Rheumatology Case: Murphy's Law and the News Anchor

Determining the appropriate dosage of an NSAID to produce the desired anti-inflammatory effect is basic to the treatment of rheumatoid arthritis. All available NSAIDs are analgesic at low doses and are both anti-inflammatory and analgesic at high doses, but it may not be easy to predict the “correct dose” for individual patients.

For example, aspirin produces analgesia at serum salicylate levels of 5 to 10 mg%, but 15 to 20 mg% levels are required to produce anti-inflammatory action, and side effects such as tinnitus and GI bleeding are common above 20 mg%. Many newer NSAIDs offer more convenient dosing regimens and minimal side effect profiles compared with aspirin. Regardless of the NSAID prescribed, it must be remembered that all have the potential to cause serious side effects.

Ibuprofen at 1,200 mg/day essentially has no anti-inflammatory effect in rheumatoid arthritis and, at best, would provide only analgesia. The minimum anti-inflammatory dose of ibuprofen is probably 2,400 mg, with most patients taking 3,200 mg and some as much as 4,000 mg/day. Increasing the dose of ibuprofen to 2,400 mg/day is the best recommendation at this time. With the increased dosage, however, the frequency of side effects increases. All NSAIDs have this dual analgesic/anti-inflammatory effect at low and high doses, so dosage selection must be thoughtful. Combinations of NSAIDs are not recommended.

If a higher dose of ibuprofen is ineffective, switching to a full anti-inflammatory dose of another NSAID would be a good choice

Six weeks later she calls and says that her arthritis is continuing to improve with less than 30 minutes of morning stiffness and no specific joint swelling. However, she is much more tired, has lost her appetite and five pounds, and her stools have become black and tarry. You instruct her to come in immediately for further evaluation.

When she arrives at the office she looks pale and tired, but is cheerful and cooperative. Blood pressure is 120/80 while supine but drops to 80/50 on sitting up. Her abdomen is flat, and bowel sounds are very active; the epigastrium is tender to direct palpation, but there are no masses.

Stat lab results show Hgb has decreased from 10 gm/dl (when she was last in the office) to 8 gm/dl, platelet count is 500,000/mm3; and the stool is black and guaiac-positive. ESR is 100 mm/hr and RF 280.

A. Schedule UGI endoscopy in one week
B. Admit to the hospital .
C. Schedule an UGI x-ray series for the morning .
D. Call the surgeons to operate .
E. Prescribe an H2 blocker and antacids and have her call back in a month .

For patients with RA, the risk of hospitalization or death from an adverse GI event is 1.3 to 1.6% per year of therapy. The likelihood that a patient will experience gastric mucosal irritation, erosion, ulceration, or perforation increases as the dosage and duration of therapy increase. It is not, however, clear that NSAID-induced mucosal erosions observed at endoscopy progress to ulceration and/or bleeding and perforation. It is even less clear whether or not NSAIDs cause duodenal mucosal lesions, although some studies suggest that NSAIDs exacerbate acid peptic disease in the duodenum.

In the early stages of any acute GI bleed, it is advisable to alert the surgery staff in case the bleeding cannot be controlled medically or signs of peritonitis develop, indicating that GI perforation has occurred. Immediate surgery, however, is not indicated for this patient.

An upper GI endoscopy, rather than x-rays ,would yield the most useful information about the pathology leading to the GI bleed.

Because of the patient’s acute condition, the endoscopy should not be delayed.

Outpatient therapy of any type with H2 blockers, antacids, misoprostol, or a proton pump inhibitor is not appropriate therapy for an active GI bleed.

In this patient, endoscopy has made it apparent that her source of bleeding is from the upper gastrointestinal tract, but NSAID-induced injury to the small bowel and colon may also occur. Occult and frank bleeding, perforation, obstruction, and acute colitis have all been described and should be considered in any patient who is taking NSAIDs and presents with GI symptoms.

Within a week she calls to report that the arthritis is much worse. She returns to your office complaining of increased joint pain, four hours of morning stiffness, and inability to work.

A. Restart high-dose ibuprofen plus misoprostol .
B. Initiate therapy with a COX-2 inhibitor .
C. Prednisone 30 mg/day .
D. Initiate a high-dose, fast-tapering schedule of prednisone .
E. Initiate low-dose prednisone (5 mg/day) and a disease-modifying anti-rheumatic drug .
F. Initiate a DMARD alone to avoid further GI bleeding .

The best option for this patient, at this time, is to initiate DMARD therapy with low-dose prednisone to control the disease and minimize side effects. Selection of the initial DMARD in a given patient depends on many factors, both patient-related and physician-related.

