She has been treated for several months by her local internist with three serial non-steroidal anti-inflammatory drugs (NSAIDs), including naproxen, rofecoxib, and celecoxib; she is currently taking celecoxib 200 mg bid.

Based on a laboratory evaluation, her internist told her that she had rheumatoid arthritis (RA). In his office, she was found to be slightly anemic with a high platelet count and a high erythrocyte sedimentation rate (ESR). She was also found to be rheumatoid factor (RF) determination positive.

 

She reported that her mother also had RA as a young woman. The patient has two junior high school children. Prior to her current illness, she had taken no regular medication. The patients response to the NSAIDs was disappointing, leading her to present for further evaluation and treatment

 

On examination the patient was found to be 52 tall and to weigh 116 lbs. Her vital signs were normal, but she had obvious synovitis across the proximal interphalangeal (PIP) and metacarpophalangeal (MCP), joints bilaterally. She also had synovitis over both wrists. Her disclosure was estimated at 50%. She had tenderness in her shoulders bilaterally, slightly limited abduction and rotation, effusions in both knees with politeal fullness, and synovitis of both ankles. Her metatarsophalangeal (MTP) joints were swollen and tender, and her spinal motion was adequate. In total, she had 15 swollen and 17 tender joints.

 

She did not have rash, mucous membrane lesions, or lymphadenopathy. Her lungs were clear to oscultation. Her cardiac examination was without murmurs or rubs. Her abdomen was benign, and she had no neurologic deficits.

 

To confirm the diagnosis, assess the level of disease activity, and establish a pretreatment baseline, which studies should the physician order at this time?

 

CBC The CBC is commonly abnormal in systemic inflammatory diseases. A low grade, normocytic, normochromic anemia is frequent in patients with rheumatoid arthritis. A baseline CBC is usually helpful for assessing disease status and for the possible monitoring of toxic effects of therapy. The platelet count is often increased in inflammatory states. Very Useful

 

Urinalysis The baseline urinalysis may be helpful for demonstrating hematuria. Previously, medications such as gold and penicillamine were monitored with urinalysis. These medications have largely been replaced, and the importance of the urinalysis is less obvious if the diagnosis of rheumatoid arthritis is established. Somewhat Useful

 

Metabolic panel - Baseline hepatic and renal function may be critical in determining disease-modifying anti-rheumatic drug (DMARD) therapy. Changes in liver and kidney function may be due to the disease itself or to medications. Methotrexate, leflunomide, and sulfasalazine alter renal and hepatic function, and their dosing may also be affected by renal and hepatic function. In addition, NSAIDs may affect hepatic and renal function. Baseline values are helpful as a reference and generally require regular monitoring with DMARD therapy. Very Useful

 

Erythrocyte sedimentation rate (ESR): The ESR correlates with systemic inflammation in association with increases in serum fibrinogen and immunoglobulins. A number of processes, including age, anemia, and renal function, may influence the ESR. However, in many patients, ESR provides a simple way to follow up systemic inflammation, although a lack of sensitivity and specificity may make it not helpful in some patients. Very Useful

 

C-reactive protein (CRP): CRP is a hepatic polypeptide that is associated with acute inflammation. It is a sensitive marker of inflammatory states, and it is much less influenced by factors other than the ESR. CRP synthesis is driven by a variety of cytokines, particularly IL-1 and IL-6. CRP levels correlate reasonably well with RA disease activity and have also been correlated with joint damage in some patients. Very Useful

 

Rheumatoid factor (RF): Rheumatoid factors are present in about 75% of patients with RA, but RF is frequently not present in early rheumatoid arthritis. The presence of RF is not necessary to establish the diagnosis of rheumatoid arthritis. Although very high levels of RF predict a more aggressive clinical course and the presence of extra-articular manifestations, absolute RF levels do not necessarily correlate with clinical disease activity. Very Useful

 

Anti-nuclear antibodies (ANA): Anti-nuclear antibodies are produced in several different systemic inflammatory disease states, including systemic lupus erythematosus. In some studies, more than 25% of patients with RA have ANAs present, but they are of uncertain clinical significance. Some biologic response modifiers may induce ANAs, but this phenomenon has uncertain clinical significance in most patients. Somewhat Useful

 

Anti-citrullinated peptide antibodies (Anti-CCP): Anti-CCP is a specific marker for RA. The antigenic targets for anti-CCP are citrullinated peptides that contain an epitope recognized in antikeratin, antiperinuclear factor, and antiflaggrin assays. This test has not yet been particularly well standardized. Anti-CCP antibodies are specific for RA and are probably most appropriate in patients who are RF negative. It is also speculated that anti-CCP positivity may be more predictive of erosive disease. Not Very Useful (in this case)

