Dr. Clifton Bingham III, director of the Johns Hopkins Arthritis center, and Malini Moni, BDS a post-doctoral research fellow investigated the presence of gum disease in patients who have rheumatoid arthritis (RA). During their research, over 300 complete oral health and rheumatological exams were done on patients who have RA. Along with the oral health and rheumatological exams, patients were given a questionnaire to complete. This questionnaire included detailed information about medical and dental history to give a full picture of the patients overall health.
A complete oral health exam includes looking at the number of teeth a patient has, if there is any gum inflammation, bleeding, or recession. The base of the teeth are also examined to see if there is any sign of bone loss or risk of tooth loss.
The rheumatological exam includes examining the joints and looking at the bloodwork for each patient to determine how severe their RA is. Patients were also tested for dry eyes, and dry mouth.
To understand whether gum disease is different in patients who have RA, healthy volunteers had a complete oral exam for comparison.
The data collected from 100 RA patients and 40 healthy volunteers was compared and analyzed. The results show that 70% of RA patients in this study had at least moderate gum disease, 30% had severe gum disease. In the general population, 35% have gum disease, with 5% of those having severe gum disease. The higher rates and more severe gum disease in RA were not explained by other risk factors for gum disease like age or smoking.
The study found that even in the early stages of RA, gum disease and even severe gum disease was present. Some of the indicators of gum inflammation were less in people receiving biological RA therapy.
This study showed that gum disease was common and often severe in patients who have RA. Additional studies are now being done to evaluate how treatment of RA using biologic medications may affect RA and oral health and how markers of inflammation from fluid around the teeth and in saliva may give us information about RA. There are also studies taking place in the lab to understand whether exposure to bacteria in the mouth may be related to the development of RA or may make it more severe.
It is important for all patients living with RA to be aware of your oral health. RA patients should get complete oral exams regularly at their dentist and should let the dentist know they have RA. Patients should let their rheumatologist know if they have any new dental problems.
TO improve overall oral health, some things to avoid are cigarette smoking, and chewing tobacco. Make sure to brush with a fluoride toothpaste, floss regularly and consider using a fluoride rinse. If arthritis affects your wrists or hands or if your grip is poor buy a battery-powered toothbrush with a large handle. If you have problems with dry mouth, let your doctor and dentist know as there may be medications and other ways to help with this symptom as well.
Johns Hopkins Arthritis Center researchers conducted a research study to evaluate the safety and effectiveness of yoga for patients with rheumatoid arthritis and osteoarthritis. After an 8 week program, there was an improvement by 20% in levels of pain, energy, mood, and physical function.
OTREXUP™ (methotrexate) injection was recently approved by the U.S. Food and Drug Administration.
It is indicated for adults with severe, active rheumatoid arthritis, or children with active polyarticular juvenile idiopathic arthritis who have failed first line therapies. It is also indicated for severe, recalcitrant, disabling psoriasis.
OTREXUP™ is delivered by auto injector as a subcutaneous injection. It will be available in four dose strengths: 10mg, 15mg, 20mg, and 25mg.
Side effects of Otrexup are unchanged for other formulations of methotrexate.
Patients using any form of methotrexate must be counseled on risks of toxicity, proper administration, risks of pregnancy and nursing, and proper storage and disposal, and the need for frequent, ongoing monitoring.
Editorial Note: While patients are very receptive to administration of medication by auto-injector, price and insurance coverage may be the determining factor in switching from oral methotrexate to Otrexup vs. vial and syringe.
Tofacitinib (Xeljanz®) is the first of a unique class of oral kinase inhibitors to be FDA approved for the treatment of rheumatoid arthritis (RA). Tofacitinib is a selective inhibitor of Janus kinase (JAK) enzymes. JAKs mediate signaling by surface receptors for several important cytokines that are fundamental to the propagation of inflammation in RA. JAK enzymes (JAK1, JAK3) are responsible for activating Signal Transducers and Activators of Transcription (STATs) which further modulate intracellular activity and gene expression. Tofacitinib prevents signaling of JAK enzymes and therefore interrupts important signal transduction of cytokines which contribute to the aberrant immune response in RA.
