Abstract

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M

AGDALENA

H

URKACZ

, A

NNA

W

IELA

−H

OJEŃSKA

The Influence of Rheumatoid Diseases

Pharmacotherapy on Laboratory Findings

Wpływ farmakoterapii chorób reumatoidalnych

na wyniki badań laboratoryjnych

Department of Clinical Pharmacology Silesian Piasts University of Medicine in Wrocław, Poland

Adv Clin Exp Med 2008, 17, 4, 471–478 ISSN 1230−025X

REVIEWS

Abstract

Rheumatoid diseases are the reason of patients life activity limitations, increasing their disability and morbidity. A lot of different drugs are used in their therapy: corticosteroids, analgesics, nonsteroidal anti−inflammatory drugs (NSAIDs), disease modifying anti−rheumatic drugs (DMARDs), immunosuppressants and biological drugs. Moreover, patients consume over the counter (OTC) drugs, often without advice of a physician, e.g. herbal medi− cines. Because of this polypharmacotherapy, the probability of different interactions is higher. The influence of drugs on the laboratory findings is the particular kind of them. They can lead to bad interpretation of the laborato− ry tests, missed diagnosed and improper analysis of therapy efficiency when this phenomenon is not taken into account in clinical practice. Therefore, drugs−laboratory results interactions and the cooperation of all medical co− workers should be always considered for optimalization of pharmacotherapy in rheumatology (Adv Clin Exp Med 2008, 17, 4, 471–478).

Key words: rheumatoid diseases, drugs, interactions, laboratory tests.

Streszczenie

Choroby reumatoidalne są przyczyną zmniejszenia aktywności życiowej chorych, zwiększenia ich niesprawności, a także śmiertelności. W ich terapii wykorzystuje się wiele różnych substancji leczniczych, w tym: kortykosteroi− dy, leki przeciwbólowe, niesteroidowe leki przeciwzapalne (n.l.p.z.), leki modyfikujące przebieg choroby, leki im− munosupresyjne oraz biologiczne. Ponadto chorzy często stosują, bez wiedzy lekarza prowadzącego, leki OTC, m.in. leki pochodzenia roślinnego. Taka polifarmakoterapia zwiększa prawdopodobieństwo wystąpienia niepożą− danych interakcji, których szczególnym rodzajem jest wpływ leków na wyniki badań laboratoryjnych. Nieuwzglę− dnianie tego zjawiska w praktyce klinicznej może być przyczyną błędnej interpretacji wyników badań, a w następ− stwie niewłaściwego rozpoznania choroby i niewłaściwej oceny skuteczności jej leczenia. Optymalizacja farmako− terapii w reumatologii wymaga zatem dokładnego poznania interakcji między lekami a badaniami laboratoryjnymi oraz współpracy wszystkich członków zespołu terapeutycznego (Adv Clin Exp Med 2008, 17, 4, 471–478).

Słowa kluczowe: choroby reumatoidalne, leki, interakcje, badania laboratoryjne.

Modern therapy of rheumatoid diseases, which depends on administration of many differ− ent drugs, can become the cause of numerous adverse effects in the organism, whose functions have already been disturbed by arthritis process, certain autoimmune diseases, osteoporosis and pain disorders. To the most common drugs, which are used in rheumatology belong: corticosteroids, analgesics, nonsteroidal anti−inflammatory drugs,

disease modifying anti−rheumatic drugs, immuno− suppressants and biological drugs. Moreover, patients consume over the counter drugs. Because of this polypharmacotherapy in rheumatological treatment, the probability of different kinds of interactions is higher [1–10].

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was observed that treatment of patients with one or two drugs results in 7% and 16.6% of the test influence, respectively. The used drugs in rheumatology differ in their chemical structure and may be the potential reason of test errors. The findings are very often unexpected and mislead− ing. They lead to unnecessary further test, missed diagnosed and additional costs. Drug−test interfer− ences produce a statistically and clinically signif− icant increase in the duration of hospital stay [11–14].

