease; however, the onset of spinal disease often precedes the diagnosis of inflammatory bowel disease. The prevalence of the different muscoloskeletal manifestations is similar in ulcerative colitis and Crohn's disease. Symptoms usually disappear after proctocolectomy. The pathogenetic mechanisms that produce the muscoloskeletal manifestations in inflammatory bowel disease are unclear. Several arguments favour an important role of the intestinal mucosa in the development of spondylarthropathy. The natural history is characterized by periods of flares and remission; therefore, the efficacy of treatment is difficult to establish. Most patients respond to rest, physical therapy and nonsteroidal anti-inflammatory drugs, but these drugs may activate bowel disease. Sulphasalazine may be recommended in some patients. There is no indication for the systemic use of steroids.     

Arthritis and the gut.

Mild arthritis/arthralgia is the most frequent extraintestinal manifestation in inflammatory bowel disease (IBD) and has been reported to occur in 10-35% of patients in different studies. A classification of peripheral arthropathy in relation to inflammatory bowel disease has recently been proposed. Type 1: pauciarticular, asymmetrical, preferably large joints, and related to IBD activity. Type 2: polyarticular, symmetrical, preferably small joints, and occurring independently of IBD activity. While this classification requires the presence of synovitis, arthralgia without swelling or other objective signs are of equal frequency but are not covered by this system. In this issue of the journal, Thomas et al. report a prospective study, incorporating strict endoscopic and histological criteria for pouchitis, which elucidates the correlation to arthropathy. Both pouchitis and symptoms of the joints occurred more frequently in ulcerative colitis patients than in patients with familial polyposis. Surprisingly, arthropathy was not more frequent among patients with pouchitis than among patients without pouchitis in this study. Extraintestinal manifestations of the joints are thus not likely to be a reactive arthritis secondary to pouchitis, which would have been an obvious explanation. Preoperative occurrence of extraintestinal manifestations from the joints does not seem to be predictive for the outcome of an ileo-anal pouch anastomosis and especially development of pouchitis. The arthritic symptoms were generally mild and not disabling.     

Management of extraintestinal manifestations and other complications of inflammatory bowel disease

The past 18 months have seen many studies of the prevalence, pathogenesis, and treatment of the extraintestinal manifestations of inflammatory bowel disease (IBD). Inhibitors of tumor necrosis factor alpha have shown effectiveness in randomized trials for the treatment of spondyloarthropathies and ocular manifestations. Open-label studies suggest that these agents may be effective for pyoderma gangrenosum as well. The epidemiology of primary sclerosing cholangitis (PSC), and its relationship to IBD, is becoming clearer. Colorectal neoplasia in PSC remains an important clinical problem. Osteoporosis occurs more commonly in IBD, but the relative importance of corticosteroid use versus underlying chronic bowel inflammation as risk factors remains controversial. Chromoendoscopy may be an important means to improve detection of colorectal neoplasia in IBD. Observational studies suggest that prolonged use of aminosalicylates is associated with decreased risk of neoplasia, but data are conflicting. A randomized trial of ursodeoxycholic acid in PSC showed decreased risk of colorectal neoplasia in patients receiving the drug relative to those on placebo.     

Clinical Features and Outcomes of Coronavirus Disease 2019 in Patients with Inflammatory Bowel Disease and Spondyloarthropathies