Based on the results of several Phase 2 and Phase 3 studies (two of which will be summarized below), the FDA has approved tofacitinib, at a dose of 5mg twice daily, for the treatment of RA in adults with moderate to severe disease, who have had an inadequate response to, or are intolerant of, methotrexate. It can be used as monotherapy or in combination with methotrexate. It is not to be used in combination with other potent immunosuppressive medications or biologic agents.
RA patients clearly demonstrated a clinical response with tofacitinib compared to placebo in these trials with improvement in the number of painful and swollen joints. However, tofacitinib did not receive a prescribing indication from the FDA for the prevention of radiographic progression, based on the available data.
Inhibition of JAK signaling is a potent pathway to interrupt, and there are some important side effects to be aware of with this drug. Notably, severe infections, including opportunistic infections, were noted in the treatment groups. However, infection rates were similar to those seen with other biologic DMARDs. All patients should be screened for latent TB prior to starting tofacitinib. Herpes zoster infections occurred at a higher rate in individuals treated with tofacitinib than placebo. This rate of herpes zoster was higher than what has been observed in other biologic DMARD studies, and while not indicated on the label, we believe that consideration should be given to vaccinating patients prior to the initiation of tofacitinib. Live vaccines (such as the herpes zoster vaccine) should not be administered to patients taking tofacitinib. Hematologic abnormalities (neutropenia, lymphopenia, and anemia) were observed with tofacitinib and need to be routinely monitored for during treatment. Monitoring of transaminases, lipids, and creatinine also should be done regularly, as abnormalities in all of these laboratory parameters were observed during the trials. Dose reduction of tofacitinib is required for patients taking CYP3A4/CYP2C19 inhibitors (i.e. ketoconazole or fluconazole) due to increased levels of the drug.
The addition of a powerful oral molecule with biologic-like efficacy on signs and symptoms of RA to the armamentarium of treatments we have to offer patients suffering with RA is an exciting prospect. However, the oral delivery of this drug should not be taken to imply increased safety or less potency than injectable or infusible biologic therapies.
Two important studies evaluating the safety and efficacy of tofacitinib for the treatment of rheumatoid arthritis were published recently in the New England Journal of Medicine. These studies are summarized below:
Adult patients with RA and active disease (≥6 tender joints + ≥ 6 swollen joints + elevated ESR/CRP) who had failed (because of lack of efficacy or side effects) at least one other RA therapy (biologic or nonbiologic DMARD) were eligible for inclusion. The study design was a randomized, double-blind, placebo-controlled, parallel-group trial. Participants were randomized to one of four possible treatment groups for a total of 6 months. 1) Tofacitinib 5mg twice daily x 6 months; 2) tofacitinib 10mg twice daily x 6 months; 3) placebo x 3 months followed by tofacitinib 5mg twice daily x 3 months; 4) placebo x 3 months followed by tofacitinib 10mg twice daily x 3 months. Comparisons were made between placebo and tofacitinib at 3 months on three primary endpoints: ACR20 response (at least 20% reduction from baseline in the number of tender and swollen joints + 20% improvement in ≥3/5 of the following: patient pain assessment, disability, CRP, global disease activity by patient, global disease activity by physician), change in HAQ-DI (disability index), and DAS28-4(ESR) score <2.6. The DAS28-4(ESR) is a composite index of 4 weighted variables (# of tender joints from 28-joint count, # swollen joints from 28-joint count, ESR, patient’s global assessment of disease activity). Adverse events were also collected and analyzed compared to placebo.
