Twitter highlights from #ACR13 review course

Juvenile Idiopathic Arthrits

Systemic Sclerosis

Rheumatic Disease and Pregnancy

Psoriatic Arthritis

Osteoarthritis

Opioids

Morbidity from DMARDs

Infectious Risk of Rituximab in Combination with Other Biologics

Rigby WF, et al. Safety of Rituximab in Combination with Other Biologic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis: An Open-label Study. J Rheumatol. 2013 Apr 1. [Epub ahead of print]

As rheumatologists, we have become fairly comfortable with the safety profile of rituximab and other biologics when used as monotherapy, but probably have never used biologics in combination, fearing infectious complications.

Unfortunately:

about 20%–40% of patients do not achieve an adequate clinical response to biologic DMARD [monotherapy] treatment

Despite these inadequate responses, data to help choose the optimal biologic therapy are limited given the limited number of RCTs comparing biologic DMARDs.

This was an open label study of 176 patients looking at the combination of rituximab plus one other biologic (adalimumab, etanercept, abatacept, or infliximab). 58/178 (33%) patients were also on MTX.

The rate of serious infections were of highest concern in this study, but results were rather reassuring:

Four serious infections were reported over 48 weeks (2.7 events/100 patient-yrs, 95% CI 1.0–7.2).

Over the 48-week study period, 104 (59.1%) of patients, did experience some type of infection.

Although there was no control group in this study, the authors noted that these findings were similar to previous data:

it is striking that no evidence of an increased safety signal was observed

Also pointing out that:

This safety profile should be considered in the context of this treatment-refractory patient population

While combinations of biologic medications are a potential next step to study, I would expect this data to only very slowly emerge. Before the practice of using rituximab with other biologics becomes more mainsteam, much better data is certainly needed.

With the above study in mind, another paper that provides some useful data on which patients might be at higher risk of infections while receiving rituximab:

Gottenberg JE, et al. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry Arthritis Rheum. 2010 Sep;62(9):2625-32. doi: 10.1002/art.27555.

Which points out risk factors for infection such as:

  • low IgG level (<6 gm/liter) before initiation of RTX treatment (odds ratio 4.9 [95% confidence interval 1.6–15.2], P = 0.005)

  • chronic lung disease and/or cardiac insufficiency (OR 3.0 [95% CI 1.3–7.3], P = 0.01)

  • RA-related extraarticular involvement (OR 2.9 [95% CI 1.3–6.7], P = 0.009)

The authors suggest checking IgG levels prior to subsequent cycles of rituximab.

The Ig concentrations should also be assessed before each new cycle of RTX, given the cumulative risk of decreased Ig levels with repeated treatments with RTX

Maintenance, reduction, or withdrawal of etanercept in RA

Smolen JS, et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial Lancet. 2013 Mar 16;381(9870):918-29. doi: 10.1016/S0140-6736(12)61811-X. Epub 2013 Jan 17.

Many patients will ask how long they need to continue taking certain medications. The PRESERVE trial is the first RCT looking at reduction or withdrawl of TNF inhibitors in RA.

This study is 52-week extension of an initial 36-week open-label trial of methotrexate plus etanercept 50mg weekly, and included only those patients who achieved sustained low disease activity.

participants were eligible for randomisation when they had completed the open-label stage (36 weeks) and achieved sustained low disease activity (mean DAS28 ≤3·2 from weeks 12 to 36 and DAS28 ≤3·2 at week 36).

604 patients were randomized 1:1:1: to:

  • 50 mg etanercept plus methotrexate
  • 25 mg etanercept plus methotrexate
  • Placebo injection plus methotrexate

The primary endpoint was the proportion of patients with low disease activity at week 88

Percentage of patients acheiving primary endpoint:

  • 50 mg etanercept + MTX: 82·6%
  • 25 mg etanercept + MTX: 79·1%
  • Placebo + MTX: 42·6%

No differences were noted in adverse events, specifically infections.

After acheiving remission, it appears that reducing the dose of etanercept to 25mg weekly is a viable option, and as the authors point out, potentially an economical option as well.