Background:We aimed to determine the clinical features, predictive factors associated with severe disease, and outcomes of coronavirus disease 2019 in patients with immune-mediated inflammatory diseases and report data on the comparison of coronavirus disease 2019 between patients with inflammatory bowel disease and spondyloarthropathies.Methods:A total of 101 patients with inflammatory bowel disease and spondyloarthropathies who had confirmed diagnosis of coronavirus disease 2019 were retrospectively analyzed. Demographics, comorbidities, immunosuppressive treatments, and the impact of immunosuppression on negative outcomes were assessed.Results:The median age of the patients was 47 (38-57) years. The most common rheumatologic diagnosis was ankylosing spondylitis (n = 24), psoriatic arthritis (n = 17), and reactive arthritis (n = 1). In the inflammatory bowel disease group, 47 patients had ulcerative colitis, 11 Crohn’s disease, and 1 unclassified. The most commonly used treatments were biologics (55%) in the spondyloarthropathies group and aminosalicylates (66.1%) in the inflammatory bowel disease group. Overall, 18.8% of the patients required hospitalization, 5% developed severe complications, and 2% died. There were no significant differences in coronavirus disease 2019-related negative outcomes between spondyloarthropathies and inflammatory bowel disease patients. The median age was higher in the patients who required hospitalization [57 (46-66) vs 47 (38-57) years, P = .008]. Bilateral opacities on chest radiographs were more common in the patients who required hospitalization in the spondyloarthropathies group [88.9% vs 14.3%, P = .016]. Comorbidity was significantly associated with hospitalization in the inflammatory bowel disease group (P ≤ .05). Baseline therapy with biologics or immunosuppressives was not associated with severe coronavirus disease 2019 outcomes.Conclusion:Older age, comorbidities, and bilateral ground-glass opacities were associated with adverse outcomes, whereas specific immune-mediated inflammatory disease diagnoses or immunosuppressive treatments were not.     

Die chronische rekurrierende multifokale Osteomyelitis in Assoziation mit chronisch entzündlichen Darmerkrankungen: Die enteropathische CRMO

The enterogenic reactive arthritides and entheropathic spondyloarthropathies are well-known entities. The so-called gut iteropathy concept offers an interesting working hypothesis to link the gut inflammation and the lymphocytic infiltration of the synovium. However, the association of rheumatic diseases belonging to the entity of the SAPHO syndrome with inflammatory bowel diseases (IBD) has only been rarely described in the literature. Among 138 cases of our (heterogenic) SAPHO cohort, we detected 5 patients (1 male, 4 females) with a proven association of SAPHO syndrome with IBD (in 4 cases Crohn's disease, in 1 case ulcerative colitis). Two patients belonged to the juvenileadolescent form and 3 to the adult form of SAPHO syndrome. In all cases the underlying osteoarticluar disease was classified as chronic recurrent multifocal osteomyelitis (CRMO), 2 of them presenting as inflammatory anterior chest wall syndrome. There was a strong association with psoriatic pustular dermatitis. Thus, we present 5 cases of "enteropathic CRMO" demonstrating several analogies to the enteropathic spondyloarthropathies. Both disease entities have in common i) metachronic development with osteoarticluar manifestations often preceding the gastrointestinal disease; ii) Crohn's like lesions that may develop from the stomach to the colon; iii) concomittent or intermittent skin pustulosis which mostly resolves; iiii) the gastrointestinal disease that often dominates the whole syndrome namely in the longterm follow-up. We suggest to transfer the hypothesis of the gut-synovium axis of enteropathic spondyloarthropathies to the entity of CRMO. This concept offers an opportunity to link the target organs gut mucosa, bone marrow and the skin via homing of antigen specific lymphocytes. This concept may help to better understand the pathogenesis of the "Skibo" (i. e., skin-bone) disease CRMO.     

Multipotent role of platelets in inflammatory bowel diseases:A clinical approach

There is evidence that inflammatory bowel diseases(IBD)combine both inflammation and coagulation in their pathogenesis and clinical manifestations.Although platelets(PLT)are well known for their role in hemo stasis,there are a rising number of studies supporting their considerable role as inflammatory amplifiers in chronic inflammatory conditions.IBD are associated with several alterations of PLT,including number shape,and function,and these abnormalities are main ly attributed to the highly activated state of circulating PLT in IBD patients.When PLT activate,they increase in size,release a great variety of bio-active inflamma tory and procoagulant molecules/particles,and express a variety of inflammatory receptors.These inflamma tory products may represent a part of the missing link between coagulation and inflammation,and can be considered as possible IBD pathogenesis instigators.In clinical practice,thrombocytosis is associated both with disease activity and iron deficiency anemia.Controlling inflammation and iron replacement in anemic patient usually leads to a normalization of PLT count.The aim of this review is to update the role of PLT in IBD and present recent data revealing the possible therapeutic implications of anti-PLT agents in future IBD remedies.     