A few years ago, DMARDs were considered second-line therapy to be used only if NSAIDs failed to control inflammation, but most evidence now points to the value of early intervention with DMARDs. Accumulating evidence indicates that methotrexate does not have the toxicity of earlier DMARDs. Today, most rheumatologists choose to begin methotrexate (MTX), either alone or in conjunction with hydroxychloroquine and/or sulfasalazine, before radiographic evidence of articular erosions develops.

The expense and the convenience of drug administration are patient-related factors important in the selection of any DMARD. Oral therapy vs. injectable therapy and the frequency of blood monitoring may be important factors in choosing a DMARD for any given patient. Making the choice of which DMARD to begin requires a decision-making partnership between patient and provider.

A DMARD alone is insufficient to control symptoms in the first weeks or months of therapy due to delay in the onset of action of these drugs. Corticosteroid therapy should allow her to continue work by suppressing her inflammatory symptoms including joint pain, swelling, and stiffness. Whichever DMARD is selected, tapering the prednisone should be attempted as quickly as possible after the onset of action of the selected DMARD.

Moderate-dose prednisone, 30 mg/day, and high-dose prednisone (1.5 mg/kg/day), even with a fast-tapering schedule, should be avoided unless serious extraarticular rheumatoid manifestations, such as vasculitis or pericarditis, develop. Prevention of corticosteroid-induced osteoporosis should be carefully considered.

A slowly increasing schedule of weekly MTX is advised, and prednisone, 5 mg/day is started. Blood work is done every four weeks to watch for changes in Hgb, Hct, WBC, platelet count, or liver function (albumin, SGOT, and SGPT). Her hemoglobin increases to 11 gm%, she gains 7 pounds, and her arthritis is improved. Physical exam reveals no synovial proliferation and only minimal tenderness over the wrists. Morning stiffness is less than 30 minutes. Prednisone is gradually tapered to 2 mg/day without increased joint pain.

After 10 weeks of therapy with 15 mg/week of methotrexate, she develops mouth sores along with fatigue and nausea on the day of MTX dosing.

A. Add folate 1 mg/day
B. Split the dose of MTX to three doses q 12 hours, once a week
C. Switch from oral to parenteral (IM or SQ)
D. Any of the above

Splitting the dose of MTX into three doses given at 12-hour intervals can reduce nausea.

switching to injectable MTX may be helpful and ensures adequate absorption at higher dosing levels. At doses greater than 17.5 mg/week, some investigators believe that a switch to injectable MTX is necessary to ensure absorption.

Many minor MTX side effects may be ameliorated by the addition of folic acid 1 mg/day, especially mouth sores and hematologic abnormalities such as macrocytosis, which results from the inhibition of tetrahydrofolate reductase.

The absence of pain, minimal synovitis, and lack of significant morning stiffness suggests that this patient’s therapy has been very successful. Since long-term data suggest continued benefit from this DMARD, even after five years of therapy, it is reasonable to explore all options for minimizing minor side effects to allow for continuing this treatment.

The nausea is controlled, and although she develops mild macrocytosis, her morning stiffness lasts less than 30 minutes, she has only occasional joint swelling, and Hgb and ESR are now normal.

On her follow-up visit, she complains of a dry, non-productive cough and fever. Her primary care physician prescribed antibiotics, but she continues to have pulmonary symptoms. Her physical examination is negative.

iagnosis and treatment of this disorder does not generally require an invasive procedure such as open lung biopsy .

Patients on MTX are just as likely to develop adverse reactions to other medications, such as ACE inhibitors, and may also be prone to opportunistic infection. If evaluation does not yield an explanation for her symptoms other than MTX, then consideration should be given to stopping the drug.

Methotrexate lung that does not respond to discontinuation of the drug or is severe may require steroid therapy, but it is not indicated at this time.

Three years later the patient continues to do well clinically, but her albumin drops slightly and her liver transaminases are mildly elevated.

A. Assume she has autoimmune hepatitis .
B. Lower the dose of methotrexate given each week and recheck .
C. Discontinue methotrexate therapy completely .
D. Consider liver biopsy .
E. Hold all other medicines metabolized in the liver .
F. Discontinue all alcohol .
G. IV methylprednisolone .

Most rheumatologists would try not to stop effective therapy in this patient and might conservatively opt for lowering the dose of methotrexate, with a plan to repeat the liver function tests and consider a liver biopsy if the abnormalities persist.

Any substances that might affect liver function such as medications and alcohol must be discontinued.

Complete discontinuation of methotrexate is not necessary for a single minor change in test values, although this would be recommended if levels are persistently elevated.

Autoimmune hepatitis is an unusual disease and should not be assumed in a patient on methotrexate whose liver function test indicates an abnormality.