Refractory Ra: How To Treat
Josef S. Smolen, MD, a rheumatologist at the Medical University of Vienna in Austria, opened his ACR 2020 talk with a clear definition of refractory rheumatoid arthritis: The inability to reach the treat-to-target goals of remission or at least low disease activity despite various changes of therapy.
To illustrate, he presented a case history of a 65-year-old woman with an 11-year history of RA. Results of ACPA and RF were both positive high titre. The patient had failed many therapies, including biologic DMARDS .
She had 14 tender joints, 10 swollen. Her CDAI was 37.9. Clearly this was refractory disease, he told the audience.
The patient was prescribed a JAK inhibitor. At six week follow-up, she had 7 tender joints, 4 swollen, and her CDAI was 18. At 12-week follow-up, she had 3 tender joints, 2 swollen, with a CDAI of 8.5.
To prevent refractory RA, said Dr. Smolen, physicians must make a rapid diagnosis, initiate DMARD therapy promptly, and follow clinical treatment guidelines about switching therapies.
Treatment should aim for best care, with shared decision-making with the patient, he noted, and should be adapted if the treatment aim is not reached within 3 to 6 months. Another key clinician consideration should be to look for a CDAI reduction of more than 50% by 3 months, target at 6 months.
How Do Comorbidities Impact The Management Of Ra
Patients with RA may have other diseases and conditions that require consideration before initiating treatment for RA. The American College of Rheumatology recommends screening for latent tuberculosis , hepatitis B virus, and hepatitis C virus infections before starting treatment.16 This is important because immunosuppression can reactivate infections, but also because a false-positive result on rheumatoid factor antibody testing can occur in the setting of chronic infections. Patients with congestive heart failure should avoid antitumor necrosis factor therapy for RA. Skin cancer screening is important in all patients with RA receiving biologic therapy.
Clinical Features Of Hbsag/hbcab+ Patients With Hbv Reactivation
The general characteristics of the HBsAg/HBcAb+ patients are shown in Table 1. With TCZ administration, one HBsAg/HBcAb+ patient experienced HBV reactivation . In this case, after 18 months of TCZ treatment, HBsAg seroreversion with serum HBV DNA appearance was observed. Her serum ALT level remained stable without evidence of hepatitis flare-up. Entecavir was initiated, and the HBV viral load was undetectable 22 months later. TCZ treatment was continued. The time course of HBV reactivation is described below and shown in Fig. 2d.
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Factors Associated With Hepatitis B Virus Reactivation
In univariate analysis, older age, male sex, HBeAg status, and baseline ALT level were not associated with HBVr . Glucocorticoid was associated with the risk of HBVr with the unadjusted hazard ratio of 2.29 . Biological disease-modifying antirheumatic drugs were not significantly associated with HBVr . Glucocorticoid in combination with sDMARDs and bDMARDs had the highest risk of HBVr, compared with sDMARDs alone .
Factors Associated With Hepatitis B Virus Reactivation Among Overall 123 Hepatitis B Surface AntigenPositive RA Patients
Cumulative risk of hepatitis B virus reactivation in rheumatoid arthritis patients stratified by with or without glucocorticoid treatment or stratified by regimens of immunosuppressive agents . C, Cumulative risk of HBVr in biological disease-modifying antirheumatic drug treated patients stratified by with or without glucocorticoid . D, Cumulative risk of mortality stratified by the development of HBVr or not in RA patients . The incidence of HBVr was evaluated by Kaplan-Meier analysis and Log-rank test. Abbreviation: sd, synthetic disease-modifying antirheumatic drugs.
Is The Use Of Biologic Agents Recommended In Rheumatoid Arthritis And Hepatitis
Patients with RA requiring treatment who are infected with hepatitis C should not be treated differently than RA patients not infected with hepatitis C. In RA patients with untreated chronic hepatitis B virus infection, as well as those with treated chronic HBV disease of Child-Pugh class B and higher, biologic agents are not recommended. In patients with HBV infection who are receiving or have received antiviral therapy, treatment recommendations are the same as in patients without HBV infection.
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Course Of Hbv Infection
HBV infection can occur in a variety of clinical formsfrom asymptomatic, by explicitly acute viral hepatitis, chronic inflammation, which can result in cirrhosis and liver cancer . The majority of adult patients of host defense mechanisms allow for total eradication HBV .