611 RA patients were randomized for this study. 122 received placebo for the first 3 months. 243 received 5mg tofacitinib twice daily, and 245 received 10mg tofacitinib twice daily. The patients had a mean age of 50-52 years, and a mean RA disease duration of 7.7-8.6 years. After 3 months, 59.8% in the 5mg tofacitinib group, 65.7% in the 10mg tofacitinib group, and 26.7% in the placebo group met ACR 20 response criteria (p<0.001). There was a significantly greater decrease in HAQ-DI scores among the treatment groups compared to placebo at 3 months (p<0.001). After 3 months, there was not a significant difference between the groups by the outcome DAS28-4(ESR), however there was by 6 months. There were more adverse events in the tofacitinib groups compared to placebo. 6 patients had serious infections. 54% had adverse events with the most common being upper respiratory tract infections, headaches, and diarrhea. Lab abnormalities that occurred more frequently among the tofacitinib groups were neutropenia, elevated transaminases, elevated LDL cholesterol, and serum creatinine.
Tofacitinib as monotherapy, compared with placebo, reduced signs and symptoms of RA and improved function among adults who had failed a previous DMARD. However, the endpoint for remission (DAS28-4(ESR)<2.6) was not met. There were more adverse events in the tofacitinib groups compared to placebo with infections, including serious infections, topping the list.
Adult patients with RA and active disease (≥6 tender joints + ≥ 6 swollen joints + elevated ESR/CRP) despite receiving treatment with 7.5-25mg of methotrexate weekly were eligible for inclusion. Important exclusion criteria were current treatment with other anti-rheumatic agents (including biolgoics), prior treatment with adalimumab, lack of response to previous anti-TNFα agent, or current infection. The study design was a randomized, phase 3 clinical trial. Participants were randomized to one of 5 possible treatment. 1) Tofacitinib 5mg twice daily; 2) tofacitinib 10mg twice daily; 3) 40mg adalimumab every other week; 4) placebo for 3 or 6 months followed by tofacitinib 5mg twice daily; 4) placebo for 3 or 6 months followed by tofacitinib 10mg twice daily. If patients who received placebo did not have a 20% reduction in swollen and tender joints after 3 months they were randomly assigned to 5 or 10mg of tofacitinib. After 6 months, all patinets on placebo were switched to tofacitinib.
The primary endpoints were: ACR20 response , HAQ-DI, and DAS28-4(ESR) score <2.6. Adverse events were also collected and analyzed compared to placebo. The study lasted 12 months.
717 RA patients were randomized for this study. 56 received placebo and 5mg tofacitinib. 52 received placebo and 10mg tofacitinib. 204 received 5mg tofacitinib twice daily. 201 received 10mg tofacitinib twice daily. 204 received 40 mg adalimumab every other week. The patients had a mean age of 52-55 years, and a mean RA disease duration of 6.9-9.0 years. After 6 months, 51.5% in the 5mg tofacitinib group, 52.6% in the 10mg tofacitinib group, 47.2% in the adalimumab group, and 28.3% in the placebo group met ACR 20 response criteria (p<0.001). There was a significantly greater decrease in HAQ-DI scores among the treatment groups compared to placebo at 3 months (p<0.001). After 3 months, there was also significantly more patients in the treatment groups compared to placebo who reached the DAS28-4(ESR) outcome.
Adverse events in the treatment groups included neutropenia, elevated transaminases, elevated LDL cholesterol, elevated serum creatinine, and low hemoglobin. Other adverse events included primarily infections. The rates of serious adverse event in the first three months were higher in tofacitinib groups than placebo or adalimumab. This included 2 cases of pulmonary tuberculosis.
Tofacitinib in combination with methotrexate was superior to placebo to treat the signs and symptoms of RA. In this study, the efficacy of tofacitinib at 12 months was numerically similar between all treatment groups, including adalimumab.