Extraintestinal manifestations of inflammatory bowel disease：Do they influence treatment and outcome？

Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases that often involve organs other than those of the gastrointestinal tract. Immune-related extraintestinal manifestations (EIMs) are usually related to disease activity, but sometimes may take an independent course. Globally, about one third of patients develop these systemic manifestations. Phenotypic classification shows that certain subsets of patients are more susceptible to developing EIMs, which frequently occur simultaneousl...     

Neurologic manifestations in inflammatory bowel diseases: Current knowledge and novel insights

BackgroundCrohn's disease (CD) and ulcerative colitis (UC), widely known as inflammatory bowel diseases (IBD), are thought to result from an inappropriate activation of the mucosal immune system driven by intestinal bacterial flora.MethodsAlthough the extraintestinal manifestations of IBD are well documented, the association of IBD with neurologic and neuromuscular involvement is rare and often controversial, with sporadic and conflicting data on its prevalence and spectrum. In addition, a serious number of the latter manifestations may become life-threatening, playing a very important role in disease morbidity. To define the pattern of neurologic involvement in IBD, the most important manifestations in these patients have been reviewed, exploring also their clinical significance.ResultsThere is evidence that UC and CD can manifest both in the PNS and CNS. Thrombotic complications are common in IBD patients, but cerebral vascular involvement is rare.ConclusionsNeurologic manifestations in IBD patients are more common than previously estimated and may follow a different pattern of involvement in CD and UC. Small numbers of patients currently preclude a better characterization of the clinical spectrum and a better understanding of pathogenesis.     

Leucocyte elastase in chronic inflammatory bowel diseases: a marker of inflammatory activity?

Leucocyte elastase is a neutral proteinase which plays an important role in the pathogenesis of inflammatory disorders. Infiltration of bowel mucosa by neutrophil and eosinophilic granulocytes is a characteristic feature of chronic inflammatory bowel diseases. We studied plasma elastase in 44 patients suffering from Crohn's disease or ulcerative colitis. Plasma levels were significantly higher in these patients compared to 7 patients with non-inflammatory bowel diseases or 53 healthy controls. Elevated plasma levels were more often found in patients with active inflammation than in those with inactive disease. Elastase did neither correlate with leucocyte counts, serum albumin, ESR, alpha 1-proteinase inhibitor and orosomucoid nor with clinical indices or the faecal excretion of 111In-labelled granulocytes. In serial studies of 15 patients, elastase did not always run parallel to the disease activity. We conclude that plasma elastase does not reliably indicate the inflammatory activity in chronic inflammatory bowel diseases.     

Thrombosis and inflammatory bowel disease.

Interaction between thrombosis and inflammation is increasingly recognized. With this, interest has arisen in the role of thrombosis in inflammatory conditions, including the inflammatory bowel diseases. Although the association between active inflammatory bowel disease and thromboembolic complications has long been known, there has been a resurgence in research into the role of thrombosis and the hemostatic system in the pathogenesis of both ulcerative colitis and Crohn's disease. Here we review the increased frequency of thromboembolic complications occurring in patients with inflammatory bowel disease; whether thrombosis might play a part in the initiation and maintenance of inflammation in inflammatory bowel disease; abnormalities of the coagulation system found in patients with inflammatory bowel disease; platelet dysfunction in inflammatory bowel disease; the mechanisms by which hemostatic processes might be proinflammatory in inflammatory bowel disease; and how these interactions might impact not only on the prevention of complications, but also on the treatment of the underlying inflammation in inflammatory bowel disease.     

