Minocycline-induced lupus in adolescents: clinical implications for physical therapists.

STUDY DESIGN: Resident's case problem. BACKGROUND: In the United States, minocycline is a frequently prescribed medication for the treatment of moderate to severe acne, a common condition in adolescents. The use of minocycline has been associated with severe adverse effects that frequently comprise a musculoskeletal component, including drug-induced lupus. Physical therapists have the responsibility to identify drug reactions that mimic musculoskeletal symptoms. The patient described herein was a 15-year-old adolescent boy who had taken minocycline for 14 days. He was initially treated by his primary physician on the 15th day of minocycline therapy for symptoms of fever, joint swelling, and a rash. The patient presented to a physical therapist on the 22nd day with complaints of severe myalgia, arthralgia, and severely limited mobility secondary to pain. The patient was referred to a pediatric rheumatologist because of the systemic nature and severity of the symptoms. DIAGNOSIS: The patient was subsequently diagnosed as having drug-induced lupus by a pediatric rheumatologist. The patient's myalgia and arthralgia subsided within 6 weeks, but his strength, coordination, and endurance did not reach their prior levels for 3 to 4 months. DISCUSSION: Physical therapists who include a comprehensive pharmacovigilance component in their patient examination may recognize musculoskeletal symptoms that arise from a nonmusculoskeletal origin. Minocycline is commonly prescribed in the United States as an antibiotic and for treatment of acne and rheumatoid arthritis. Therefore, physical therapists should screen for minocycline use when an adolescent patient or a patient with rheumatoid arthritis presents with diffuse musculoskeletal symptoms. An automated medication monitoring system would provide physical therapists with a means of accessing current information on medication use.

Drug-induced lupus associated with synthetic conjugated estrogens.

OBJECTIVE: To report a case of drug-induced lupus (DIL) in a patient taking Cenestin, a combination product of synthetic conjugated estrogens. CASE SUMMARY: A 54-year-old white female presented with a 4 month history of bilateral arm pain that developed and progressively worsened after initiating Cenestin 0.625 mg daily. The patient's symptoms, findings on physical examination (eg, degenerative changes of the acromioclavicular joint), and laboratory test results (eg, antinuclear antibody titer 1-640 [normal <1-40]) were suggestive of DIL. Her symptoms rapidly resolved with discontinuation of Cenestin and promptly resumed with reinitiation of the drug. Laboratory test values also improved significantly with discontinuation of Cenestin. Based on these findings and the Naranjo probability scale score, this reaction was probably associated with Cenestin. DISCUSSION: DIL differs from systemic lupus erythematosus in that it is caused by prolonged exposure at adequate doses to a drug rather than being an autoimmune reaction. The most commonly reported and studied medications are hydralazine, quinidine, and procainamide. Other medications have been associated with DIL; however, data are limited in these reports, especially with estrogen. There have been no previous reports in the literature of synthetic estrogen products associated with DIL. CONCLUSIONS: A diagnosis of DIL can be very challenging to make, especially since there are no clear criteria on which to base it. While estrogen has rarely been reported to be associated with DIL, it may be considered as a possible cause.

Shining light on lupus and UV.

People exposed to sunlight can develop erythema, DNA damage, and photoimmunosupression. Extended exposure of normal epidermis to sunlight will induce dysmorphic keratinocytes with pyknotic nuclei scattered throughout the spinous layer. These 'sunburn cells' are apoptotic keratinocytes and are usually cleared within 48 hours after sunburn. Patients with lupus erythematosus, however, whether it be the discoid, subacute cutaneous, systemic, or tumid form, develop new cutaneous lesions and can experience systemic worsening of their disease. Are sunlight-induced keratinocyte apoptosis and the immune response to these cells abnormal in lupus patients?

The ever-expanding association between rheumatologic diseases and tuberculosis.

