Evaluating a Young Patient with Joint Pain and Stiffness Part 2

You see a 29-year-old female insurance saleswoman with a 6-week history of joint pains and swelling affecting both hands and wrists, both feet and her left knee. Her symptoms are worse when she first gets up in the morning and it takes a few hours before her joints seem to loosen up.

Physical examination revealed warmth and swelling over her wrists, left knee, and the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of her hands and a positive “squeeze” test of the MCP and metatarsophalangeal (MTP) joints. After ordering an initial battery of laboratory tests, you prescribed naproxen 500 mg BID. The patient reports no benefit and she states she been unable to go to work. Laboratory evaluation reveals a Westergren erythrocyte sedimentation rate of 80 mm/hr, a positive rheumatoid factor at a 1:1280 titer, and a strongly positive anti-CCP titer

You confirm the diagnosis of rheumatoid arthritis (RA). What would be the initial management?

If her hepatitis B virus (HBV) and hepatitis C virus (HCV) screens are both negative I would start methotrexate (MTX). I would start her on oral MTX at 7.5 mg for the first week, increase to 15 mg weekly and within 4 weeks would raise the dosage to 20 mg weekly. I would also start folic acid 1 mg daily for the days that she is not taking MTX to reduce the risk of oral ulcers, dyspepsia and nausea. I might also give her an IM injection of Depomedrol 80 mg and start prednisone 10 mg daily.

Would you raise the dose to 20 mg weekly even if her symptoms improve with a lower dose?

I raise the dosage to 20 mg weekly even if she is getting a response at a lower dose since several early RA studies have confirmed that at 20 mg of MTX weekly is the optimal dosage. If she gets a good response but has GI intolerance despite adding folic acid I would switch her over to injectable MTX once weekly.

This this dosage can then be raised to 25 mg weekly if necessary. About a third of patients with early RA obtain complete suppression of disease (i.e. remission) within 3 to 6 months of treatment with MTX alone.

What is the strategy behind adding a steroid?

Adding prednisone at 5-10mg daily is a useful strategy to help relieve systemic symptoms of malaise and fatigue and to boost the anti-inflammatory effects of MTX. The plan is to limit prednisone to the first 6 months of treatment and to then taper and stop prednisone as the disease comes under control.

An NSAID such as naproxen may be used in conjunction with MTX and prednisone but only for the short-term. It is the first drug that I will reduce and stop as soon as the joint pains are under control.

What would you do if she was hepatitis B or C positive?

If she is hepatitis B or C positive then I cannot use MTX and will substitute sulfasalazine (SSZ) and/or hydroxychloroquine (HCQ.) These drugs are much less effective options and I may go straight to a biological agent as monotherapy without MTX rather than persist with these drugs.

Chronic active Hepatitis B is a problem even if we avoid MTX and use a biological agent since HBV can reactivate during immunosuppression and there are cases of fulminant hepatitis. The plan best screen for HBV is to perform both HBsAg and HBV core antibody. A positive HBsAg implies chronic active HBV and the patient needs suppression for a month with an antiviral agent such as entecavir before starting the biologic drug.

However, if HBsAg is negative and HBV core antibody is positive I additionally will check the HBV DNA level since there are patients with low-level chronic active hepatitis who show only HBV core antibody positivity. If HBV DNA is present then the patient needs suppression with an antiviral agent before starting either MTX or a biologic drug. Leflunomide is a potent alternative to MTX and may be substituted if MTX is not tolerated. However, like MTX, it also cannot be used in HBV or HCV positive patients.

In general, when should an RA patient be referred to a rheumatologist?

I recommend an initial referral to a rheumatologist whenever the diagnosis of RA is suspected, especially if there are confounding issues in the history and physical examination as discussed above. Working closely with a rheumatologist who will see the patient at select intervals ensures optimal management.

The most effective strategy for treating RA so as to limit the extent of joint damage and prevent disability is to adopt a treat-to-target policy. For patients like our subject who has very aggressive early RA, the goal is complete remission of her disease. For patients with more advanced disease beyond 3 years and when significant joint damage has accrued we adopt “low disease activity” as our goal.

The treat-to-target plan implies that we perform an objective assessment of her disease activity at certain intervals, typically once 3 three months. We use a tool such as DAS-28 (disease activity score based on 28 joints), CDAI (clinical disease activity index) or SDAI (simplified disease activity index) to document the state of our patient’s disease at fixed intervals and we modify our treatment if the specified target is not achieved. While you may monitor the patient routinely, it is helpful to have a rheumatologist see your patient periodically and recommend treatment changes as needed to make sure that you have stayed on target.