 

Radiographs of hands, wrists, and feet: It is now clear that even patients with early RA may have radiographic damage. Juxta-articular demantalization, erosions and joint space narrowing may be present even when synovitis is minimal. Baseline radiographs, particularly of the hands, wrists, and feet, are important at baseline and later at regular intervals (eg, yearly), help determine the efficacy of DMARD treatment. One of the goals of the more aggressive approach to RA therapy is the cessation of radiographic progression. Very Useful

 

Bone densitometry: Although this woman is premenopausal, she has an inflammatory arthritis and small stature, which are risk factors for low bone density. She may also require corticosteroids at some point in her RA therapy. A baseline bone marrow density study to demonstrate baseline density and perhaps the existence of osteopenia and or osteoporosis might be important as her overall medication program is developed. Useful

 

Health Assessment Questionnaire (HAQ): RA produces functional impairment that is not related simply to the severity of the disease process. Many patients are more concerned with potential loss of function than with discomfort. The HAQ is a widely accepted, validated, relatively specific instrument used to assess physical function in patients with RA. The HAQ is easy for patients to understand and relatively easy for physicians to score. It can be a useful tool to follow patients with RA over time, particularly if they have aggressive disease. A baseline HAQ determination would be reasonable in this patient at this time. Useful

 

Disease Activity Score (DAS28): The DAS is a composite index that enables clinicians to assess the level of a patients disease activity from baseline to follow up, so the disease progression can be assessed and a response to treatment evaluated. The DAS28 assesses joint tenderness and joint swelling in 28 joints in the body. The DAS28 is calculated using a relatively complicated equation, but computer software is available that allows relatively rapid calculation of this score.

 

 It includes four variables: 1) the number of tender joints among the 28 joints; 2) the number of swollen joints among the 28 joints; 3) the ESR; and 4) general health status assessed by the patient using 100 mm visual analog scale.

 

Using the DAS28, patients are determined to have high disease activity if their DAS score is >5.1 or low disease activity if the DAS score is <3.2. These indicators are used more frequently in study situations and apparently by rheumatologists in Great Britain and Europe. Objective measurement of disease activity probably will be an increasingly important variable, particularly given the recent trend toward aggressive treatment and the need to more carefully measure and justify responses to these agents. Somewhat Useful

 

Which treatment(s) should be initiated at this time?

 

A different NSAID: NSAIDs may suppress the inflammatory response to some degree but do not affect the natural history of RA. Although these agents may provide a degree of symptomatic relief, they are not sufficient to achieve clinical remission. Although they may be helpful for symptoms, they should not interfere with the progression to the more aggressive potentially disease-modifying agent. This patient has already been treated with three different NSAIDs without significant symptomatic relief. More aggressive therapy than NSAIDs is warranted. Somewhat Useful

 

Prednisone: Low-dose corticosteroids are extremely helpful in the treatment of the symptoms of RA. They are probably best used as a bridge to more aggressive treatments with potential disease-modifying agents, which may take several weeks to months to become efficacious. In this patient, corticosteroids may provide rather rapid symptomatic relief and allow her the possibility of transiently improving her functional capacity. There is some evidence that corticosteroids may also retard radiographic progression. If corticosteroids are to be used for months rather than weeks, then consideration should be given to protection from osteopenia and osteoporosis, probably with bisphosphonates. Useful

 

Hydroxychloroquine (HCQ): HCQ as monotherapy in this setting may not be efficient enough to achieve disease modification. This medication is probably now best used as add-on therapy in combination with other agents including methotrexate (MTX) and sulfasalazine (SSZ). HCQ has never been clearly shown to retard radiographic progression. Because this agent has a long half-life, it will take a fairly long time to know whether or not it is effective. Somewhat Useful

 

Sulfasalazine (SSZ): SSZ is a useful drug for symptomatic treatment of RA, and some studies suggest this agent retards radiographic progression. It is generally well tolerated, although adverse effects may include nausea, abdominal pain, headache, and dizziness. SSZ may cause neutropenia or a granulocytosis, which usually occurs within the first 4 to 6 months of treatment. This potential toxicity requires monitoring of the white blood cell count every 3 to 4 weeks when the agent is administered. Whether doses higher than 2 g daily provide greater efficacy than lower doses remains uncertain. SSZ has been more popular in Great Britain and Europe than in the United States for reasons that remain unclear. Useful