Interactions between drugs and laboratory tests are divided into two groups. One of them involves the change in the clinical status of the patient and some pathophysiological processes in the organism. The second group of interactions includes drugs and chemical substances used in the analysis. The drugs or their metabolites can interfere the analytical reaction. The interactions between drug and the organism are observed more often than between drug and chemical test [11, 15–20].

This problem is still not well known, there is insufficiently number of publications about it in medical literature and some clinical or laboratory observations are necessary [17, 21, 22].

Corticosteroids

It is one of the most important group of drugs that have been used in rheumatology since 1948. At the same time they cause a number of adverse drug reactions, which are depended on the dose and duration of treatment. According to modern guidelines of most expert groups, the patients should be informed about adverse drug reactions of corticosteroid therapy and a “corticosteroids treatment card” including information on the doses and some modifications of pharmacotherapy should be run [4, 5, 7, 9, 22–24].

Corticosteroids may increase glucose blood concentration by enhancing the gluconeogenesis in the liver and intensifying glycogenolysis. They decrease the uptake of glucose in lipid tissue and in muscle. Glucose tolerance and sensitivity to insulin are reduced. Hyperglycemia after corticos− teroid therapy depends on the dose, duration of treatment and kind of specimen. It is observed for the first 6 weeks since the beginning of pharma− cotherapy. Insulin resistance usually maintains for 48 hours from cessation of therapy. Corticoste− roids increase chromium losses. Moreover, they play a role in electrolyte disturbances by stopping water and sodium in the organism. Corti− costeroids have also been found to decrease the concentration of potassium, calcium, chloride and

phosphorus in the blood. Hypercholesterolemia and hypertriglyceridemia are additional potential complications during long term corticosteroid therapy. Total protein concentration is increased too. They also change creatinine and uric acid concentrations [4, 7, 11, 13, 23, 25–28].

No significant effect of corticosteroids on the biochemical examinations has been observed [11, 27, 28].

Analgesics

In the course of a rheumatoid diseases the patient must often take analgesics drugs. This effect is deciduous and symptomatic to decrease pain on movement, which reduces the activity and passive range of motion. Drugs, which are used in analgesia belong to various groups, one of them is paracetamol. It is an extremely safe analgesic when taken in therapeutic doses. A mild increase in hepatic enzymes activity may sometimes occur in the absence of jaundice [7]. However, acute overdose can cause potentially fatal liver damage. The hepato−toxicity of paracetamol is considered to be due to its toxic metabolite, N−acetyl−p− benzo−quinone imine (NAPQI). Under normal conditions it is detoxified by conjugation with glutathione, but with high doses of drug, the sul− fate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI. As a result, hepatocellular supplies of glutathione become exhausted and NAPQI is free to react with cellular membrane molecules, resulting in hepatocyte damage and death, leading to acute hepatic necrosis. Recent studies has documented that 38% of acute liver failure cases in 22 hospi− tals in the United States were associated with excessive paracetamol usage. The drug causes hypoglycemia as a result of hepatic failure and disturbances in carbohydrate metabolism. Rarely, acute renal failure also may occur. It increases the concentration of blood urea nitrogen. Hemolytic anemia and methemoglobinemia are very rare [7, 23, 24, 26, 29–32].

Paracetamol has oxidoreductive property and it falsely increases glucose blood concentration assessed by enzymatic method. On the other hand, it increases the level of uric acid measured by means of an enzymatic method. However, it does not affect other biochemical parameters assess− ments [11, 22, 27, 32].

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Nonsteroidal

Anti−inflammatory Drugs

NSAIDs are a very important heterogeneous group of organic acids drugs that have analgesic, antipyretic, anti−inflammatory, and platelet inhi− bitory actions, uses in rheumatology. Prolonged administration of NSAIDs may cause a number of adverse reactions [7].

