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Gold salts(-rarely used -currently) the first agents used to treat RA, include the orally-administered auranofin
and two available intramuscular formulations, aurothioglucose and gold sodium thiomalate. These agents are DMARDs that generally
show antirheumatic effects within 3 to 6 months. Gold salts, as do many of the historical DMARDs, have many toxicities that
may limit their use.
Toxicities are manifested in patients as metallic taste, skin rash, stomatitis, hematuria, proteinuria, leukopenia, thrombocytopenia,
nausea, vomiting, diarrhea, flushing, palpitations, hypotension, tachycardia, headache, and diplopia. Due to their toxicity
and delayed onset, gold salts are seldom used in clinical practice today.
d-Penicillamine; Also rarely used in current clinical practice, d-penicillamine was introduced as an antirheumatic agent
in the 1960s. Although a clinical response is usually seen within 6 months, d-penicillamine, a DMARD, begins to demonstrate
positive effects within 1 to 3 months of initiation. Oral dosing begins with 250 mg once daily and is titrated up to 250 mg
three times daily as needed. Absorption of d-penicillamine is reduced with concurrent food, iron, and antacid intake, so patients
should be educated about dose separation when combining these agents with d-penicillamine.
Adverse effects for d-penicillamine include an early pruritic erythematous skin rash, metallic taste, nausea, vomiting,
dyspepsia, and glomerular nephritis. The agent should be immediately discontinued if the patient develops other autoimmune
diseases, such as systemic lupus erythematosus or myasthenia gravis. This therapy is usually reserved for patients who have
failed all other DMARD therapies.
Azathioprine; With effects seen within 3 to 4 weeks, azathioprine, a DMARD and cytotoxic purine analog, should be given
a trial of at least 12 weeks before treatment failure is declared. Dosing ranges from 0.75 mg/kg to 2.5 mg/kg per day. Since
the drug is primarily eliminated renally, the dose must be adjusted downward by 25% to 50% for patients with a creatinine
clearance (CrCl) <50 mL/min.
Adverse effects seen with azathioprine include reversible bone-marrow suppression, gastrointestinal intolerance, oncogenic
potential, stomatitis, infections, drug fever, and hepatotoxicity. Bone-marrow suppression appears to be dose-related and
may be reversed by discontinuing the drug. Patients taking allopurinol require a 30% dose reduction due to azathioprine's
interference with allopurinol metabolism.
Hydroxychloroquine; Another historical DMARD, hydroxychloroquine, has an onset of action of approximately 6 weeks and
should be used for at least 6 months before treatment failure is declared. For patients with early RA, typical dosing ranges
from 200 to 400 mg per day. Although hydroxychloroquine is associated with ocular, dermatologic, and neurologic toxicities,
it lacks the myelosuppressive, hepatic, and renal toxicities associated with many of the other historical DMARDs, making for
reduced monitoring.
Monitoring should focus on the major concern with this agent, ocular toxicity, as it can lead to blindness. Patients
should be instructed to have ophthalmic exams every 6 months. Because of its relatively mild toxicity profile, hydroxychloroquine
is still a viable treatment option in clinical practice today, especially for patients with early RA and as part of combination
therapy.
Sulfasalazine; Sulfasalazine is an effective agent used in clinical practice today, often included in combination therapy.
A DMARD and prodrug, sulfasalazine requires colonic bacterial exposure in order to be activated and achieves antirheumatic
effects in 1 to 2 months. Certain antibiotics may reduce the effectiveness of sulfasalazine via reduction of colonic bacterial
flora. Although its mechanism is not clearly defined, it appears to possess anti-inflammatory, immunomodulatory, and antibacterial
effects. Patients should be started at 1 gram per day to minimize adverse effects and titrated up to 2 to 3 grams daily in
divided doses.
The many adverse effects caused by this agent include gastrointestinal, dermatologic, and hematologic complications;
however, many can be reversed or corrected. For example, nausea, vomiting, and diarrhea can be reversed with smaller doses,
gradual titration, dividing doses evenly throughout the day, and by administering enteric-coated preparations. Rash and urticaria
can be reversed with antihistamines or corticosteroids, unless a hypersensitivity reaction occurs. In that case, sulfasalazine
should be discontinued immediately, and the patient should be switched to another DMARD.
Patients should be warned that their urine may turn orange while taking this agent. Patients should also be educated
to separate intake of iron from sulfasalazine, as iron inhibits sulfasalazine absorption. Since sulfasalazine can potentiate
the effects of warfarin, a patient's INR should be monitored closely and patients should be made aware of the increased risk
of bleeding.