We summarized most of the rheumatologic manifestations of tuberculosis (TB) and the occurrence of Mycobacterium tuberculosis disease associated with rheumatologic diseases. We established 4 different categories: (1) direct musculoskeletal involvement of M. tuberculosis, including spondylitis, osteomyelitis, septic arthritis, and tenosynovitis; (2) M. tuberculosis as an infectious pathogen in rheumatologic diseases, particularly with the use of newer agents such as tumor necrosis factor-alpha inhibitors; (3) antimycobacterial drug-induced rheumatologic syndromes, including tendinopathy, drug-induced lupus, and others; and (4) reactive immunologic phenomena caused by TB, such as reactive arthritis, erythema nodosum, and others. In addition, Bacille-Calmette-Guérin vaccination used for the prevention of TB or as a chemotherapeutic agent for bladder carcinoma also may be associated with musculoskeletal adverse events. We conclude that M. tuberculosis can directly or indirectly affect the musculoskeletal system.

Toxicity of infliximab in the course of treatment of Crohn's disease.

Infliximab is a monoclonal antibody directed against the pro-inflammatory mediator TNF-alpha, which was approved in the US in 1998 for treatment-resistant Crohn's disease. Since that time, the indications have dramatically expanded to include rheumatoid arthritis, ankylosing spondylitis, psoriasis and most recently, active ulcerative colitis. Although the safety profile in the initial studies was quite favourable, subsequent studies have shown that a small percentage of patients reported severe side effects, including pneumonia, tuberculosis, lymphoma, drug-induced lupus and hepatotoxicity. Although these complications are rare, it is important to properly screen patients for predisposing conditions before beginning treatment. Furthermore, concurrent use of other immunosuppresive agents, such as 6-mercaptopurine, may reduce the incidence of less serious side effects, such as arthralgias, myopathies and other antibody-associated diseases. Since its approval, infliximab has revolutionised the treatment of Crohn's disease and has shown benefit in a variety of other inflammatory conditions, but significant toxicities can occur that necessitate thorough screening protocols and periodic clinical evaluation.

Induction of lupus-related specific autoantibodies by non-specific inflammation caused by an intraperitoneal injection of n-hexadecane in BALB/c mice.

A single intraperitoneal (i.p.) injection of pristane, incomplete Freund's adjuvant (IFA), or the adjuvant oil squalene, but not high molecular weight medicinal mineral oils, induces lupus-related autoantibodies to nRNP/Sm and -Su in non-autoimmune strains of mice. This ability appears to be associated with the low molecular weight and adjuvanticity of hydrocarbon. n-Hexadecane (C(16)H(34)), which is present in petroleum, has adjuvant activity and induces arthritis in rodents like other lupus-inducing oils. In addition to dietary exposure to n-hexadecane in mineral oils, exposure also occurs via inhalation of oil mist, jet fuel, or diesel exhaust or by absorption through the skin. Since n-hexadecane is a low molecular weight adjuvant hydrocarbon oil similar to other lupus-inducing hydrocarbons, the present study examined whether it can also induce lupus-related autoantibodies in mice. Female BALB/cJ mice received a single i.p. injection of 0.5 ml of n-hexadecane, pristane, or saline (control). Pathology and serology (immunoglobulin levels, autoantibodies by immunofluorescence, immunoprecipitation, and ELISA) were examined 3 months later. Unexpectedly, all n-hexadecane-treated mice, but none in the other groups, developed inflammatory ascites within 2.5 months. n-Hexadecane induced hypergammaglobulinemia (IgG1, IgG2a), antinuclear (titer>1:160, 67%) and -cytoplasmic antibodies (58%) and autoantibodies to nRNP/Sm (25%), Su (33%), ssDNA (83%), and chromatin (100%). Therefore, non-specific inflammation caused by n-hexadecane resulted in the production of a limited set of specific autoantibodies. These previously unrecognized immunological effects of n-hexadecane may have implications in monitoring human exposure to hydrocarbons and in the pathogenesis of autoimmune diseases.

Adalimumab: a review of side effects.