There are the following phases of HBV infection :
Immune tolerance phasedue to the low immune response, aminotransferase levels are low, and inflammatory changes in liver histopathology not significantly increased despite a high viral load of HBV DNA . If this occurs during the integration of HBV DNA with the host DNA in hepatocytes, the likelihood of HBV eradication decreasesboth spontaneous and induced by treatment
Immune clearance phaseactive immune response against HBV-infected hepatocytes, leading to an elevated aminotransferase levels and severe necro-inflammatory changes in liver histopathology. HBs antigen is always present, and HBe antigenpositive or negativeantibodies to HBe may be present. HBV DNA viral load is moderately high . The majority of patients in this phase present a spontaneous loss of HBeAg antigen and the appearance of antibodies to HBeAg, called seroconversion
Immune control phaseafter HBeAg seroconversion antibodies to HBe are present, HBV DNA replication is low , transaminase activity is normal or slightly increased, and the histopathological changes in the liver are absent or minimal
Tocilizumab For Rheumatoid Arthritis With Chronic Hepatitis B Virus Infection Without Antiviral Therapy
To the Editor:
In their editorial in the June 2009 issue of The Journal, Wendling, et al cited our report as evidence that tocilizumab had been used uneventfully for more than 5 years to treat a patient with rheumatoid arthritis who was a hepatitis B virus carrier. However, they misunderstood that our patient had received tocilizumab along with prophylactic entecavir throughout her treatment. Actually, we started tocilizumab in August 2001, without confirming her HBV status. After she was incidentally found to be HBV-positive in March 2008, we added treatment with entecavir from May 2008. Recently, serum from this patient stored in 1999 was reexamined, showing that HBsAg was already positive and the viral load was quite high at that time. In other words, HBV infection already existed before the initiation of tocilizumab therapy, and she was treated with tocilizumab for almost 7 years without entecavir. This was an unusual case because her viral load was high, HBeAg was positive, and anti-HBe was negative. Hence, our patient is quite different from previous cases with respect to both her viral status and the use of antiviral therapy.
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What Are The Extra
Extra-articular manifestations of RA include keratoconjunctivitis sicca, episcleritis, interstitial lung disease, pulmonary nodules, rheumatoid nodules, and pleural effusions . The prevalence of extra-articular manifestation varies from approximately 8% to 40%, depending on the patient population and how the manifestations are defined.
Extra-Articular Manifestations of Rheumatoid Arthritis
Leading cause of death in patients with RA
Present in 30% to 50% of persons with RA on autopsy, rarely leads to tamponade
Acute, red, painful eye occurs in less than 1% of patients with RA
Secondary Sjögren syndrome, dry mouth may also occur
Peripheral ulcerative keratitis
More severe scleritis, if untreated can perforate anterior chamber
Caused by C1C2 subluxation, seen on flexion-extension radiography
Carpal tunnel, mononeuritis multiplex
Nodules and pneumoconiosis
Interstitial lung disease
May resemble bronchiolitis obliterans with organizing pneumonia, idiopathic pulmonary fibrosis, patient may also have pulmonary arterial hypertension
Exudative effusion with markedly low glucose level
Firm or rubbery, located on pressure areas
Poor prognosis, increased mortality, rare but occurs with severe RA
RA = rheumatoid arthritis.
Extra-Articular Manifestations of Rheumatoid Arthritis
RA = rheumatoid arthritis.
Can Patients With Ra Taper Or Discontinue Medication Use And Remain In Remission
Tapering and discontinuing medication use while maintaining remission is possible. Patients who have been in remission for more than six months on a stable medication regimen and who test negative for anti-citrullinated protein antibodies are most likely to maintain remission without medication.
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Incidence And Baseline Characteristics Of Hepatitis B Virus Reactivation
After the follow-up of 3459 person-months , 30 patients developed HBVr, an incidence rate of 8.6 per 1000 person-months . The mean time to HBVr was 13.6 ± 11.5 months after the start of immunosuppressants, sDMARDs, or bDMARDs. Patients developing HBVr had higher baseline serum HBV load than those without HBVr among cases with available HBV DNA data . The frequency of GC use was significantly higher in patients with HBVr versus those without HBVr . However, the frequency of bDMARD use was similar between patients with and without HBVr . According to the treatment regimens, patients were classified into 4 groups: sDMARDs alone , sDMARDs in combination with bDMARDs , GC in combination with sDMARDs , and GC in combination with sDMARDs and bDMARDs . The risk of HBVr was associated with the regimens of immunosuppressant . There were no differences in age at diagnosis, sex, and baseline serum ALT/AST levels between those with and without HBVr .