 

Methotrexate (MTX): MTX is probably the most commonly used DMARD in recent years, due to its reasonable rate of efficacy and relative lack of significant side effects leading to discontinuation. The results of several studies suggest that MTX retards radiographic progression in patients with RA. Patients taking MTX must be monitored carefully for adverse effects on blood counts as well as hepatic and pulmonary function. Mild transaminitis is not infrequent and is usually of little concern. The utility of liver biopsy has been questioned in recent years and is not done routinely. Although hepatic fibrosis may rarely occur, progression to cirrhosis is very unusual. Teratogenicity is a definite concern, and the drug should not be used if the patient is pregnant or considering pregnancy in the near future. The use of concomitant folic acid may diminish certain toxicities. Very Useful

 

Leflunomide (LEF): LEF has been shown to be efficacious for decreasing signs and symptoms as well as radiographic progression in patients with RA. The agent also improved all categories of function and quality of life assessment. LEF has shown equal efficacy to MTX in clinical trials. The agent is associated with GI toxicity, including diarrhea and nausea in some patients. Hepatoxicity, alopecia, and rashes have also been reported. These toxicities usually reverse with discontinuation, and this agent may also be eliminated if necessary by substituting cholestyramine. Because of its associated toxicities, administration of LEF also requires careful monitoring of blood count and liver function tests. Very Useful (in this case)

 

A biologic DMARD: Biologic DMARDs (etanercept, infliximab, adalimumab, and anakinra) have been established as very effective for decreasing the signs and symptoms of RA as well as for slowing or halting radiographic progression and improving overall function. Whether biologic agents should be indicated for initial DMARD therapy remains controversial, and this decision may be affected by the cost of these agents. Etanercept and adalimumab have been demonstrated to be effective as monotherapy, and all the agents have been established as effective in combination with MTX. Whether patients with aggressive disease should be given these drugs early in their course also remains to be established but is the subject of several on going trials. Very Useful

 

The patients hemoglobin was 10.9 g%, white blood cell count was normal at 7,200/mm3, and slightly elevated platelet count of 460/mm3. The ESR was elevated at 63 mm/hr. CRP determination was three times the upper limit of normal. Baseline chemistries were normal, including liver function tests and creatinine level. RF determination was positive at 390 IU by nephelometry. An ANA determination was negative.

 

Radiographs of the hands, wrists, and feet demonstrated juxta-articular osteoporosis with several early erosions of the second and third MCP joints bilaterally, as well as the third and fourth MTP joints bilaterally. Joint space narrowing was not noted. Finally, bone marrow density determination demonstrated T-scores > -1.0, suggesting reasonably normal density at this time.

 

MTX therapy was initiated in a dose of 12.5 mg/wk with concomitant folic acid 1 mg daily. Low dose prednisone was initiated at 7.5 mg daily with tapering after 4 weeks to 5 mg daily in a single dose. The patient returned 6 weeks after MTX therapy was initiated. Repeat laboratory monitoring demonstrated no change in her blood count, although her ESR had fallen to 48 mm/hr. Her liver function tests were still normal, and she was symptomatically somewhat better, with slightly less morning stiffness and slightly more energy. The MTX dose was then increased to 17.5 mg weekly in a single oral dose and the prednisone was continued.

 

Another 6 weeks later (3 months after MTX initiation), the patient returned for another review. She continued to manifest active synovitis, with multiple swollen and tender PIP and MCP joints bilaterally, as well as persistent swelling in her wrists, which now showed a slight loss of extension. Both shoulders continued to demonstrate pain on abduction, which was limited. Her left elbow had a small effusion, and her knees continued to demonstrate effusions, although these were probably slightly less pronounced than last time. Her MTP joints continued to be swollen and tender. She had a total of 13 swollen and 16 tender joints. The remainder of her examination was unchanged.

 

Hemoglobin was 11.7 g% with a normal white blood cell count and a platelet count of 462,000/mm3. ESR was 54 mm/hr. CRP was twice the upper limit of normal. Liver function tests continued to be normal, as did a baseline creatinine level.
 
Which treatment(s) should be recommend at this time?

 

Increase the dose of corticosteroids: Increasing the dose may result in somewhat less stiffness and swelling, and this effect may be quite rapid. This may allow the patient to complete her job and home responsibilities more easily. However, the toxicity potential is clearly related to dose and duration of corticosteroid exposure, and one of the more significant side effects is decreased bone marrow density. The prophylactic use of bisphosphonates might be helpful for mitigating this problem.