Hepatotoxicity has been reported with all of the structural classes of NSAIDs. Serious hepato− cellular reactions have been well documented with phenylbutazone. Liver failure is manifested by increased activity of the enzymes, such as alanine aminotransferase – AlAT and aspartate amino− transferase – AspAT. Phenylbutazone is one of the most dangerous drug. It should be used only when less toxic alternatives are unavailable. Significant adverse effects can affect up to 40% of patients. Ibuprofen is not directly hepatotoxic, but the liver can be damaged as a part of generalized hypersen− sitivity reactions [7, 9, 11, 33].

NSAIDs can cause severe hematological dis− orders – thrombocytopenia, agranulocytosis, aplastic and hemolytic anemia. Thrombocytopenia is generally mild and reversible but deaths from bleeding have been observed with indometacin, oxyphenbutazone and phenylbutazone. Analgesics significantly associated with agranulocytosis were indometacin, oxyphenbutazone and phenylbuta− zone. A significantly increased risk for aplastic anemia is associated with indometacin, butazones, diclofenac therapy and hemolytic anemia – with mefenamic acid, ibuprofen and sulindac adminis− tration. Gastrointestinal blood loss due to ibupro− fen can cause iron deficiency anemia [7, 33].

Many of the NSAIDs are associated with renal disorders. They can produce functional renal insufficiency, nephrotic syndrome, renal papillary necrosis, chronic interstitial nephritis, acute tubu− lar necrosis, vasculitis, glomerulonephritis, and obstructive nephropathy. All NSAIDs can cause the functional renal insufficiency. It is usually mild

and reversible within a few days of withdrawing NSAIDs. Acute interstital nephritis has been reported in patients taking fenoprofen. Ibuprofen can cause renal impairment, ranging from an insignificant reduction to an acute fall in creatinine clearance. It brings increase of creatinine kinase activity and uric acid concentration in serum. Renal papillary necrosis has been reported after long term intake of acetylsalicylic acid and other NSAIDs. Acetylsalicylic acid increses creatinine (38%) and uric acid (17%) blood concentration. Naproxen therapy 750 mg/day reduces glomerular filtration rate, renal plasma flow and renal prostaglandin excretion [7, 11, 32, 33].

NSAIDs can interfere with fluid and electrolyte homeostasis, which can lead to edema, hyponatrem− ia and hyperkalemia, especially in patients with dia− betes mellitus, renal failure, increased age, or those receiving concomitant therapy with adrenergic blockers, angiotensin−converting enzyme inhibitors and cyclosporine. About 10% of patients show signs of salt and fluid retention during phenylbutazone treatment. Adverse drug reactions of NSAIDs depend on the kind of specimen, dose, time and route of drug application [7, 9, 11, 22–24, 33].

Salicylates often produce false test results. They increase blood glucose concentration, which is evaluated by means of the enzymatic method. They also increase uric acid concentration in serum by the influence on phosphorotungstic acid method and decrease enzymes activity: creatine kinase (CK), alanine aminotransferase, alkaline phosphatase (AP), lactate dehydrogenase (LDH), which are measured by enzymatic or kinetic meth− ods. Acetylsalicylic acid causes false results of blood cholesterol concentration and total protein measurement (biuretic method) [11, 27].

Ketoprofen evokes disturbances in the mea− surement of glucose concentration in whole blood by enzymatic method. It decreases the activity of alanine and aspartate aminotransferase, creatine kinase, lactate dehydrogenase, which are mea− sured by colorimetric method, increases bilirubin concentration in serum, which is measured by Jendrassik−Grof method. Ketoprofen use has been followed by red discoloration of urine [11, 27, 33].

Ibuprofen increases activity of alanine amino− transferase and blood bilirubin concentration. Diclofenac falsely increases whole blood glucose concentration, which is measured by enzymatic method, uric acid level and urea – by enzymatic method too [11].

Salicylates (in high concentrations), phenylbu− tazone and diclofenac alter thyroid hormone tests, causing a fall in serum triiodothyronine, by inter− fering with it serum protein binding. Butapirazol causes positive Coombs test [11, 27, 28].