Extraintestinal manifestations of ulcerative colitis following restorative proctocolectomy.

BACKGROUND: Rheumatological and other extraintestinal manifestations (EIM) are common in inflammatory bowel disease (IBD) but also seem to occur in patients after restorative proctocolectomy and formation of an ileo-anal pouch. The prevalence and significance of these symptoms have not been established in this clinical context. OBJECTIVE: To evaluate prospectively the prevalence and associations of EIM of IBD in ulcerative colitis (UC) patients following restorative proctocolectomy (RP) and to compare the findings to those in a control group of familial adenomatous polyposis (FAP) patients who had undergone similar surgery. METHODS: One hundred and twenty-three (97 UC and 26 FAP) consecutive patients with ileal pouches undergoing long-term follow-up underwent an assessment of rheumatological symptoms and signs, similarly of other EIM; each underwent pouch endoscopy and biopsy. RESULTS: Symptoms in the joints were reported in 30 (31%) of UC patients compared to two (8%) FAP patients (P = 0.02). Twenty-four (80%) of the affected patients had a polyarticular arthralgia affecting primarily the knees, and small joints of the hands. Clinical findings and radiological investigations were almost exclusively normal. Most patients had mild symptoms, with only 12 of the 30 reporting interference with daily life. The presence of symptoms in the joints was not associated with a positive family history for IBD or other EIM, the presence of non-rheumatological EIM or the presence of pouchitis. Histological scores of pouch inflammation did not differ between those with and without symptoms of the joints. CONCLUSIONS: A mild polyarticular arthralgia, similar to that associated with active IBD, is common following RP and may commence after surgery. It is not associated with the presence of pouch inflammation.     

The role of infection in the pathogenesis of spondyloarthropathies with special reference to human leukocyte antigen-B27

Spondyloarthropathies consist of many inflammatory diseases that are closely associated with human leukocyte antigen (HLA)-B27. One of these diseases is reactive arthritis (ReA), which is a joint inflammation that occurs after infections that are caused by certain gram-negative bacteria. The importance of these infections as causative agents of ReA has been clearly established. It is not clear, however, whether these infections contribute to the development of other forms of spondyloarthropathies. The exact mechanism by which HLA-B27 influences disease susceptibility in spondyloarthropathies remains to be determined. The role of HLA-B27 as an antigen-presenting molecule is certainly important in the pathogenesis of these diseases; however, recent data indicate that this molecule may exhibit other functions unrelated to antigen presentation, which may be important in the pathogenesis of ReA. In this paper, the authors summarize the current knowledge of the role of infection in the spondyloarthropathies.     

Hepatic manifestations of inflammatory bowel diseases

Inflammatory bowel diseases are associated with various hepatobiliary disorders, reported both in Crohn's disease and ulcerative colitis. They may occur at any moment in the natural course of the disease. The prevalence of liver dysfunction rises from 3% to 50% accordingly to definitions used in different studies. Fatty liver is considered as the most common hepatobiliary complication in inflammatory bowel diseases while primary sclerosing cholangitis is the most specific one. Less frequently, inflammatory bowel diseases‐associated hepatobiliary disorders include: autoimmune hepatitis/ primary sclerosing cholangitis overlap syndrome, IgG4‐associated cholangiopathy, primary biliary cholangitis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis and liver abscess. The spectrum of these manifestations varies according to the type of inflammatory bowel diseases. Treatments of inflammatory bowel diseases may cause liver toxicity, although incidence of serious complications remains low. However, early diagnosis of drug‐induced liver injury is of major importance as it affects future clinical management. When facing abnormal liver tests, clinicians should undertake a full diagnostic work‐up in order to determine whether the hepatic abnormalities are related to the inflammatory bowel diseases or not. Management of hepatic manifestations in inflammatory bowel diseases usually involves both hepatologists and gastroenterologists because of the complexity of some situations.     