Cyclosporine; Cyclosporine is an immunosuppressive DMARD that produces antirheumatic effects by reducing the production
of cytokines. The typical onset of antirheumatic effects from cyclosporine occur within 1 to 3 months. Dosing for RA ranges
from 3 to 5 mg/kg/day. Since the use of this agent is limited by many cautions and adverse effects, it is usually reserved
for patients who fail conventional therapies. Reversible toxicities include hypertension and nephrotoxicity. Other adverse
effects include hyperglycemia, gastrointestinal intolerance, hirsutism, and gingival hyperplasia.
Patients over age 65, with controlled hypertension, premalignant conditions, active infection, or patients who are pregnant
or lactating should be cautioned against taking cyclosporine. In addition, patients taking antiepileptics, ketoconazole, fluconazole,
trimethoprim, erythromycin, verapamil, diltiazem, NSAIDs, or alkylating agents like cyclophosphamide should also be cautioned
against taking cyclosporine. Patients with current or previous malignancy, uncontrolled hypertension, renal dysfunction, immunodeficiency,
leukopenia, thrombocytopenia, or hepatic enzyme increases greater than two times the upper limit of normal should not take
cyclosporine. Cyclosporine is typically used in conjunction with methotrexate and/or other agents for patients with severe
RA.
Methotrexate; Methotrexate is currently one of the most commonly used DMARDs as it has many advantages over the other
historical DMARDs. It has a 2- to 3-week onset, can be taken at weekly intervals, and is an effective antirheumatic agent
with relatively few serious side effects. Patients may have their doses titrated up to 22.5 mg per week after initiating dosage
with 7.5 mg per week. Hepatic toxicities are minimized with this dosing regimen and patient adherence is maximized. Remissions,
although rare, have been observed with methotrexate, and limited data from long-term studies indicate that antirheumatic effects
can last as long as 2 years with continued therapy. It can be administered intramuscularly, subcutaneously (SC), or orally.
The toxicities associated with this agent are often preventable through monitoring. Toxicities are gastrointestinal,
hematologic, pulmonary, and hepatic in nature. They are manifested as nausea, vomiting, diarrhea, thrombocytopenia, leukopenia,
pulmonary fibrosis, pneumonitis, and increased hepatic enzymes. These adverse effects are preventable through careful monitoring,
especially of hematological, pulmonary, and hepatic parameters. A liver biopsy should be performed prior to initiating the
agent in patients with a history of excessive alcohol use, current hepatitis B or C, or increased hepatic enzymes. Patients
with hepatic, renal, or pulmonary dysfunction, immunodeficiency, thrombocytopenia, leukopenia, or a creatinine clearance less
than 40 mL/min should not take methotrexate.
Since folic acid deficiency is often associated with methotrexate therapy and the root of many of its side effects, patients
often benefit from folic acid supplementation. Patients should also be cautioned against alcohol intake during methotrexate
therapy because of an increased risk of hepatic toxicity.
Patients who are of child-bearing age should be advised to use contraception during methotrexate therapy because of its
teratogenic effects and those who are pregnant should discontinue the agent.
DMARDsNEWER AGENTS; There has been a proliferation of new RA agents over the past 3 years following the introduction
of the first new agents for the disease in 10 years. The newer DMARDs for RA are distinguished from their predecessors by
reduced toxicity, increased short-term efficacy, and a general dearth of long-term safety data. Primarily because of the lack
of long-term safety data, their place in therapy is usually as second- or third-line agents after historical therapies have
failed. In light of the emerging early and aggressive preventive approach to RA treatment and recent data, these agents may
be beneficial even before the treatment failure of a historical agent.
The new agents include leflunomide and the biologic response modifiers, infliximab, etanercept, and anakinra. They may
be an option for patients taking agents that have lost effectiveness or caused severe toxicities.
Leflunomide (Arava); Leflunomide is in its own category for the treatment of RA, since its mechanism of action involves
inhibition of pyrimidine synthesis. An addition to the RA treatment armamentarium just 3 years ago, leflunomide offers an
efficacy similar to or greater than methotrexate or sulfasalazine, and a response that is usually seen within 1 month. Its
delayed response is explained by a long half life, which justifies an initial oral loading dose of 100 mg daily for 3 days,
then 20 mg daily thereafter.6 Although leflunomide lacks bone marrow-associated complications common to many other DMARDs,
diarrhea, rash, alopecia, and elevated liver enzymes (ie, AST and ALT) are common adverse effects.