Table 1. The most commonly reported analytical interfer− ences between paracetamol and laboratory diagnostic tests

Tabela 1. Najczęściej obserwowane interferencje anality− czne między paracetamolem a metodami badań laborato− ryjnych

The influence of paracetamol on the biochemical tests (Wpływ paracetamolu na badania laboratoryjne) Increasing glucose blood concentration – enzymatic

method

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The analytical interferences between NSAIDs and laboratory diagnostic tests are shown in Table 2.

Disease Modifying

Anti−rheumatic Drugs

Sulphasalazine

This drug probably inhibits prostaglandin and leukotriens synthesis. It exerts a negative effect on biochemical changes in the organism. Sulpha− salazine causes a lot of different adverse drug reac− tions, for example hepatotoxicity (hipoalbumin, disturbances of coagulation factors and increases activity of liver enzymes – lactate dehydrogenase, alanine aminotransferase, aspartate aminotrans− ferase, γ−glutamyl transferase – GGT). Moreover, sulphasalazine increases plasma bilirubin concen− tration. Sulphasalazine causes hematological dis− turbances. It can cause a drop in the number of white blood cells, and can decrease the number of platelets [7, 9].

Sulphasalazine causes an orange discoloura− tion of the urine and perspiration may be a little orange−tinged [27]. There are unknown interac− tions with substances used in laboratory analyzes [11, 27].

Gold Salts

Gold salts were introduced to the therapy of rheumatic diseases in 1929. In spite of good results observe during their administration, they are with−

drawn from therapy in some countries e.g. in Poland in 2004 with the reason of significant toxi− city [7,9,34]. Eosinophilia in the peripheral blood is connected with parenteral drug administration and it is observed in 40% of patients. Leukopenia is rare, sometimes very mild. Granulocytopenia can evolve slowly or suddenly. Thrombocytopenia occurs in 0.7–3% of patients and can be severe. Mild and transient abnormalities in serum transaminase and alkaline phosphatase activities have been reported during its administration (0.4%). Besides, they are the cause of nephrotoxi− city, which is manifested as proteinuria and hema− turia. The urinary excretion of beta−glu− cosaminidase, leucine aminopeptidase, beta2− microglobulin and other tubular proteins has often been found to be increase in patients treated with gold compounds [7, 35].

The interactions with biochemical reactions, which are used in laboratory tests are not known in literature [11, 27, 35].

Methotrexate

Methotrexate (MTX) is a basic modifying drug, formerly known as amethopterin. It is a folic acid inhibitor with anti−inflammatory and immuno− modulatory effects. It’s the main problem in ther− apy because of its numerous adverse effects. First of all it causes hepatological adverse effects, espe− cially during prolonged treatment. They are mani− fested as an increase in liver enzyme activity, aspartate aminotransferase and alanine amino− transferase. Their values quickly settle to the norm after temporary therapy withdrawal. This effect

Table 2.The most commonly reported analytical interferences between nonsteroidal anti−inflammatory drugs and laboratory diagnostic tests

Tabela 2.Najczęściej obserwowane interferencje analityczne między niesteroidowymi lekami przeciwzapalnymi a metoda− mi badań laboratoryjnych

The influence of NSAIDs on the biochemical tests (Wpływ n.l.p.z. na badania laboratoryjne) Increasing blood glucose concentration – enzymatic method: acetylsalicylic acid (4%), ketoprofen (4%), diclofenac,

indomethacin (5%)

Increasing activity of alanine aminotransferase – ibuprofen

Increasing blood bilirubin concentration – Jendrassik−Grof method: ketoprofen (12%), ibuprofen (10%) Increasing uric acid serum concentration – phosphorotungstic acid method: salicylates

Increasing uric acid concentration – enzymatic method: diclofenac (7%), indomethacin (7%) Increasing of urate level – enzymatic method: diclofenac

Decreasing activity of: alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase: salicylates; alanine amino− transferase: ketoprofen (8%); aspartate aminotransferase – colorimetric method: ketoprofen (8%); creatine kinase: salicylates, ketoprofen; lactate dehydrogenase – enzymatic or kinetic methods: ketoprofen

