Inflammatory Muscle Diseases

Posted by Carla Rothaus • May 1st, 2015

The four main types of inflammatory muscle disease — dermatomyositis, polymyositis, necrotizing autoimmune myositis, and inclusion-body myositis — are summarized in a new review article. Pathogenesis, differential diagnosis, and treatment approaches are discussed.

The inflammatory myopathies constitute a heterogeneous group of disorders that are best classified, on the basis of distinct clinicopathologic features, as four subtypes: dermatomyositis, polymyositis, necrotizing autoimmune myositis, and inclusion-body myositis.

Clinical Pearls

- What are the general clinical features of the inflammatory myopathies?

Patients with inflammatory myopathies have increasing difficulty with tasks requiring the use of proximal muscles, such as getting up from a chair, climbing steps, or lifting objects. In all disease subtypes, neck-extensor and pharyngeal muscles can be involved, which results in difficulty holding up the head (head drop) or in dysphagia. In advanced and rare acute cases, the respiratory muscles can be affected. Extramuscular manifestations may occur in all inflammatory myopathies, although they occur in inclusion-body myositis only in rare cases.

- Are there any clues to facilitate the early clinical diagnosis of inclusion-body myositis?

Inclusion-body myositis is the most common and disabling inflammatory myopathy among persons 50 years of age or older. Although inclusion-body myositis is commonly suspected when a patient with presumed polymyositis does not respond to therapy, features that can lead to an early clinical diagnosis include the observation of early involvement of distal muscles, especially foot extensors and finger flexors; evident atrophy of the forearms and quadriceps muscles; a history of frequent falls due to quadriceps muscle weakness causing buckling of the knees; and the presence of mild facial-muscle weakness.

Morning Report Questions

Q: What are some of the features of polymyositis and necrotizing autoimmune myositis?

A: Polymyositis is rare and often misdiagnosed. It remains a diagnosis of exclusion and is best defined as a subacute proximal myopathy in adults who do not have rash, a family history of neuromuscular disease, exposure to myotoxic drugs (e.g., statins, penicillamine, and zidovudine), involvement of facial and extraocular muscles, endocrinopathy, or the clinical phenotype of inclusion-body myositis. Necrotizing autoimmune myositis is a distinct clinicopathologic entity that occurs more frequently than polymyositis, accounting for up to 19% of all inflammatory myopathies. It can occur at any age but is seen primarily in adults; it starts either acutely, reaching its peak over a period of days or weeks, or subacutely, progressing steadily and causing severe weakness and very high creatine kinase levels. Necrotizing autoimmune myositis occurs alone or after viral infections, in association with cancer, or in patients taking statins, in whom the myopathy continues to worsen after statin withdrawal. Most patients with necrotizing autoimmune myositis have antibodies against signal recognition particle (SRP) or against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR).

Q: How are the inflammatory myopathies diagnosed and treated?

A: The diagnosis of the exact subtype of inflammatory myopathy is based on the combination of clinical history, tempo of disease progression, pattern of muscle involvement, muscle enzyme levels, electromyographic findings, muscle-biopsy analysis, and for some conditions, the presence of certain autoantibodies. Oral prednisone administered once daily after breakfast at a dose of 1 mg per kilogram of body weight, up to 100 mg per day, is the first-line drug for the treatment of dermatomyositis, polymyositis, and necrotizing autoimmune myositis; this choice of drug is based on experience but not on controlled trials. In patients whose condition responds to glucocorticoids, azathioprine, mycophenolate mofetil, methotrexate, or cyclosporine is empirically used for glucocorticoid sparing. When glucocorticoids fail to induce remission or in rapidly progressive cases, intravenous immune globulin therapy is appropriate. With respect to inclusion-body myositis, glucocorticoids, methotrexate, cyclosporine, azathioprine, and mycophenolate are ineffective, and although some patients initially have mild improvements when treated with one of these agents, no long-term benefit is achieved.

Intravenous immune globulin has been found to be ineffective in controlled trials but may transiently help some patients, especially those with dysphagia.

Table 1. Criteria Supporting the Diagnosis of Inflammatory Myopathies.

Table 2. Treatment of Inflammatory Myopathies: A Step-by-Step Approach.