Recently, rare cases of severe hepatic injury, some with fatal outcomes, have raised concern about the safety of this
agent. These cases, reported from Europe, were confounded by many factors. These factors were mostly reversible, but they
served to emphasize the importance of regular liver enzyme monitoring for patients taking leflunomide. Since these reports,
an effort has been made to clarify the labeling guidelines for monitoring hepatic function in patients taking the agent. Liver
enzymes, most importantly ALT, should be monitored once a month initially and periodically thereafter. The dose should be
reduced in patients with moderate liver function test elevations and discontinued in those with persistent elevations. Leflunomide
is not recommended for patients with significant hepatic impairment or evidence of active infection with hepatitis B or C.
Dosing should be initiated with a 100 mg loading dose daily for 3 days, followed by a 20 mg maintenance dose daily thereafter.
Because of teratogenicity, leflunomide is contraindicated during pregnancy. A washout procedure with cholestyramine is required
for patients before reinitiating the agent. The annual drug cost for leflunomide is approximately $3500. Leflunomide is typically
used in combination with other DMARDs and is seen as an add-on or second-line agent for the treatment of RA. It may, however,
be administered as a first-line, single agent DMARD.
Abatacept (Orencia-B cell), etanercept (Enbrel-TNF), infliximab (Remicade-TNF), adalimumab (Humira-TNF), and anakinra
(Kineret-IL 1ra) are FDA-approved biologic agents for treatment of rheumatoid arthritis. They interfere with immune system
chemicals called cytokines -- all of which are involved in inflammation-related joint and tissue damage.
TNF-alpha Inhibitors: Infliximab (Remicade) and Etanercept (Enbrel) :
TNF-alpha inhibitors, the first biologic agents for the treatment of RA, include infliximab and etanercept. By binding
to the cytokine TNF, these agents prevent TNF binding to inflammatory cell surface receptors, which inhibits the cytokine's
pro-inflammatory aspects. With both DMARD agents, a response generally takes from 1 to 4 weeks. Available parenterally (infliximab
as an IV infusion every 4 to 8 weeks and etanercept as a twice weekly SC injection), both are also beneficial alone or in
combination with methotrexate. The annual cost for infliximab is approximately $28,000 (based on a 70 kilogram patient) and
approximately $17,200 for etanercept.
Adverse effects from infliximab include headache, infusion reactions, nausea, and upper respiratory tract infections.
Etanercept's adverse effects include injection site reactions such as pain, itching, and erythema; upper respiratory tract
infections; and rare reports of central nervous system (CNS) disorders. Recently, additional adverse effects have emerged
with TNF inhibitors, most notably hematologic, neurologic, and immunologic complications.
Several cases of pancytopenia and aplastic anemia resulting in five deaths have been reported with etanercept. Even more
recently, although limited in number, cases of opportunistic infections such as with Mycobacterium tuberculosis, demyelinating
disorders, multiple sclerosis (MS), optic neuritis, seizures, colonic perforations, lupus-like manifestations, and lymphoma
have led to a revised package insert for infliximab and enhanced pharmacosurveillance efforts for the two agents.
The increased pharmacosurveillance by the FDA Advisory Committee is aimed at educating physicians and patients about
etanercept and infliximab. Caution should be used when prescribing a TNF inhibitor for patients with MS, a history of seizures,
and those with a history of optic neuritis or other demyelinating disorders. Physicians are now advised to perform PPD skin
testing in patients who will receive or are receiving infliximab. Although it remains unclear whether skin testing should
be performed for those on etanercept, it is advisable. Prospective observational studies are now needed to further confirm
the long-term safety of TNF inhibitors.
Anakinra (Kineret); Anakinra, an interleukin-1 receptor antagonist (IL-1ra), is a biological agent that antagonizes the
inflammation and pain associated with moderate to severe rheumatoid arthritis. Anakinra is the first IL-1 blocker to treat
RA.
Indications: Anakinra is indicated for the reduction in signs and symptoms of active RA in subjects 18 years of age or
older who have failed on one or more DMARDs. Anakinra can be used alone or in combination with other DMARDs, other than anti-TNF
therapies.
Mechanism of Action: This new agent has a unique mechanism of action. Anakinra blocks the pro-inflammatory, biologic
activity of IL-1 by inhibiting its binding to IL-1 receptors.