Decreasing blood cholesterol concentration – Liebermann−Burghard method: acetylsalicylic acid (7%) Decreasing total plasma protein concentration – biuretic method: salicylates (7%)

Decreasing urine glucose concentration: salicylates

Interfering with the results of diagnostic thyroid function test: salicylates (in high concentrations), phenylbutazone, diclofenac

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may occur in up to 15% of patients. MTX causes increasing bilirubin and bile acids concentrations in serum. Moderate leukopenia and thrombocy− topenia are observed during methotrexate therapy. A very rare but the most serious complication is pancytopenia. MTX increases homocysteine level in serum, too. Moreover, there are some reports on renal fibrosis and vascular sclerosis during its ther− apy. Methotrexate causes increase in urea blood concentration and slight decrease in glomerular filtration rate and creatinine clearance, as well as a decrease in N−acetyl−beta−D−glucosaminidase activity and albumin concentrations in urine [7–9, 11, 33, 36–38].

There is no information about interactions between MTX and laboratory tests [27, 33].

Immunosuppressants

Cyclophosphamide

Cyclophosphamide is an alkylating nitrogen mustard derivative, which is used in chronic inflammatory disorders or autoimmune diseases as an immunosuppressant. It evokes a lot of adverse effects. Leucopenia, and less commonly throm− pocytopenia or anemia are typically dose−related in the therapeutic range. Cyclophosphamide− induced, dose−related liver damage is probably caused as a result of impaired clearance of its metabolite acrolein. This causes raised transami− nases activity, bilirubin and bile acids concentra− tion in serum. Even low−dose cyclophosphamide treatment can cause a syndrome that manifests inappropriate secretion of antidiuretic hormone, with severe hyponatriemia and symptoms of water intoxication [7, 39].

However, there is unknown data on interac− tions between cyclophosphamide and biochemical reagents [27, 39].

Cyclosporine

Cyclosporine is an immunosuppressant drug that is considered a disease modifying anti− rheumatic drug because it not only decreases the pain and swelling of arthritis but it may also pre− vent joint damage and reduce the risk of long term disability. Renal insufficiency and electrolyte abnormalities are the most common of its adverse effects. Creatinine clearance is reduced very often, but usually returns to the normal level after drug cessation. It also increases plasma creatinine (50–67%), urea and urea acid (10%) concentra− tions. Therapy with this drug is associated with hypomagnesaemia. Furthermore, increasing potas−

sium plasma concentration. Cyclosporine may also induce the liver enzyme activity and elevation bilirubin. It’s therapy significantly raises plasma lipoprotein concentrations by increasing the total serum cholesterol [7, 11, 40–42].

There is unknown data on interactions between cyclosporine and biochemical reagents [11, 27, 42].

Tacrolimus

Pharmacotherapy with this drug have a similar spectrum of adverse effects for infections compli− cations, lymphoproliferative disorders and nephro− toxicity to ciclosporin. Tacrolimus increases the concentration of potassium, creatinine, urea in serum and decreases magnesium level. Severe or persistent tacrolimus−related adverse reactions, e.g. gastrointestinal disorders, neurotoxicity or diabetes mellitus can abate after replacement by ciclosporin. Especially after high doses of tacrolimus it is observed the alteration of glucose metabolism and subsequent hyperglycemia. The findings of mild to moderate liver function test abnormalities that normalized on dosage reduction or withdrawal of tacrolimus has been suggested a possible dose−related hepatotoxicity. It can cause increase of transaminase and lactate dehydroge− nase activities. Tacrolimus also affects the bone marrow function, which is manifested as leucope− nia, agranulocytosis and thrombocytopenia [7, 40, 41, 43, 44].

There is unknown data on interactions between cyclosporine and biochemical reagents [43].