A Woman with Shortness of Breath

Posted by Carla Rothaus • May 1st, 2015

In the latest Case Record of the Massachusetts General Hospital, a 58-year-old woman presented with an 8-month history of shortness of breath on exertion. Previous chest imaging had shown pleural thickening and peripheral nodules in the upper lung zones, without lymphadenopathy. A diagnostic procedure was performed.

When a pulmonologist is presented with a case of interstitial lung disease with predominant involvement of the upper zones, a number of disease entities should come to mind. These include two fairly common interstitial lung diseases, sarcoidosis and hypersensitivity pneumonitis, as well as rarer diseases, such as pulmonary Langerhans’-cell histiocytosis and the pneumoconioses (berylliosis, silicosis, and coal worker’s pneumoconiosis).

Clinical Pearls

- Interstitial lung disease may be seen in association with what connective tissue diseases?

Interstitial lung disease is a common manifestation of many connective-tissue diseases, including systemic sclerosis, rheumatoid arthritis, dermatomyositis, polymyositis, Sjogren’s syndrome, mixed connective-tissue disease, and systemic lupus erythematosus.

- What is the typical appearance of chronic eosinophilic pneumonia on chest imaging?

Chronic eosinophilic pneumonia is an idiopathic interstitial lung disease that is associated with the presence of peripheral opacities on chest imaging, a finding that is often referred to as the photographic negative of pulmonary edema.

Morning Report Questions

Q: What category of lung disease does idiopathic pleuroparenchymal fibroelastosis (PPFE) belong to?

A: There is no complete agreement about whether idiopathic PPFE should be viewed as a specific type of interstitial lung disease. The pathogenetic mechanisms of idiopathic PPFE are unclear. It is possible that the disease is a variant of usual interstitial pneumonitis or nonspecific interstitial pneumonitis, that the disease is some form of pneumoconiosis, that some cases in patients who have undergone lung transplantation represent chronic allograft rejection, or that the disease is an exaggerated form of a pleural apical cap. A few familial cases have been reported.

Q: What are some of the histologic and clinical features of PPFE?

A: The histopathological findings associated with idiopathic PPFE include a particularly dense elastotic subpleural band, with elastic tissue exceeding collagen in the scar. There may be extension of fibrosis into the interstitium in the underlying lung. The absence of a diffuse lymphocytic infiltrate serves to differentiate this condition from nonspecific interstitial pneumonitis. Predominant involvement of the upper lung zones and a chronic progressive course are common. Pneumothorax is relatively common. The vast majority of patients with PPFE appear to have clinically significant impaired lung function, and most have disease progression over time, even when they are treated aggressively with glucocorticoids and immunosuppressive therapy.

Now on the NEJM Group Open Forum

Posted by Karen Buckley • April 27th, 2015

There’s a lot happening on the NEJM Group Open Forum:

Talk with authors and experts about a new study involving multiple US neonatal intensive care units that demonstrated a substantial increase in admissions for neonatal abstinence syndrome between 2004 and 2011, as well as increases in associated length of stay and in the percentage of NICU days nationwide attributed to the syndrome.  Read the discussion, comment, like and share- now on the NEJM Group Open Forum. This discussion is ongoing until May 7.

Can empathy be taught? We’re discussing whether the ability to compassionately connect with patients is an inherent part of a good doctor’s DNA or it can be a learned skill.  This conversation, ongoing through April 30, explores some of the barriers to sustained empathy among physicians and discusses how to deal with poor interpersonal skills in medical school and beyond.

Thinking of taking a leave of absence? How can physicians plan their departure and re-entry, and what hurdles do they have to overcome to get back into practice? This NEJM CareerCenter Conversation is ongoing through April 30.

You may also wish to check out preview NEJM CareerCenter Conversations, including Flexible Work SchedulesFinding a Mentor, and Women Transforming the Culture of Medicine.  And, beginning on May 5, we’ll be talking about launching from residency into a career.

The NEJM Group Open Forum is a pilot project we are running in collaboration with Medstro, a social professional network for physicians. Free registration is required; social login is available through Facebook, Twitter, Google, and LinkedIn.

Let us know what you think!

A Woman with Arthralgias

Posted by Carla Rothaus • April 24th, 2015

In the latest Case Record of the Massachusetts General Hospital, a 27-year-old woman was seen in the emergency department of this hospital during the summer because of fever, arthralgias, and a rash. Three days before the onset of illness, she had returned from a vacation in the Caribbean. A diagnostic test was performed.