Efficacy; According to studies completed thus far, anakinra has been found to reduce the signs and symptoms of RA and
to slow disease progression. Several placebo-controlled trials have demonstrated that subjects treated with anakinra, whether
as monotherapy or in combination with methotrexate, achieve both clinically and statistically significant improvements in
the signs and symptoms of RA compared to controls.
Three major, pivotal placebo-controlled clinical trials in patients with RA have been conducted to assess the efficacy
of anakinra. In these trials, anakinra was studied as monotherapy or in combination with other DMARDs.
Study 1, a monotherapy study, investigated the efficacy of anakinra as monotherapy compared with placebo. Enrolled subjects
were required to have early active RA and have failed on no more than two previous DMARDs. They were randomized in equal numbers
to 30, 75, or 150 mg of daily SC doses of anakinra or placebo for 24 weeks. Study endpoints included the proportion of subjects
demonstrating at least 20% improvement from baseline (ACR-20) at week. The results showed that anakinra subjects, at the 150
mg dose, were more likely to achieve an ACR-20 response (43% vs. 27%) at week 24 than placebo subjects.
Overall, the 30 mg and 150 mg treatment groups demonstrated statistically significant improvement when compared to placebo.
Most importantly, the 150 mg treatment group demonstrated statistically significant improvements in all ACR criteria at 24
weeks. The primary adverse effect observed in this studyinjection site reactionswas determined not to have influenced the
efficacy of anakinra. Thus, anakinra was found to be a safe and effective agent for reducing the signs and symptoms of RA.
The second study, a methotrexate combination study, was also a double blind, randomized, placebo-controlled trial to
investigate the efficacy and safety of anakinra combined with methotrexate. Subjects were required to have active RA and to
be taking methotrexate. A placebo group was compared to five anakinra treatment groups taking 0.04, 0.10, 0.40, 1.0, or 2.0
mg/kg for up to 24 weeks. All subjects were on stable doses of methotrexate concurrently.
Major endpoints included the proportion of subjects achieving an ACR-20 response at week 12, an ACR-20, ACR-50, and ACR-70
response at week 24, and safety was also assessed. At week 12, there was a highly significant dose-response between ACR-20
response rates and anakinra. This correlation also occurred at week 24. Higher anakinra doses were associated with increasing
ACR-20 response rates. This study concluded that anakinra in combination with methotrexate is an effective treatment for the
signs and symptoms of RA.
The third study, a confirmatory efficacy study, was a double blind, randomized, placebo-controlled study designed to
investigate the efficacy and safety of anakinra over 24 weeks. Subjects were required to have active RA and to take stable
doses of methotrexate. Subjects were randomized either to 100 mg daily of anakinra SC or placebo. The group treated with 100
mg daily SC anakinra and stable dosing of methotrexate were more likely to achieve an ACR-20 response at 24 weeks than subjects
treated with placebo and stable methotrexate.
This group was also twice as likely to achieve even greater magnitudes of improvement?0% up to 70%in clinical response
(ACR-50, ACR-70; versus controls. The effects of anakinra were demonstrated rapidly at 4 weeks and were maintained throughout
the 24-week treatment period and at a higher magnitude of improvement compared to placebo subjects receiving only stable methotrexate.
This study confirmed that 100 mg daily dosing of anakinra is effective for reducing signs and symptoms of RA.
Dosing and Administration; The dose for anakinra is 100 mg administered daily via SC injection. Patients should be instructed
to rotate injection sites among the abdomen, thighs, and back of the upper arms. An auto-injector device has been developed
to assist patients in self-administration. The device consists of a carrying case with a syringe handle, syringe housing,
and test glass syringe. The injection system has several major advantages: it conceals the needle before and during injection,
it allows for easy travel dosing, and helps prevent inadvertent needle sticks. It also assists patients who have dexterity
problems with the SC injection technique.
Adverse Effects; The most often experienced adverse effects with anakinra are mild to moderate injection site reactions.
These reactions are often associated with erythema, pruritus, rash, and/or pain, and occur with an increased incidence at
higher doses. In clinical studies, patients taking anakinra compared with placebo had slightly higher rates of some types
of infections, such as pneumonia, and of other adverse events such as headache and nausea.
Potential Drug Interactions; No studies on drug interactions with anakinra have been reported. However, in clinical trials
involving patients with active RA, other drugs ;including methotrexate, corticosteroids, and NSAIDs ;were used in conjunction
with anakinra without any reports of significant drug interactions. More study is required to clearly elucidate potential
drug interactions.