Mycophenolate Mofetil

Mycophenolate mofetil was first derived from the mould Penicillium glaucumin the 1940s. It is metabolised in the liver to the active moiety mycophenolic acid. It causes bone marrow func− tion and coagulation damage. There was observed a dose−related increase in the incidence of leukopenia. However, there is unknown data on interactions between mycophenolate and laborato− ry analyzes, but its impact on immunological methods is probable [7].

Azathioprine

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patients with inflammatory bowel disease and occurs 2 weeks to 11 years after the start of thera− py. Azathioprine and mercaptopurine increase the liver enzyme activity e.g. alkaline phosphatase and bilirubin concentration in serum [7].

Mercaptopurine gives false reduction (18– 29%) for uric acid concentration in blood [11, 45].

Biological Drugs

Three drugs, such adalimumab, etanercept and infliximab are antibodies that bind TNF−α, a proinflammatory cytokine and are used for the treatment of rheumatoid arthritis or other rheumat− ic diseases. It was observed a nephrotic syndrome during treatment with adalimumab. The protein− uria disappeared spontaneusly after cessation of the drug. In addition, hypercholesterolemia, hyperlipidemia, hematuria and alkaline phos− phatase increased were reported during adalimum− ab therapy. Biological drugs are responsible for hematological disturbances such as leucopenia, neutropenia, thromocytopenia, anemia. Besides, they cause hyperglycemia, decreasing plasma potassium concentration, increasing liver enzymes activity (lactate dehydrogenase). In connection with the mechanism of action, this drugs inhibits produc− tion of immunoglobulin in the organism [7, 46, 47].

Herbal Medicines

A lot of people who use herbal medicines do not inform their physicians about them, because about 65% of patients thought that this kind of medicines is absolutely safe. It isn’t a right opin− ion. Herbal medicines contain powerful active substances, which can be responsible for different adverse reactions. They can influence the labora− tory tests, cause abnormal results and confusion in proper diagnosis e.g. chaparral and borage oil use in rheumatoid arthritis increase the liver enzymes activity [48, 49].

Another problem is unexpected alteration of

laboratory test results in people, who don’t know of using that herbal medicine contains some drugs. For example, it was observed in a 12−year old boy treated with herbal medications such laboratory test value: a hemoglobin concentration – 8 g/dL, a neutrophil count – 200/mL, and a platelet count – 5.000/mL. These hematologic abnormalities were related to phenylbutazone, which was an ingredient of herbal drug not listed in the package insert. Nonsteroidal anti−inflammatory drugs have been found in many Chinese medicines sold out− side Asia [49].

Laboratory tests are an integral part of the therapeutic procedure, and constitute up to 80% of the physician’s diagnosis and treatment method. They have been changing over time. In the past physicians made laboratory tests by themselves. Now there is a highly specialized, diagnosticians, and well educated laboratory staff. In addition have modern and precise analyzers at their dispos− al. This is associated with some profits, for exam− ple precision and specificity of the results. Unfortunately, it appears new problems. The num− ber of drugs is increasing day to day, the fact of drug interference on laboratory tests is also on the rise. When the laboratory is in a different part of hospital, detailed information about the patient may be not known by the diagnosticians. This is one of the most important problems which some− times occur in the interpretation of laboratory tests. The cooperation between physicians and other medical co−workers (pharmacists, nurses, diagnosticians, radiologists, microbiologists) is necessary and very important. Some information about the patient, for example about pharma− cotherapy, must be placed on a laboratory order. To avoid or minimize some analytical errors, many hospitals use computerized systems of the labora− tory control. These databases control the accuracy of analyses and also take information about drugs [15–21].

In conclusion, drug effects on laboratory find− ings should be always considered when interpret− ing laboratory results for improvement of efficien− cy, as well as safety of pharmacological treatment.

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Address for correspondence:

Magdalena Hurkacz

Department of Clinical Pharmacology Silesian Piasts University of Medicine Bujwida 44

50−435 Wrocław Poland

Tel. 071 328−61−82

E−mail: [email protected]

Conflict of interest: None declared