 

Corticosteroids should be viewed as a bridge to more aggressive therapy to the other agents and hopefully would be a temporary measure. Useful

 

Increase the dose of MTX: The current standard of care suggests that increasing the MTX dose to toleration may be important. This is usually a dose of 20 mg to 25 mg weekly. The patient had been tolerating the MTX quite well to this point, and attempting to increase the dose is certainly reasonable. Higher doses may result in more efficacy through the dose range of 25 mg/wk if not slighter higher, but tolerability may become an issue. Consideration should be given to administering the drug parenterally to insure effective bioavailability. Very Useful

 

Add conventional DMARDs: Studies suggest that the addition of a second and even a third conventional DMARD is likely to yield improved responses when combined with MTX . The addition of HCQ and SSZ may be considered in this patients clinical setting. However, their onset of action tends to be gradual, requiring weeks to months to produce significant efficacy. LEF has also been demonstrated to be more efficacious in combination with MTX, compared with MTX monotherapy.  MTX  has proven  more efficacious than LEF when treated alone. This presents another option, although careful monitoring for hepatoxicity is critical. Useful

 

At the time of her next scheduled visit, she continued to try to work full time but still described one hour of morning stiffness and some afternoon fatigue. She still had some swelling and tenderness involving several joints in her hands, wrists, and her forefeet. The right olecranon nodule was slightly bigger on her appraisal. She tolerated the MTX injections with some nausea, usually the day after her injection. She also tolerated the etanercept injections, with only a single mild injection site reaction, which resolved spontaneously. She did not have any obvious infectious symptoms and did not think the etanercept was causing any other side effects.

 

Next visit: On examination, she continued to have synovitis and joint tenderness at several MCP, PIP, and MTP joints and wrists. Her tender joint count had declined to 7 and her swollen joint count to 5, but the right olecrenon nodule was slightly bigger. She did not have evidence for significant injection site reactions. She did not have mucous membrane lesions. Her lungs remained clear to oscultation, and her abdominal examination was unchanged.

Laboratory evaluation demonstrated a hemoglobin of 11.2 g%, a normal white blood cell count, and a platelet count of 452,000/mm3. The ESR was 43 mm/hour. Her AST level remained slightly elevated at 38 U/L, but the alkaline phosphatase and creatinine levels remained normal.

 

With persistent disease activity, which of the following changes in her regimen should the rheumatologist choose at this time?

 

Increase the dose of oral corticosteroids: Although more corticosteroids might help her with the symptoms, at this point, her disease seems to be aggressive despite other DMARDs. It seems apparent that she will need more aggressive treatment to control her disease, but to increase the corticosteroids would still be considered a bridge to attempts at improved disease control with other agents. Since it is likely that other agents will be tried, the corticosteroids may mask underlying symptoms. There is little data to support the notion that more corticosteroids at this point will help to slow down her underlying disease progression, and the risk of potential side effects, including steroid-induced osteopenia and osteoporosis will become a more pronounced as the dose and duration of corticosteroid exposure is increased. Minimally Useful (case)

 

Increase the dose of MTX: The patient has developed some nausea with a significant dose of MTX via the parenteral route. Folic acid administration may help with some of the drug-induced symptoms, but at this dose, might also reduce efficacy slightly. At the current dose of MTX (22.5 mg weekly), a further increase in dose would not necessarily be expected to improve disease control or be tolerated by this patient. Moreover, the patient clearly has a fair amount of residual disease despite aggressive MTX dosing. Minimally Useful

 

Add another conventional DMARD: A number of medications have demonstrated efficacy in addition to MTX in patients who are partial MTX responders. The addition of other medications to the combination of MTX plus a biologic response modifier has not been studied. The addition of both HCQ and SSZ at this point might still be considered, although it is less clear that this triple combination is effective in people who have not had adequate responses to aggressively dosed MTX . LEF might be added, although the combination of MTX and LEF with etanercept has never been studied.