When considering possible exposures in a returning traveler, it is important to consider the location of travel, food or water consumed, history of insect bites, contact with animals, use of medications or recreational drugs, and sexual contacts.

Clinical Pearls

- Describe the arthralgias associated with Parvovius B19 infection in adults.

Approximately 60% of adults with parvovirus B19 infection have symmetric, polyarticular arthralgias; this infection is more common among women than men, frequently affects the proximal interphalangeal and metacarpophalangeal joints, and has been reported to involve the knees, wrists, and ankles.

- What diseases are common in persons who travel to the Caribbean or Central America?

Of patients who seek medical attention for travel-related diseases after spending time in the Caribbean or Central America, 17.7% present with fever. No specific diagnosis is made in 40% of cases of fever in persons returning from international travel; when a diagnosis is made, the most common cause is dengue, and malaria, typhoid, and hepatitis A are other common causes. Within the Caribbean, malaria has been reported only in Haiti and the Dominican Republic. Leptospirosis is important to consider in any patient returning from the Caribbean, since this illness can be missed on routine testing.”

Table 2. Incubation Periods of Common Infectious Diseases among Travelers Returning from the Caribbean or Central America.

Morning Report Questions

Q: What clinical findings help distinguish between chikungunya virus infection and dengue?

A: The clinical presentations of dengue and chikungunya virus infection overlap considerably.  The incubation periods of both viral diseases are short. Both diseases are typically manifested by fevers and myalgias. Headache, rash, nausea, and vomiting are  also commonly associated with both diseases. Abnormal laboratory findings, especially thrombocytopenia, are typically more pronounced in patients with severe dengue than in those with chikungunya virus infection. Hemorrhagic manifestations  are more common in patients with dengue than in those with chikungunya virus infection.   Symmetric polyarthralgia involving the small and medium joints is the hallmark of chikungunya virus infection and is less commonly reported in patients with dengue.”

Table 3. Clinical Features of Chikungunya Virus Infection.

Q: What diagnostic tests are available for chikungunya virus infection?

A: Several diagnostic tests are available for chikungunya virus infection. Enzyme-linked immunosorbent assay can aid in the diagnosis, and depending on the timing of the patient’s presentation, detection of viral nucleic acids may also be possible. High-level viremia is detectable within a week after illness onset; IgM antibodies are typically present within 5 to 7 days after illness onset and persist for several months, and shortly thereafter, IgG antibodies are present and persist for life.

Uterine Fibroids

Posted by Carla Rothaus • April 24th, 2015

Fibroids, which are common in women of reproductive age, may cause heavy menstrual bleeding and symptoms related to leiomyoma bulk. Hysterectomy is an effective treatment, but many uterus-sparing options are available and should be discussed with patients. The latest Clinical Practice review is on this topic, and comes from Elizabeth A. Stewart, M.D., at the Mayo Clinic.

The lifetime prevalence of fibroids exceeds 80% among black women and approaches 70% among white women. Despite the high prevalence of fibroids and related annual U.S. health care costs exceeding $34 billion, there are few randomized trials to guide treatment.

Clinical Pearls

- What are some of the risk factors for uterine fibroids?

Increasing age up to menopause and black race are the major risk factors for fibroids. Increasing parity is associated with a decreased risk, possibly through elimination of incipient fibroids as the uterus involutes post partum. Early menarche and the use of oral contraceptives before 16 years of age are associated with an increased risk, whereas the use of progestin-only injectable contraceptives is associated with a reduced risk.

- What is the role of uterine artery embolization?

Uterine-artery embolization is a minimally invasive interventional radiologic technique that has been shown in randomized trials to result in quality of life that is similar to that after surgery, with shorter hospital stays and less time to resumption of usual activities. The rates of major complications after embolization are similar to those after surgery, but embolization is associated with a higher risk of minor complications and of the need for additional surgical intervention (typically hysterectomy). In large case series and multisite registries, common complications include mild fever and pain (a constellation of symptoms called the postembolization syndrome) and vaginal expulsion of fibroids. Concerns about the safety of future pregnancies and impaired ovarian function currently limit wider use of embolization.

Figure 4. Uterine-Artery Embolization.