TNFα inhibitors have demonstrated great efficacy for the treatment of rheumatoid arthritis (RA). However, they are not without potential side effects with one being the reactivation of latent tuberculosis (TB). This complication can be minimized by screening for latent TB prior to the initiation of a TNFα inhibitor and initiating treatment. Unfortunately, there is no gold standard by which to screen for latent TB. Tuberculin skin testing with purified protein derivative (PPD) is commonly used as a screen for TB before the initiation of TNFα inhibitors; although imperfections in the test (particularly for individuals already on immunosuppression) are not insignificant. The following study summarized below sought to compare the standard PPD test to the interferon-gamma release assay (IGRA) blood test for latent TB screening among patients with RA, psoriatic arthritis, or ankylosing spondylitis starting the TNFα inhibitor, golimumab [Hsia EC, et al. Interferon-gamma release assay versus tuberculin skin test prior to treatment with golimumab, a human anti-tumor necrosis factor antibody, in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis. Arthritis & Rheumatism 2012;64(7):2068-2077].
Methods:Pooled data from patients who had undergone screening for TB with both the IGRA and PPD test while enrolled in 1 of 5 phase III randomized placebo-controlled clinical trials for golimumab were included in these analyses. The 5 pooled studies included patients with RA (early and previously treated with TNFα inhibitors), psoriatic arthritis, and ankylosing spondylitis. These were international trials, so a wide range of patients were represented. Patients were screened for eligibility in the trials with the same criteria which included 3 TB screening tests: standard PPD, IGRA, and a chest x-ray. Analyses for this study included concordance between the PPD and IGRA results overall, by known BCG vaccination status, and by geographic region. Logistic regression was also completed to evaluate for factors associated with the screening test results.
2303 patients with inflammatory arthritis were included in these analyses from the 5 pooled trials with a median age of 49 years. Almost half were from North America (41.8%) and were receiving corticosteroids (43.4%, median dose 5mg/day). 788 patients had received the BCG vaccine, and 255 had unknown BCG status. 317 patients (13.8%) began treatment for latent TB because of this testing. 99.1% of the patients had both IGRA and PPD testing. 13.8% of all 2282 patients had at least one TB screening test that was positive. 9.4% had positive PPDs, and 7.0% had positive IGRA, and 2.6% were positive on both. 1.8% had indeterminate results on IGRA. Among the patients positive by IGRA, 36.9% were also positive by PPD. Among the patients with a positive PPD, 27.4% were also positive by IGRA. The kappa coefficient for agreement between the 2 tests was 0.22 (95% CI 0.157-0.279). Among those with a known history of BCG vaccination, 15.2% had positive PPD testing compared to 9.1% with positive IGRA testing (p=<0.001). Factors associated with a positive IGRA by logistic regression were age (≥65 years) and geographic areas outside of North America. Individuals who received the BCG vaccine had a higher odds of a having a positive PPD than those who did not receive the vaccine (OR 2.47, 95% CI 1.71-3.55).
With a kappa coefficient of 0.22 there was considerable discordance in the rate of positive results between PPD and IGRA testing. Among those with BCG vaccine, the rate of PPD positivity was significantly greater than IGRA positivity suggesting this may represent some false positive results with PPD in this population. These data suggest IGRA may provide greater specificity for latent TB among those with inflammatory arthritis than PPD.
Screening for latent TB in patients with inflammatory arthritis who will be starting TNFα inhibitors is important to prevent complications of TB-reactivation. However, currently there is no ‘gold standard’ for the diagnosis of latent TB. PPD is a good option as it is inexpensive, easy to administer, and has been used as a screening test for over a century. But many of the short-comings of PPD, which are reviewed in this article, are important in a population with inflammatory arthritis – such as inaccuracies in immunosuppressed patients (leading to false-negative results) and those who have received BCG vaccination (leading to false-positive results). Hence, having another option for screening, such as IGRA, is a meaningful advance. Unfortunately, without a definitive ‘gold standard’ we are left having to make inferences about the performance of the IGRA test; hence results should be interpreted with caution.