Expanding Applications: The Potential Usage of 5-Aminosalicylic Acid in Diverticular Disease

Diverticular disease is a common bowel condition, the pathogenesis of which is incompletely understood. Acute exacerbations of diverticular disease usually require dietary changes, antibiotic therapy, and may necessitate urgent surgery. Approximately 25–33% of patients experience symptomatic and acute inflammatory disease recurrence, suggesting that current long-term management is inadequate. Because inflammatory complications of diverticular disease, including diverticulitis, are similarities to inflammatory bowel diseases, evidence suggests that patients may respond to anti-inflammatory therapies used in these conditions. Here, we explore the rationale and evidence for use of inflammatory bowel disease treatment, namely 5-aminosalicylic acid (5-ASA; mesalamine), in diverticular disease, and review clinical data on the efficacy of mesalamine either alone or in combination with other agents for the treatment of diverticular disease. PubMed and conference abstracts were searched for clinical studies examining the use of mesalamine in treating diverticular disease. Studies were evaluated for treatment efficacy in symptom reduction, recurrence prevention, or improving quality of life. The results of our search suggest that single-agent mesalamine can reduce diverticular disease symptoms and improve quality of life more effectively than antibiotic treatment alone. Mesalamine in combination with antibiotics can also reduce symptoms and improve quality of life with greater efficacy than either treatment alone. Combining mesalamine and probiotics treatments may reduce recurrent attacks of diverticular disease. Further randomized, well-controlled studies are required for validation; however, it seems that mesalamine is an important agent in future diverticular disease management.     

Psoriatic disease--from skin to bone

Psoriatic arthritis is an inflammatory joint disease that is heterogeneous in presentation and clinical course. Evidence that this disease is distinct from rheumatoid arthritis and other spondyloarthropathies is based on data derived from characteristic clinical features, histopathologic analyses, immunogenetic associations and musculoskeletal imaging. Emphasis has centered previously on a dominant role for the T lymphocyte in the inflammatory process; however, studies provide support for a major contribution from monocyte-macrophages in the initiation and perpetuation of joint and skin inflammation. The occurrence of arthritis in the absence of psoriasis in a minority of patients with psoriatic arthritis, coupled with divergent genetic risk factors, indicates that psoriatic arthritis is distinct from psoriatic skin inflammation. A new terminology, psoriatic disease, has emerged that encompasses the various manifestations of tissue and organ involvement observed in many psoriasis patients, including inflammation in the joint, eye and gut. Moreover, adverse cardiovascular and metabolic outcomes in patients with psoriasis or psoriatic arthritis might be directly linked to the cutaneous and musculoskeletal manifestations of these diseases via subsets of circulating monocytes and tissue macrophages activated by inflammatory cytokine networks that arise in the skin and possibly the joint.     

Abdominal and digestive system associations of familial Mediterranean fever

Familial Mediterranean fever (FMF) is a hereditary epidosic febrile syndrome that is expressed by acute spells of fever, painful manifestations in the abdomen, chest and joints, and slow development of nephropathic amyloidosis. Despite the recent cloning of the FMF gene ( MEFV) and the identification of about 40 disease-related mutations, the diagnosis is still clinically dependent, and the pathogenesis and most of the clinical heterogeneity remain to be explained.
Because episodic abdominal pain affects 95% of FMF patients, most of them are seen by gastroenterologists and undergo complete or partial abdominal imaging before the diagnosis is made. Focusing on recent advances in FMF, this article reviews both common and infrequent manifestations that a gastroenterologist may encounter during workups of FMF patients. These include episodic abdominal pain, paralytic or mechanical ileus, constipation, diarrhea, ascites, malabsorption, bowel infarction, and bleeding, arising directly from FMF or secondary to FMF common associations such as amyloidosis, vasculitides, inflammatory bowel disease, irritable bowel syndrome, or colchicine side effects. This article will help the gastroenterologist to cope with most clinical situations related to the abdominal and alimentary tract in patients with FMF.