Morning Report Questions

Q: What medical therapies are available for women with heavy menstrual bleeding from fibroids?

A: Tranexamic acid, an oral antifibrinolytic agent that is taken only during heavy menstrual bleeding, results in decreased bleeding and improved quality of life with minimal side effects. Although its mechanism of action raises concern about thrombotic risk, this association has not been seen in clinical studies. The levonorgestrel-releasing intrauterine device (IUD) effectively decreases menstrual bleeding and provides contraception; however, the rate of expulsion of the IUD among women with submucosal fibroids may be high (12% in one case series). Observational data support the use of oral contraceptives to reduce menstrual bleeding in women with fibroids. A meta-analysis of randomized trials concluded that nonsteroidal antiinflammatory drugs, as compared with placebo, decreased menstrual pain and heavy menstrual bleeding, but they were less effective in reducing bleeding than tranexamic acid or the levonorgestrel-releasing IUD.

Q: When is surgical myomectomy recommended?

A: For most women in whom submucosal fibroids with a large intracavitary component (FIGO types 0 and 1) are found to be the cause of bleeding, hysteroscopic myomectomy is the best therapeutic option. Most guidelines support surgical myomectomy as the preferred option for treatment of symptomatic intramural and subserosal fibroids in women who wish to have a subsequent pregnancy. Nonetheless, abdominal myomectomy confers substantial risks with respect to fertility, including a 3 to 4% risk of intraoperative conversion to hysterectomy and frequent development of postoperative adhesions. Data are lacking from comparative-effectiveness research regarding fertility in women who have received various therapies for fibroids. Since intramural fibroids are themselves associated with an increased risk of infertility and pregnancy complications, and myomectomy does not reduce that risk, treatment of asymptomatic intramural fibroids is not recommended. Recurrence of fibroids is also common; at least 25% of women who have undergone myomectomy require additional treatment.

Figure 2. Algorithm for the Management of Symptomatic Uterine Fibroids.

Prednisolone or Pentoxifylline for Alcoholic Hepatitis

Posted by Chana Sacks • April 22nd, 2015

Intern year, they say, is about learning to distinguish “sick” from “not sick.”

As the intern on-call overnight, you call the Emergency Department physician for pass off on Mr. Jones; when you hear “46-year-old man with heavy alcohol use disorder presenting with new jaundice and mild confusion,” it takes you only a split second to recognize that your patient is “sick.”

You have flipped through the labs, and as you walk down to the Emergency Department, you plug Mr. J’s bilirubin and prothrombin time into the medical calculator app on your phone. Maddrey’s discriminant function of 60.  Knowing that anything above 32 indicates severe alcoholic hepatitis, your pace quickens.

You take a history and examine Mr. J, confirming the time course of his symptoms and his alcohol use history with his brother.  After reviewing the work-up already underway, you become confident in your clinical diagnosis of alcoholic hepatitis, and you consider treatment options.  Prednisolone and pentoxifylline are the two you know of, but even your senior resident hems and haws when you ask how effective each of these treatments is.  She is not alone – data from prior studies have been mixed, leaving doubts about how best to treat this clinical syndrome.

To address this uncertainty, Thursz and colleagues conducted the STOPAH trial, now published in NEJM.  Using a 2×2 factorial design, 1100 adults with a clinical diagnosis of severe alcoholic hepatitis from 65 hospitals in the United Kingdom were randomized to receive either prednisolone, pentoxifylline, both, or placebo.

Similar to your patient, trial participants were on average in their late 40s, majority male, and had a mean discriminant function in the 60s. The assigned treatment was continued for 28 days.

The results: for pentoxifylline, there was no improvement in 28-day mortality. 16% of patients who were treated with pentoxifylline died – the same percentage as those who did not receive it.  For prednisolone, mortality was 14% among those who received glucocorticoids versus 18% for those who did not. With a p-value of 0.06, this trend toward benefit fell just short of statistical significance. Neither treatment improved longer-term survival at 90 days or 1 year; serious infections were nearly twice as common among those receiving prednisolone (13% vs 7%, P=0.002).

For pentoxifylline, then, these data seem conclusive. However, for prednisolone, these data don’t offer a clear directive.  Deputy Editor Dr. Mary Beth Hamel addresses this gray zone: “For prednisolone, some uncertainty persists about a possible short-term benefit. But it is clear that any benefit is far from a durable, long-term solution for those suffering from alcoholic hepatitis.”