An additional useful tool is to perform baseline x-rays of the hands and feet before initial treatment and repeat them yearly to make sure that there no new erosions or joint space narrowing to suggest persistent damage.

What is the current role of biological agents?

Biological agents are designed to attack a specific locus of the immune-mediated damage in RA. The target could be inflammatory molecules called cytokines such as tumor necrosis factor (TNF) or the interleukins — IL-6, IL-1, and IL-17. They could also be designed to suppress T-cell activation or reduce B-cells.

Oral agents called “small molecules are now available.They target intra-cytoplasmic signals that lead to immune activation. These drugs are so effective in treating RA that they have allowed such ambitious goals as “complete remission” and “low disease activity” in the vast majority of our patients.

Before the “biological era” it was hard to control RA and many patients eventually ended up disabled and with severe joint damage.

When would you consider prescribing a biological agent?

We still start with MTX as our drug of choice. It is customary to give a 3-month period for MTX to work either alone or in combination with prednisone and an NSAID. If the goal is not met at 3 months we either add a biological agent or we adopt the strategy of “triple therapy.” This is a 3-drug regimen of MTX-SSZ-HCQ that in several studies is found to be as effective as an anti-TNF agent such as etanercept in combination with MTX. It also has the benefit of being lower in cost.

Because they were the first biological agents to be shown effective in treating RA, we usually will add an anti-TNF agent to MTX if MTX fails to control the disease adequately at 3 or 6 months. The combination of an anti-TNF drug with MTX is found to be more effective than the anti-TNF agent used alone even in patients who have not responded well to MTX.

If we wish to avoid or discontinue MTX then abatacept (a T-cell modulator) or tocilizumab (a monoclonal antibody (mAb) that targets IL-6 receptor) may be excellent choices since they work very well as monotherapy. We may use rituximab, a mAb that depletes B cells — this drug is reserved for patients who previously had lymphoma or recent cancer or have failed the TNF inhibitors. We do not combine biological agents – there is no added benefit and a much increased risk of serious infection.

The patient continues to have symptoms despite MTX. You decide to add weekly Enbrel (etanercept).

What special precautions need to be taken before initiating it?

Enbrel, a TNF inhibitor, is an excellent first choice in many patients who have an inadequate response to MTX alone. We add Enbrel to the MTX regimen rather than use Enbrel as monotherapy. Before doing so the patient should have at least a PPD skin test for latent tuberculosis and I often add an interferon-γ release assay such as the Quantiferon-Gold test to look for T cell immune response to TB. A chest x-ray is added in high-risk patients such as recent immigrants from an endemic region of the world.

Anti-TNF agents inhibit the natural function of TNF to preserve the integrity of the histiocytic wall in the granuloma that keeps the tubercular bacillus confined in latent TB. There is a risk of TB re-activation if such patients are treated. If any test is found positive for latent TB the patient needs to be treated with daily isoniazid or the more recent recommended weekly combination of isoniazid and rifapentine for at least 4 weeks before starting the anti-TNF agent.

During ongoing treatment with a biological agent periodic screening for TB is advised in patients living in high-risk regions and sero-converters should receive a 9-month course of isoniazid.

Her PPD is negative and Enbrel is added to MTX. The patient has an excellent response to therapy. Three months into therapy she calls your office and states that for the past 2 days she has had a sore throat and cough with a low grade fever?

How should she be evaluated?

This patient was initially found to be PPD skin test-negative. She did well on Enbrel and MTX and 3 months into treatment has a cough, sore throat and low-grade fever.

I recommend bringing her in for an examination of her throat and lungs and to obtain chest x-rays. I suggest that she withhold further Enbrel and MTX until she is seen. The worry here is either TB reactivation or a community- acquired pneumonia (CAP) or an opportunistic infection.

Since Enbrel suppresses TNF it may reduce the body’s ability to defend quickly itself adequately against an infection. If she has a virus-like picture and is not otherwise toxic I resume Enbrel but wait until all lung symptoms are resolved before resuming MTX. Rarely, MTX may cause an inflammatory lung disorder that mimics viral pneumonitis. If her symptoms return upon resuming MTX then I stop MTX permanently.

Patients with CAP are evaluated using the CURB-65 prediction rule (Confusion, Urea, Respiratory Rate, Blood pressure, and age 65.) If patients on a biological agent require hospitalization I empirically cover them with broad-spectrum antibiotics and for MRSA and if they need admittance to the ICU I also add anti-fungal treatment until the etiology is determined.