Place in Therapy ;Anakinra is an important new therapy option for patients who are refractory or inadequately responsive
to one or more DMARDs. Furthermore, since there is no cure for RA, this agent may provide another effective alternative for
these patients, whether used alone or in combination with other DMARDs.
ALTERNATIVE THERAPIES; In light of heightened public interest in the alternative medicine field, it is important to become
educated about the alternative therapies for RA. All patients should be educated to consult their physician prior to beginning
any alternative therapy.
Supported by data from 13 double blind, placebo-controlled trials and over 500 study participants, fish oil appears to
be an effective alternative therapy for relieving the symptoms of RA in some patients. Results may require several months
of treatment. Fish oil has not been shown to slow the progression of the disease. The most common adverse effect for patients
taking fish oil is a fishy-smelling burp. Patients taking Coumadin should be strongly cautioned against taking this agent
as the combination may lead to excessive bleeding.
Other alternative therapies suggested for RA therapy include black currant oil, borage oil, boron, Boswellia, cat's claw,
collagen, devil's claw, evening primrose oil, flaxseed, ginger, selenium, stinging nettle, thunder god vine, turmeric, curcumin,
yucca, gamma-linolenic acid, zinc, vitamin E, and monosodium glutamate. Overall, these alternative treatments lack the magnitude
of clinical efficacy needed for a wide range of support.
Boswellia has demonstrated some promise in the treatment of RA in several clinical trials, but dissenting data has also
called into question its role for treating RA until further studies are performed. Several studies have demonstrated that
devil's claw is beneficial for reducing the pain and inflammation of RA.
One small double-blind study has demonstrated the effectiveness of curcumin for reducing inflammation in RA. All other
alternative therapies are suspect as to their role in the treatment of RA as very little data support their use in these patients.
Summary: The past few years have witnessed a revolution in the treatment of RA. The new biologic agents for treating
RA are the response to research that focuses on the role of cytokines in disease progression. Anakinra, etanercept, and infliximab
offer new options that assist in preventing the progression of RA and relieving its signs and symptoms. Although not innocuous,
these agents are often combined with historical DMARDs and NSAIDs for optimal treatment of RA. The combination offers viable
and relatively safe alternatives for patients with RA, for whom a cure is not available.
Celecoxib (Celebrex, Searle/Pfizer): Celecoxib was the first selective cyclo-oygenase 2 (COX-2) inhibitor to be marketed
for treatment of rheumatoid arthritis. COX-2 inhibitors are nonsteroidal anti-inflammatory drugs (NSAIDs) that exhibit anti-inflammatory,
analgesic, and antipyretic activities but are highly selective inhibitors of COX-2. The traditional NSAIDs have various levels
of selectivity for COX-2 and COX-1.
COX-2 is an important enzyme in the production of inflammatory and pain inducing prostaglandins whereas COX-1 is responsible
for the production of vasodilatory and protective prostaglandins in the kidney and stomach respectively. The proposed benefit
of COX-2 selectivity is that by inhibiting only COX-2 the kidney and stomach damaging effects of traditional NSAIDs will be
avoided. It is unknown whether the COX-2 selective agents will truly cause a lower incidence of stomach ulceration and kidney
dysfunction. Both were reported in lower incidence in clinical trials.
Indication: Currently celecoxib is indicated for the treatment of pain and inflammation in RA and osteoarthritis (OA)
and for reduction in the number of adenomatous colorectal polyps in patients with familial adenomatous polyposis (FAP).
Efficacy: In premarketing studies, celecoxib 200 to 400 mg daily was found to be equivalent in effectiveness to naproxen
500 mg bid, diclofenac 75 mg bid, and ibuprofen 800 mg tid. The onset of pain relief occurs within 24 to 48 hours. Anti-inflammatory
effects may take one to two weeks.
Administration: The dose for RA is 100 to 200 mg twice daily. For OA, celecoxib is given as 200 mg once daily or 100
mg twice daily. For FAP the recommended oral dose is 400 mg twice daily.
Adverse effects: The common adverse effects with celecoxib are those seen with other NSAIDs including diarrhea, dyspepsia,
and abdominal pain. Kidney dysfunction was seen in less than 2% of patients in studies. Gastrointestinal ulcerations were
seen endoscopically in studies. The rate of ulcerations was four times lower than the rate with comparison NSAIDs (0.2% versus
2%).