So to your patient: do you administer either of these treatments? Pentoxifylline – probably not.  Prednisolone is a tougher decision. You know there is no magic to the P value of 0.05, and you think the possibility of even a short-term mortality benefit is worth the increased risk of infection. But before you write the order, you want to see what your senior resident thinks.

As you walk back to the work room, you scroll through your phone. You close the discriminant function calculator and then Google helps you find that famous Scottish proverb that has been swirling in your head: “They speak of my drinking, but never think of my thirst.”  You think about how that would make a good opening for an article about how we need better ways to have helped Mr. Jones before it came to this – before he became “sick.” But you don’t have time to think about that now – it’s almost morning. You put your phone back in your white coat pocket, sit down at a computer, and start your note.

View the NEJM Quick Take video summary of the results of this article on

A Newborn Boy with Respiratory Distress

Posted by Carla Rothaus • April 17th, 2015

In the latest Case Record of the Massachusetts General Hospital, a newborn boy was admitted to the hospital because of respiratory distress and hypotension. At delivery, meconium was suctioned from the airway. Respiration and blood pressure improved after intervention, but lethargy and myoclonus developed.

Neonatal brain tumors are often not apparent in utero; only 18% are identified on prenatal ultrasound, even when polyhydramnios and hydrocephalus are present. This is because neonatal brain tumors tend to grow rapidly in the third trimester, after the period when prenatal ultrasonography is performed during uncomplicated pregnancies.

Clinical Pearls

- What is the mortality rate associated with meconium aspiration syndrome?

Meconium is present in 3 to 18% of term deliveries, and in such cases, the meconium aspiration syndrome develops in 2 to 9% of the neonates. The meconium aspiration syndrome accounts for 10% of all neonatal respiratory failure and is associated with a mortality rate of 39%.

- What is the mechanism of lung injury in meconium aspiration syndrome?

Meconium, which is thick and particulate, can physically obstruct the airways, causing a ball-valve phenomenon that then leads to air trapping and hyperinflation. Asymmetric lung inflation, with areas of collapse and hyperinflation, increases the likelihood of pneumothorax and of ventilation-perfusion mismatch. Meconium can cause surfactant inactivation and is also toxic to the type II cells, thereby decreasing production of surfactant. Meconium can also indirectly affect the lung tissue, by inducing inflammatory mediators and apoptosis and by inhibiting lung-fluid resorption.

Morning Report Questions

Q: What lesions are included in the differential diagnosis for congenital brain tumors?:

A: Congenital brain tumors are uncommon, accounting for only 1 to 2% of all brain tumors in pediatric patients (1 to 3 cases per 1 million live births). The differential diagnosis of brain tumors in infants differs from that in older children. Teratomas account for 35 to 45% of all brain tumors in newborns, whereas low-grade astrocytomas comprise the largest proportion of brain tumors affecting older children. Aggressive embryonal tumors — including medulloblastomas, supratentorial primitive neuroectodermal tumors, and atypical teratoid-rhabdoid tumors — account for nearly one quarter of all brain tumors in both infants and older children, with atypical teratoid-rhabdoid tumors occurring most frequently in infants and very young children. Tumors of the central nervous system in older children are more commonly infratentorial, whereas 60 to 70% of tumors of the central nervous system in neonates are supratentorial.

Q: What is the prognosis for an infant with a congenital brain tumor?

A: Given the large size of many neonatal tumors and the limited therapeutic options, the outcome for newborns and infants who receive a diagnosis of a brain tumor other than choroid plexus papilloma is very poor. The prognosis for neonates with a highly aggressive embryonal tumor is particularly poor; less than 20% of affected children survive. Patients who do survive typically have global impairments, including neurocognitive deficits (69% of affected children have a full-scale intelligence quotient of <85, and 54% have a full-scale intelligence quotient of <70, the standard threshold for mental retardation), motor delays (in 85%), visual impairment, hearing deficits and speech delays (in 50%), and feeding problems and endocrine deficits (in 25%).