The median baseline HBV load was 132 IU/mL in the sDMARDs alone group, 41 IU/mL in the sDMARDs in combination with bDMARDs group, 2350 IU/mL in the GC in combination with sDMARDs group, and 721 IU/mL in GC in combination with sDMARDs and bDMARDs group. The peak HBV loads during HBVr ranged 3800> 170000000 IU/mL the peak ALT levels ranged 1052207 IU/mL and the peak total bilirubin level ranged 0.4323.31 mg/dL.
The Impact Of Hepatitis Screening On Diagnosis And Treatment In Rheumatoid Arthritis
Richard Conway1, Michele Doran2, Finbar D. O’Shea3 and Gaye Cunnane2, 1Rheumatology, St James’s Hospital, Dublin, Ireland, 2Dept of Rheumatology, St James’s Hospital, Dublin, Ireland, 3Rheumatology Dept, St James’s Hospital, Dublin, Ireland
Session Type: Abstract Submissions
Hepatitis testing is an important pre-requisite to the diagnosis and treatment of patients with rheumatic disease. Joint symptoms may be a manifestation of acute or chronic hepatitis B or C. Immunosuppressive treatment may increase viral load in patients with undiagnosed viral hepatitis. The prevalence of hepatitis varies amongst populations, but even in areas with low endemic levels, it is imperative to identify those in whom current or past infection may influence clinical outcome. The CDC recommends testing for 4 components: hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody and hepatitis C antibody. Although ACR recommendations do not specifically recommend hepatitis screening, they do advocate vaccination against hepatitis B in all patients. This study was conducted in order to identify new cases of hepatitis in a cohort of patients with RA attending a large university teaching hospital and to evaluate the extent of the hepatitis screen undertaken.
Table 1: Completeness of Hepatitis Screening
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Exercise And Physical Therapy
Results of randomized controlled trials support physical exercise to improve quality of life and muscle strength in patients with RA.32,33 Exercise training programs have not been shown to have deleterious effects on RA disease activity, pain scores, or radiographic joint damage.34 Tai chi has been shown to improve ankle range of motion in persons with RA, although randomized trials are limited.35 Randomized controlled trials of Iyengar yoga in young adults with RA are underway.36
Treatment And Clinical Data Collection
All patients were treated according to the 2008/2012 ACR and the 2010/2013 EULAR recommendations for the management of RA. The therapeutic target was defined as DAS28-CRP < 2.6 in all patients or < 3.2 in patients with long disease duration . Available clinical data on patients with RA were collected in this study at baseline and at visits at months 1, 3, 6, and 12, as described before , including 28-joint tender and swollen joint counts , patient and provider global assessment of disease activity , pain visual analog scale , the Stanford Health Assessment Questionnaire , erythrocyte sedimentation rate , CRP, rheumatoid factor , and anti-cyclic citrullinated peptide antibody . Besides DAS28-CRP, disease activity was also assessed using the Simplified Disease Activity Index , the Clinical Disease Activity Index , and the Routine Assessment of Patient Index Data 3 . Cumulative doses of oral glucocorticosteroids and disease-modifying anti-rheumatic drugs were recorded during one-year follow up. GC doses were converted to a prednisone-equivalent dose.
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Incidence Of Hepatitis B Virus Reactivation In Patients With Rheumatoid Arthritis During Treatment With Biologics
1, Takao Nagashima1, Katsuya Nagatani2, Taku Yoshio3, Masahiro Iwamoto4 and Seiji Minota5, 1Rheumatology and Clinical Immunology, Jichi Medical University, Tochigi, Japan, 2Division of Rheumatology and Clinical Immunology, Jichi Medical University, Tochigi, Japan, 3Division of Rheumatology and Clinical Immunology, Jichi Medical University, School of Medicine, Shimotsuke-shi, Tochigi-ken, Japan, 4Division of Rheumatology and Clinical Immunology, Jichi Medical University, Shimotsuke, Tochigi, Japan, 5The Safety Evaluation Committee of Actemra® for JIA, Tokyo, Japan
Session Type: Abstract Submissions
Background/Purpose: Reactivation of hepatitis B virus is very problematic in patients who are receiving biologics. Optimal precaution and management for those patients are still controversial. The aim of this study is to clarify the incidence of HBV reactivation in rheumatoid arthritis patients on biologics and to find out whether there is difference in reactivation rates among different biologics.