 

Similarly, cyclosporine might be added to MTX, but there are no data about this combination in addition to etanercept, and no studies have compared the combination of MTX and LEF to MTX and cyclosporine. This remains a controversial area, and although partial responses to our aggressive medications are frequent, no studies have yet provided clear direction on how to treat patients with a partial response to MTX plus a biologic agent. Useful

 

Continue the etanercept: Etanercept in studies has worked quickly in patients with RA, even in patients who were partial responders to MTX. Almost all patients who had a positive response improved within 3 months of exposure to the drug, and most patients had a significant response earlier than 3 months. There were a very few if any late responders, and the utility of prolonged exposure beyond 3 months when the efficacy is questionable seems dubious. Also, etanercept is available in a fixed dose schedule only, and there are no data about whether increasing the dose either per injection or with more frequent injections adds efficacy in patients with RA who do not have an impressive response to the usual dose. Not Useful (in this case)

 

Change to a Different Biologic Agent: There are little data (mostly only case reports) about patients who have not had an impressive response to one TNF antagonist switching to another. In patients who switch from the soluble receptor to the monoclonal antibody or vice versa, it remains uncertain as to whether the mechanisms of action and pharmacologic characteristics of the two different approaches to TNF inhibition result in clinical differences. The fixed dosage schedule of etanercept allows for the rapid achievement of steady state of serum concentrations. On the other hand, the initial schedule for infliximab allows for a higher serum concentration but an ability to vary this concentration significantly through the dosing interval. In some patients, there may be value in switching from one TNF drug to another, but formal studies of this possibility are not yet available. Somewhat Useful

 

The patient was switched to infliximab 3 mg/kg on the usual dosing schedule where the drug is administered at 0, 2, and 6 weeks and then every 8 weeks thereafter. MTX was continued at a dose of 22.5 mg sc weekly. Prednisone was also continued at 5 mg bid. Before the third infliximab infusion, the patient reported marked improvement with less morning stiffness, less fatigue, fewer swollen and tender joints, and an improved sense of well-being.

 

However, during the third infusion, the patient developed puritis, then chills and a temperature of 101° F, and her blood pressure dropped to 90/70 mm/Hg. The infliximab infusion was discontinued, and the patient was treated with 500 cc of fluid and 25 mg of diphenhydramine hydrochloride intravenously. Within an hour, her vital signs normalized, she felt better overall, and the puritis resolved without obvious rash. The patient did not wish to complete the infusion.

 

The patient was reluctant to receive more infliximab. Her RA continued to be active with residual synovitis in several joints in her hands, wrists, and feet. The decision was made to change to adalimumab 40 mg every other week. Within 6 weeks, the patient seemed to improve, with morning stiffness decreasing to 30 minutes or less, her energy level improving, and the number of tender and swollen joints decreasing still further.

 

At the time of her last visit to the office, she had some residual swelling and pain in the right wrist, the right second MCP, and the left third PIP joint, but essentially no involvement elsewhere, including her feet, which were improved. She was tolerating the adalimumab without any significant adverse effects, including no injection site reactions to date.

 

How to treat patients with RA who have a partial response to aggressive therapy remains uncertain. This patient had a partial response to aggressively dosed MTX combined with anti-TNF medications. The initial anti-TNF agent (etanercept) was not particularly helpful, and the second agent (infliximab) resulted in an infusion reaction, but the third medication (adalimumab) was better tolerated and appeared to be more effective.

 

 The studies in which MTX has been combined with an anti-TNF drug demonstrate significant efficacy when compared to MTX used alone, but the majority of the treated patients still have less than a complete response. If, in fact, our goals have been transformed so that no residual disease activity is now a reasonable possibility, then rheumatologists will continue to be concerned about those patients with a partial response. 

 

Whether one anti-TNF drug is better than another or even significantly different than another, remains to be established. With no head to head studies currently underway, this will probably be an ongoing issue for years to come. Further research, including laboratory studies, is needed to establish with greater certainty whether the pharmacologic characteristics and the mechanisms of action of the different TNF inhibitors make a significant clinical difference. Any clinical implications of these potential differences need to be clarified, particularly with regard to the efficacy and safety of these agents.

 

It also remains uncertain as to whether higher doses or more frequent dosing of these agents might improve their efficacy and safety profiles. The development of neutralizing antibodies in a certain proportion of patients may also affect the need for higher doses or more frequent administration. This has been established for some patients receiving monoclonal antibodies. Interfering with pro-inflammatory cytokine signaling may upset the balance between protection and toxicity, and the goals of TNF inhibition and the optimal level of this inhibition are still being assessed. The clinical experience from rheumatologists may help to address some of this uncertainty, but many questions remain.

 

Nonetheless, new aggressive treatments for RA have already made a significant impact on the morbidity and mortality of this disease. Which patients qualify for this medication and when these agents should best be used should continue to be discussed and objectively evaluated. However, these questions should in no way interfere with rheumatologists enthusiasm for what they do, for what they can offer their patients, and for the new opportunities to treat inflammatory rheumatologic diseases more effectively.