Clostridium difficile Infection

Posted by Carla Rothaus • April 17th, 2015

A new review article on Clostridium difficile Infection covers the pathogenesis, epidemiology, diagnosis, and treatment of this nosocomial and potentially fatal infectious diarrhea, as well as the associated risk factors. New treatments include fecal microbiota transplantation for disease that is resistant to vancomycin.

Clostridium difficile is an anaerobic gram-positive, spore-forming, toxin-producing bacillus that is transmitted among humans through the fecal-oral route. C. difficile has emerged as a major enteric pathogen with a worldwide distribution. In the United States, C. difficile is the most frequently reported nosocomial pathogen.

Clinical Pearls

- Who is at risk for C. difficile infection?

The most important risk factor for C. difficile infection remains antibiotic use. Ampicillin, amoxicillin, cephalosporins, clindamycin, and fluoroquinolones are the antibiotics that are most frequently associated with the disease, but almost all antibiotics have been associated with infection. The risk of C. difficile infection and the severity of infection increase as age increases. In one study, the risk of contracting C. difficile during an outbreak was 10 times as high among persons older than 65 years of age as among younger inpatients. The majority of C. difficile infections are hospital-acquired, but community-acquired infection has increased dramatically in the past decade and may now account for up to a third of new cases. Other documented risk factors for infection include advanced age, inflammatory bowel disease, organ transplantation, chemotherapy, chronic kidney disease, immunodeficiency, and exposure to an infant carrier or infected adult.

Table 1. Antibiotic Classes and Their Association with Clostridium difficile Infection.

- How is C. difficile infection diagnosed?

Stool culture for C. difficile requires anaerobic culture and is not widely available. Enzyme immunoassay used to be the mainstay of testing for C. difficile infection, since it is rapid and easily performed. Recently, many hospital laboratories have adopted DNA-based tests that detect toxigenic strains and provide higher sensitivity and specificity than does enzyme immunoassay.

Morning Report Questions

Q: What is the recommended treatment for acute C. difficile infection?

A: Metronidazole and oral vancomycin have been the mainstays of treatment for C. difficile infection since the 1970s. For the treatment of severe disease, vancomycin is better than metronidazole, but for mild-to-moderate infection, the two antibiotics have been considered to be equivalent. However, a marked rise in clinical failure associated with metronidazole, especially in patients with the BI/NAP1/027 strain, has been seen in the past decade. Previous studies were underpowered to evaluate differences between metronidazole and vancomycin in cases of nonsevere infection, but recent data suggest an overall superiority of vancomycin. In 2011, fidaxomicin, a poorly absorbed, bactericidal, macrocyclic antibiotic with activity against specific anaerobic gram-positive bacteria, was approved by the Food and Drug Administration for the treatment of C. difficile infection. In phase 3 clinical trials, the cure rate for acute infection was nearly equivalent among patients receiving fidaxomicin and those receiving vancomycin (approximately 90% for each), but the risk of recurrence was 15% among patients receiving  fidaxomicin, as compared with 25% among those receiving vancomycin. However, a reduced risk of recurrence was not seen among patients infected with BI/NAP1/027 strains, which were found in 38% of isolates. The markedly higher cost of fidaxomicin has limited its use, despite its superiority to vancomycin in reducing the risk of recurrence.

Q: How are recurrent C. difficile infections treated?

A: Treatment of a first episode of recurrent infection with a repeat course of either metronidazole or vancomycin for 10 to 14 days is successful in approximately 50% of patients. Second and subsequent recurrences can be difficult to cure, primarily because of the persistence of spores in the bowel or environment and the inability of the patient to mount an effective immune response to C. difficile toxins, rather than to antibiotic resistance. Second recurrences can be treated with fidaxomicin or by a vancomycin regimen involving tapered and pulsed dosing. Recent data suggest that fidaxomicin may be more effective than vancomycin at preventing further episodes of C. difficile after an initial recurrence. Fecal microbial transplantation, a procedure that was first reported in 1958, has recently emerged as an accepted, safe, and effective treatment for recurrent C. difficile infection.

Table 2. Treatment of Clostridium difficile Infection.

Inflammatory Bowel Disease

Posted by Carla Rothaus • April 9th, 2015

A new review article covers the wide range of cancers associated with inflammatory bowel disease and the drugs used to manage them. Surveillance recommendations are presented.