Rheumatoid Arthritis: Common Questions About Diagnosis And Management
AMY WASSERMAN, MD, Westchester Medical Center, New York Medical College, Valhalla, New York
Am Fam Physician. 2018 Apr 1 97:455-462.
Patient information: A handout on this topic is available at .
Rheumatoid arthritis is the most common autoimmune inflammatory arthritis, with a lifetime prevalence of up to 1% worldwide.1 It has a significant impact on occupational and daily activities, as well as mortality.24 This article reviews common questions on the diagnosis and management of RA, and presents evidence-based answers.
WHAT IS NEW ON THIS TOPIC
The 2015 American College of Rheumatology guidelines continue to recommend methotrexate as the first-line treatment for rheumatoid arthritis, unless contraindications are present.
In a randomized trial of patients who were on stable disease-modifying antirheumatic drug regimens and in clinical remission for at least six months, 84% of patients who continued full DMARD treatment remained in remission after 12 months, compared with 61% who tapered DMARDs by 50%, and with 48% of those who stopped all DMARDs.
SORT: KEY RECOMMENDATIONS FOR PRACTICE
Methotrexate should be the first-line disease-modifying antirheumatic drug in patients with rheumatoid arthritis unless there are contraindications.
SORT: KEY RECOMMENDATIONS FOR PRACTICE
Recommendations from the Choosing Wisely Campaign
BEST PRACTICES IN RHEUMATOLOGY
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Inflammatory Arthritis Following Hepatitis B Vaccination In An Infant
Sana S. Rahimi
1Department of Primary Care Pediatrics, Nemours Childrens Health System, Milford, DE, USA
2Department of Pediatrics, Bernard and Millie Duker Childrens Hospital at Albany Medical Center, Albany, NY, USA
Inflammatory arthritis in children may be idiopathic in nature or may be due to or follow infections. Rare reports identify inflammatory arthritis temporally related to vaccination in children. Herein, we describe the first reported case of an infant who developed inflammatory arthritis following hepatitis B vaccination. A 10-day-old female presented for evaluation of decreased movement of the right lower extremity and right knee swelling. Of note, the patient received a hepatitis B vaccine in her right thigh at birth. A workup found the patient to have a negative ANA but the presence of HLA B27. Findings resolved using ibuprofen. A literature review identified reports of what has been termed reactive arthritis in adult patients following the hepatitis B vaccine, frequently in association with HLA B27. No prior pediatric cases have been published. Healthcare providers must be aware of the rare development of postvaccination inflammatory arthritis.
This case presents a very young infant who developed an inflammatory arthritis believed to be secondary to the initial hepatitis B vaccine.
3.1. Inflammatory Arthritis after Hepatitis B Vaccination
3.2. Very Early-Onset JIA
Factors Influencing The Antibody Response To Hepatitis B Vaccine
Lack of humoral response was significantly associated with older age age 59 in non-responders v 46.3 in responders) and increased daytime pain at vaccination in non-responders v 2.2 in responders). The humoral response was not associated with the number of tender and swollen joints at vaccination, ESR, CRP or the use and doses of drugs such as prednisone, methotrexate, azathioprine, hydroxychloroquine, intramuscular gold, and non-steroidal anti-inflammatory drugs.
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Hepatitis B Vaccination And Rheumatoid Arthritis
Extract from report of GACVS meeting of 12-13 December 2007, published in the WHO Weekly Epidemiological Record on 25 January 2008
GACVS considered the potential association of hepatitis B vaccination and rheumatoid arthritis . Prior to previous discussions on this topic held in June 2006, the committee had commissioned a comprehensive literature review. At this meeting, it had reviewed more recent information, particularly on genetic issues.
The literature relating HBV to RA comprises mainly single case reports, case series and a few casecontrol studies. The published studies are limited and difficult to interpret owing to problems in the methodology and control of confounding. The one high-quality casecontrol study did not find a statistically significant association, but it had limited power and wide confidence intervals. However, as only a small proportion of cases had received HBV, there is at most a very small contribution of HBV to the incidence of RA. GACVS had also seen the preliminary results of a large study based on the United States Vaccine Safety DataLink project in June 2006, which was analysed in several ways, but none showed a significant association between HBV and RA.
There are various subtypes of HLA DRB1*04, of which 9 occurred in this study analyses were limited to 2 of the subtypes.