Contraindications
a) Known hypersensitivity
b) Allergy to sulfonamides (Celecoxib is a sulfonamide and cross-reactivity may occur.)
c) History of asthma, urticaria, or allergic-type reactions to aspirin or other NSAIDs
Celecoxib use should be avoided in patients with preexisting renal dysfunction because of the lack of information available
regarding use and the potential for worsening renal function. The drug should be avoided during the third trimester of pregnancy
because of the potential for premature closure of the ductus arteriosus in the fetus.
Limited information is available about the drug interactions with celecoxib because few studies have been done. Reports
of drug interactions are now appearing in the medical literature because of the widespread use of this agent.
The drug is metabolized by cytochrome P450 2C9 (CYP2C9), potentially causing significant interactions with other agents
metabolized by this same isoenzyme system. Case reports of elevated INRs and bleeding episodes when celecoxib was used in
combination with warfarin have appeared in the literature. INRs should be monitored closely when celecoxib is added or stopped
in a patient on warfarin.
Celecoxib can cause a 17% increase in lithium serum concentrations. Lithium serum concentrations should be monitored
closely when this drug is started or discontinued. Fluconazole can cause a two-fold increase in celecoxib serum concentrations.
If this combination must be used together, the lowest dose of celecoxib should be used.
The American College of Rheumatology (ACR) recommends monitoring for gastrointestinal ulcerations and bleeding, liver
dysfunction, and kidney dysfunction when NSAIDs are used. No specific guidelines have been published by the ACR for monitoring
celecoxib therapy.
Biologics are manufactured in living cells such as bacteria, yeast or mammalian cells. They specifically target individual
proteins or cells that are involved in the disease process at a fundamental level, and are thus more highly targeted than
are the broad-spectrum anti-inflammatories and DMARDs. Due to their uniqueness and the complexity of their manufacture,
biologics are very expensive.
Some biologic therapies target proteins called cytokines, which carry messages from one cell in the body to another.
Cytokines either stimulate or suppress joint-damaging inflammation. Others block the action of cells involved in the inflammatory
process (T and B cells).
Six biologic therapies are currently approved for the treatment of rheumatoid arthritis. Three of them, adalimumab (Humira),
etanercept (Enbrel) and infliximab (Remicade), work in different ways to inhibit an inflammatory cytokine called tumor necrosis
factor (TNF). Remicade is used in combination with methotrexate.
The fourth, anakinra (Kineret), blocks the action of another inflammatory cytokine called interleukin-1.
The fifth is Orencia (abatacept), and it is approved for use in patients who have failed prior treatment with DMARDs
or TNF antagonists. Orencia is a T-cell inhibitor, and T cells are part of the inflammatory process in RA.
These drugs can treat symptoms of rheumatoid arthritis and also slow or prevent damage to joints.
The sixth and most recent is Rituxan (rituximab). This drug is approved for use in combination with methotrexate to reduce
signs and symptoms in patients who have failed prior treatment with one of the anti-TNF agents. Rituxan targets certain B
cells that are also part of the inflammatory process in RA.
There have been serious side effects noted with these therapies, and you should discuss the risks and benefits with your
doctor. Biologics are not for everyone, and their use must be monitored carefully by a physician.
The currently available biologic therapies must either be injected under the skin (Enbrel, Humira, Kineret) or infused
through an IV (Remicade, Orencia and Rituxan).
Corticosteriods:
Patients with arthritis who are treated with glucocorticoids face a highly increased risk of developing osteoporosis.
Belgian researchers at the 64th Annual scientific Meeting of the American College of Rheumatology (ACR) in Philadelphia Pennsylvania,stated
that pamidronate,as a primary preventive therapy can help arthritis patients maintain bone mineral density and fight off glucocorticoid-induced
osteoporosis.
Yves Boutsen,MD,Clinical Adjunctive Chief of Rheumatology,St-Luc University Clinic of Mont Godinne Belgium,led a team
of researchers in a prospective,controlled,one-year study comparing single-infusion pamidronate,
three-month therapy with pamidronate and calcium therapy alone in patients requiring first-time treatment with glucocorticoids.
Patients were examined at one year to determine differences in bone mineral density (BMD).