Cancers complicating inflammatory bowel disease can be attributed to chronic intestinal inflammation or to the carcinogenic effects of the immunosuppressive drugs used to treat inflammatory bowel disease.

Clinical Pearls

- What is the epidemiology of colorectal cancer in patients with inflammatory bowel disease?

Patients with inflammatory bowel disease without colonic inflammation and patients with ulcerative colitis limited to the rectum are not at excess risk for colorectal cancer. In contrast, patients with primary sclerosing cholangitis associated with inflammatory bowel disease are at high risk for colorectal cancer, beginning at the time of the diagnosis. In other patients with inflammatory bowel disease, the excess risk of colorectal cancer, as compared with the risk among persons of the same age and sex without inflammatory bowel disease, is driven by the extent, duration, and severity of colonic inflammation.

Table 1. Risk Factors for Colorectal Cancer in Patients with Inflammatory Bowel Disease.

Table 2. Crude Incidence Rate and Standardized Incidence Ratio of Colorectal Cancer in Patients with Inflammatory Bowel Disease.

- How do the precursor colitis-associated dysplastic lesions compare with the dysplastic lesions seen in sporadic colorectal cancer?

As in sporadic colorectal cancer, in which the precursor dysplastic lesion is usually a visible polyp, in colitis, most dysplasia is also visible in the colon. However, colitis-associated dysplastic lesions are often flatter and have less distinct borders, and they can even be invisible when standard endoscopic techniques are used. This has prompted the recommendation to perform extensive biopsies throughout the colorectum, taking care to target any raised or suspicious lesions. Newer endoscopic techniques, especially high-definition white-light colonoscopy and chromoendoscopy with mucosal dye-spraying, enhance the detection of dysplasia, as compared with standard-light colonoscopy. This is why most international authorities now favor chromoendoscopy with targeted biopsies over random biopsies, although the latter approach, alone or in combination with targeted biopsies, has not yet been fully abandoned.

Figure 1. Pathogenesis of Colorectal Carcinoma.

Morning Report Questions

Q: What is the relative risk of cancer in patients with inflammatory bowel disease treated with thiopurines as compared to TNF-alpha antagonists?

A: After adjustment for confounders, current use of thiopurines for inflammatory bowel disease has been shown to be associated with an overall relative risk of cancer of 1.3 to 1.7 in adequately powered cohort studies. This excess risk is reversible after thiopurine withdrawal. There is no overall excess risk of cancer in patients treated with TNF-alpha antagonists for inflammatory bowel disease, but a long-term excess risk due to accumulated doses cannot yet be ruled out because of the relatively recent use of biologics.

Q: What is the most common type of lymphoma induced by thiopurines in this population?

A: Thiopurines were shown in the 1970s to increase the incidence of non-Hodgkin’s lymphoma after kidney transplantation. This phenomenon was established in the early 2000s in patients with inflammatory bowel disease. Most of the lymphomas induced by thiopurines are posttransplant-like EBV-associated B-cell lymphomas. These lymphomas may occur in patients seropositive for EBV (i.e., almost all adults >30 years of age); in these patients, non-Hodgkin’s lymphoma is attributed to the cytotoxic effects of thiopurines on EBV-specific immune cells that prevent the proliferation of EBV-infected B lymphocytes.

Table 3. Risks of Cancer in Patients with Inflammatory Bowel Disease Exposed to Thiopurines and TNF-alpha Antagonists.

Take the New Interactive Medical Case!

Posted by Karen Buckley • April 9th, 2015

A 43-year-old man with a 6-week history of abdominal pain and diarrhea. The pain was initially epigastric and occurred after eating but then became more constant and diffuse.  The patient rated the pain at 7 on a scale of 0 to 10, with 10 being the most severe pain.  The diarrhea began gradually and was watery, occurred six or seven times daily (including when the patient fasted, at night), and was associated with urgency and tenesmus.

Test your diagnostic and therapeutic skills with this latest Interactive Medical Case, and earn CME credit or MOC points.

Interactive Medical Cases are online simulations based on a real patient’s experience of illness. You follow interactive steps through an evolving patient’s history, diagnosis, and management, from presentation to outcome. During the presentation of the case, you access videos, lab results and brief commentary that explain concepts important for diagnosis and treatment.

You may also wish to browse the list of 35 previous Interactive Medical Cases.