Testing for Hepatitis B infection Prior to Immunosuppressive Therapy

After the Choosing Wisely Campaign sought to raise awareness of uncessary testing in medicine, I wondered about the best test(s) to screen patients for hepatitis B prior to immunosuppresion. After polling a few colleagues gave varying responses, I began to learn it isn't just us that are unclear on this topic.

Unfortunately, guidelines from the various societies are also inconsistent on this topic.

The 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis gives this noncommital suggestion (in the footnote under table 4):

Evaluation might include tests for hepatitis B surface antigen, hepatitis B antibodies, hepatitis B core antibodies...

The CDC has a Hepatitis B page that includes a number of resources on this topic:

The tests used to screen persons for HBV should include HBsAg and hepatitis B surface antibody (anti-HBs).

Alternatively, hepatitis B core antibody (anti-HBc) can be utilized as long as those who test positive are further tested for both HBsAg and anti-HBs to differentiate infection from immunity

Persons receiving cytotoxic or immunosuppressive therapy ... should be tested for serologic markers of HBV infection (i.e., HBsAg, anti-HBc, and anti-HBs)

Throughout these guideliness, recommendations for testing of anti-HBc is the most inconsistent part. To recall, the hepatitis B core antibody:

Anti-HBc appears at the onset of symptoms or liver-test abnormalities in acute HBV infection and persists for life in the majority of persons. MMWR

However, an isolated positive hepatitis B core antibody might be a false positive, especially in low-risk populations:

In low-prevalence populations, isolated anti-HBc may be found in 10%--20% of persons with serologic markers of HBV infection, most of whom will demonstrate a primary response after hepatitis B vaccination

They also point out that:

Isolated anti-HBc positivity can represent:

1) resolved HBV infection in persons who have recovered but whose anti-HBs levels have waned, most commonly in high-prevalence populations;

2) chronic infection in which circulating HBsAg is not detectable by commercial serology, most commonly in high-prevalence populations and among persons with HIV or HCV infection (HBV DNA has been isolated from the blood in <5% of persons with isolated anti-HBc); or

3) false-positive reaction.

Unfortunately, the 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis did not give any additional suggestion regarding the isolated hepatitis B core antibody:

The panel did not make recommendations regarding the use of any biologic agent for treatment in RA patients with a history of hepatitis B and a positive hepatitis B core antibody.

After digesting all of this a bit, it seems most reasonable to:

  1. Test for HBsAg and HBsAb in low risk populations.
  2. In higher risk populations, also include anti-HBc

What is your take on this? Should all patients be tested for anti-HBc?

Leflunomide in Psoriatic Arthritis

Behrens F, et al. Leflunomide in psoriatic arthritis: Results from a large European prospective observational study. Arthritis Care Res. 2013 Mar;65(3):464-470. doi: 10.1002/acr.21848.

A total of 514 patients were enrolled in this study (mean age 50.7 years, mean disease duration 6.1 years). In the primary effectiveness analysis, 380 (86.4%) of 440 patients (95% confidence interval 82.8%–89.4%) achieved a PsARC response at 24 weeks. Significant improvements were observed in tender and swollen joint scores and counts, patient and physician global assessments, fatigue, pain, skin disease, dactylitis, and nail lesions.

This was a prospective observational trial with a large number of patients, and provides additional necessary evidence that leflunomide is effective in psoriatic arthritis.

The most frequent ADRs were diarrhea (16.3% of all ADRs), alopecia (9.2%), hypertension (8.2%), and pruritus (5.1%).

The discontinuation rate was 12.3%. Ninety-eight adverse drug reactions occurred in 62 (12.1%) patients; 3 drug reactions were serious (2 increased liver enzymes, 1 hypertensive crisis).

Here, I just want to point out that leflunomide has been known to cause hypertension. Something we should watch for.

There is evidence that adding leflunomide to concomitant DMARD therapy did not lead to an increase in adverse events

Leflunomide might be a nice option to add to patients already on anti-TNF monotherapy with uncontrolled disease.