Thirty-two patients requiring first-time,long-term glucocortoids (at least 10 mg predisonolone daily) were studied. With
initiation of glucocortcoid therapy, patients all received 800 mg of elemental calcium daily,given as calcium carbonate. More
importanly,patients were also randomely allocated to receive one of the following; Group A received a single infusion of pamidronate
90 mg; Group B received a first infusion of pamidronate 90 mg followed by a 30-mg infusion of pamidronate every three months;
Group C received the calcium supplement alone.
Lumbar spine and hip (total and subregions) BMDs were measured at the onset and repeated at six-month intervals by dual-energy
x-ray absorptiometry (DEXA). Bone turnover was assessed by measurement of total and bone-specific serum alkaline phosphatase
activity,serum osteocalcin and serum C-telopeptide crosslinks of type-1 collagen.
After one year, results showed that the mean BMD changes for groups A,B and C were 1.7 %,2.3 % and-4.6 % respectively,at
the lumbar spine. BMD changes at the femoral neck were 1.2 % and-3.1 % respectively; and at the total hip refion were 1.0
%,2.6 % and-2.2 %.respectively.
No significant difference was observed between the pamidronate groups (A & B),but a significant difference was observed
between both pamidronate groups as compared to the calcium-alone regions. The researchers concluded that intravenous pamidronate
effectively achieved prevention of glucocortoid-induced osteoporosis.
Patients at high risk of steroid-induced osteoporosis should start bone-protective therapy at the same time they begin
glucocorticoids, Britain's Royal College of Physicians (RCP) recommends.
In a guidance document issued Monday, the RCP, the Bone and Tooth Society of Great Britain and the National Osteoporosis
Society update their 1999 advice on treating and preventing osteoporosis, which did not include steroid-induced disease.
High-risk patients include people over 65, and those who have had a previous fragility fracture.
"Glucocorticoids are an important but still relatively neglected cause of osteoporosis," said Dr. Juliet Compston, chair
of the RCP's guidelines development group. "There are now effective prevention measures and these guidelines provide an evidence-based
approach to the manage ment of glucocorticoid-treated patients," she said.
At any one time, about 1% of the adult population in the UK is taking oral glucocorticoids, most commonly prednisolone.
As many as 350,000 people in the UK could be at risk of glucocorticoid-induced osteo porosis, according to the RCP.
Patients receiving glucocorticoids should also have their bone mineral density measured with dual energy X-ray absorptiometry,
the physician group adds.
Measures to reduce bone loss include reduction of glucocorticoid dosage to a minimum, consideration of other formulations
or ways of administering the drug and prescription of alternative immuno suppressive drugs, the guidance says.
Patients should also be encouraged to cut back on alcohol and tobacco, and to maintain good nutrition, an adequate dietary
calcium intake and appropriate physical activity
The Story About Alice and her perspective:
Alice was in such bad shape that she thought she was going to die. There were times she prayed to die,because it was
so,so painful. She didn't really think of taking her life.she just prayed that one day she'd sleep and not wake up. What kept
Alice 39,going was her daughter theresa,who turned sixteen in early 1975. Alice said,"When I'd think that way,I'd say,no I
want to see my daughter grow up. I want to know she's going to be able to take care of herself".
Alice was a young college student and new single mom when her arthritis began,with swelling and pain in her right elbow.
A couple of month's later,the joints of two fingers on her left hand started to swell up.. by the time she finished school
and landed a job as a telephone operator with Bell Canada,an ankle was also affected. Then she had her really bad flare: "Practically
all my joints were involved. I woke up one morning and I couldn't get out of bed",recalls Alice.
A rheumatologist had some fluid from her elbow tested and diagnosed her with rheumatoid arthritis. He gave her cortisone
injections in her elbow for the pain,but he didn't really explain what she was facing. "In the early stages they jusy say
this is what you have,RA,"Alice says looking up at the ceiling.,"and I want you to take some of this,a coated form of Tylenol,and
I want you to come to my office once a week. They would inject my joints with cortisone,maybe once in three months (hands),different
joints like knee once a year. Some joints he repeated,others he did not. This continued for a while,and the pain just kept
progressing and I would be taking off time from work all the time."
The physiothapist kept telling her to keep her joints moving,because if she didn't,she wouldn't be able to move them.
Alice didn't quite understand the full impact of the therapist's words. "Exercise with all that pain,and I can barely walk
?,thought Alice. The occupational therapist made a special support for her hands and arms so she could sleep at night. She
would roll over and pin her hands under her body and according to Alice,"The pain was unbelievable".
Later,a new rheumatologist closer to her home had her hospitalized. For three weeks,she was prodded and poked, tested
and injected. In her condition,they finally concluded,Alice shouldn't even be working,a daunting prospect for a single mom
with a toddler to take care of. Fortunately,Alice's sister ccame from her family home and stayed to help out,and the initial
treatments,a combination of gold injections,water therapy,splints for her hands,more Acetaminophen, and lots of rest,seemed
to be helping.
Over the next several years,Alice was up and down,mostly down,with flares and remissions,but the RA was taking over.
The pain was becoming consistently bad,she was still on regular gold injections and taking a lot of Acetaminophen, she suffered
periods of deep depression,and her mobility was slowly eroding. She couldn't handle a few light chores,but she relied on her
sister for help with her daughter. She couldn't even comb her own hair,because her shoulders were so bad.
For another two years her conditioned worsened. Nothing seemed to help,and she landed in hospital again. This time she
saw a friendly,and interested physiotherapist who asked if she'd been in touch with The Arthritis Society. "You've been sick
for fourteen years,and nobody told you about them ?" the physio asked. "Well no",Alice replied. And he said,"I'm going to
sign you up right now"and Alice thanked God,she didn't know they had social workers you could sit and talk to,and physiotherapists
and occupational therapist. (One may have problems getting through at times,because they are very busy } That was what Alice
needed,to really understand what was happening with her arthritis,to be educated about it. ( Alice was also cautioned
about some members and staff,after all,people are people . I experienced some real bad ones.) She seen a local nurse,but
she didn't really understand Alice's disease,at all.
That same year,Alice was referred to an orthopedic surgeon for her knees. He took x-rays and gave her the news
in no uncertain terms "He said."You have to make up your mind. You have no cartilage left in your knees. You're too young,but
you can have surgery done now or wait till later,and be in a wheelchair and go through all the pain". (things have changed
now)
"By then"says Alice,"my arthritis was so bad I couldn't comb my hair,I couldn't wash myself,I couldn't feed myself,let
alone walk. Just to take one step was agnonizing." She decided to go with total joint replacements,both knees,four months
apart.
"After the first operation it was very painful,but after I started going on it I felt better. I didn't have all that
pain I'd experienced before. I was able to put my foot down and walk with a walker,then a cane". The second operation, though,wasn't
as good. Alice's right knee doesn't bend as much as it should,making it difficult for her to sit comfortably,for example,in
the back of a car. "My patella doesn't move at all in the right knee,but it doesn't pain".
Alice still has arthritis "all over",and since the operation her right ankle has been very painful. She walks with a
limp,but she can walk,and the pain in her knee,while it isn't totally gone,is bearable. "Before I had to think when I got
up," she explains. "Now I can just get up,OK,ther's going to be a little discomfort,but not like before,when I fell I wanted
to faint because the pain was so bad.
Without a doubt,the results would have been better if the operations had been performed earlier,something Alice's going
to have to consider as she contemplates the continuing deterioration of her other joints. Her right hip is "acting up a little
bit",and the other hip may eventually be affected,too,either by the progression of the disease,or because of the uneven wear
her hips are subjected to because of her mismatched knees.
"I don't even want to think about having my hips replaced right now,"she says,"but it's a possibility. My hands are still
the same,my elbows,my shoulders,it's affected my shoulders,real bad,and my elbows have gotten worse".
Overall,though Alice is better than she was. Her knee surgery has given her a measure of independence she didn't have
before, and The Arthritis Society occupational therapists have helped set her up with a labour-saving devices to make her
domestic tasks easier,and have given her instruction in how to perform those tasks with the least possible stress on her aching
joints. "I have to make ways of doing things",she says,"but I feel much better that I'm doing things for myself,because before
my sister and my daughter used to be doing everything."
She's even doing occasional volunteer work for the Arthritis Society,attending meetings to talk about her arthritis and
she agreed to attend a meeting of medical students and talk about the real world of arthritis.
" You can't help but think about the future,"Alice says"but I try not to. I say,whenever I reach the river,then I'll
cross over the bridge,but now I don't want to think about it. I just want to thank God for what I have and try to make it
better,if I can."
I met and talked to Alice,and I wonder,sometimes,if she had gotten better medical treatment earlier and got a better
understanding about her disease ,things may be a lot of different. Alice started treatment 25 years ago. I hope this story
may help some patients about dropping conventional therapy,to reconsider,and think about Alice and her story. Complementary
therapy if it helps,yes !,but total,Alternate therapy No !!
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