Adalimumab (Humira) is a human monoclonal TNF-alpha antibody that blocks the effects of TNF-alpha. It is administered by subcutaneous injection. It has been approved alone or in combination with methotrexate for the treatment of rheumatoid arthritis in the EU and US. Approval for its use for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis is expected in the near future. Its side effect profile is favourable when compared with traditional systemic treatments for these diseases. It does not require laboratory monitoring. The most common side effects of adalimumab are injection site reactions. Adalimumab increases the risk of rare serious infections. There is a two-fold risk of serious infections with the use of adalimumab, as reported in the Premier trial. This risk should not be minimised in this way. It should not be used during periods of active infection. Its most notable infectious complication is the reactivation of tuberculosis. Tuberculosis screening should be according to country standards and may or may not include purified protein derivative test or chest X-ray. Deep fungal and other serious and atypical infection can also be promoted by adalimumab. It has been associated infrequently with skin rashes. Rare side effects include: worsening or initiation of congestive heart failure, a lupus-like syndrome, a promotion of lymphoma, medically significant cytopenias, and worsening or initiation of a multiple sclerosis/neurological disease. There has been reported pancytopenia and elevated transamines with the use of adalimumab, which suggest that laboratory monitoring blood counts and liver functions, at least intermittently, are useful. In patients with any of the foregoing problems, its use should be extremely carefully considered. Adalimumab is a useful medication which can be safely used if its side effects are recognised.

Acceleration of autoimmunity by organochlorine pesticides in (NZB x NZW)F1 mice.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that affects women more frequently than men. In the (NZB times NZW)F1 mouse, a murine SLE model, the presence or absence of estrogen markedly influences the rate of progression of disease. Three organochlorine pesticides with estrogenic effects were administered chronically to ovariectomized female (NZB times NZW)F1 mice, and we measured the time to development of renal disease, the principal clinical manifestation of lupus in this model. Treatment with chlordecone, methoxychlor, or o,p -dichlorodiphenyltrichloroethane (o,p -DDT) significantly decreased the time to onset of renal impairment, as did treatment with 17ss-estradiol used as a positive control. In an expanded study of chlordecone, we found a dose-related early appearance of elevated anti-double-strand DNA autoantibody titers that corresponded with subsequent development of glomerulonephritis. Immunohistofluorescence confirmed early deposition of immune complexes in kidneys of mice treated with chlordecone. These observations are consistent with an effect of these organochlorine pesticides to accelerate the natural course of SLE in the (NZB times NZW)F1 mouse. Although we originally hypothesized that the effect on progression of autoimmunity was due to estrogenic properties of the pesticides, autoimmune effects and estrogenicity, assessed through measurement of uterine hypertrophy, were not well correlated. This may indicate that uterine hypertrophy is a poor indicator of comparative estrogenic effects of organochlorine pesticides on the immune system, or that the pesticides are influencing autoimmunity through a mode of action unrelated to their estrogenicity.

Drug-induced lupus.

Autoantibodies and, less commonly, systemic rheumatic symptoms are associated with treatment with numerous medications and other types of ingested compounds. Distinct syndromes can be distinguished, based on clinical and laboratory features, as well as exposure history. Drug-induced lupus has been reported as a side-effect of long-term therapy with over 40 medications. Its clinical and laboratory features are similar to systemic lupus erythematosus, except that patients fully recover after the offending medication is discontinued. This syndrome differs from typical drug hypersensitivity reactions in that drug-specific T-cells or antibodies are not involved in induction of autoimmunity, it usually requires many months to years of drug exposure, is drug dose-dependent and generally does not result in immune sensitization to the drug. Circumstantial evidence strongly suggests that oxidative metabolites of the parent compound trigger autoimmunity. Several mechanisms for induction of autoimmunity will be discussed, including bystander activation of autoreactive lymphocytes due to drug-specific immunity or to non-specific activation of lymphocytes, direct cytotoxicity with release of autoantigens and disruption of central T-cell tolerance. The latter hypothesis will be supported by a mouse model in which a reactive metabolite of procainamide introduced into the thymus results in lupus-like autoantibody induction. These findings, as well as evidence for thymic function in drug-induced lupus patients, support the concept that abnormalities during T-cell selection in the thymus initiate autoimmunity.

A comprehensive review and evaluation of the side effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab.

For more than 5 years, infliximab and etanercept have been utilized to treat rheumatoid arthritis and Crohn's disease. There is therefore much post-approval data on their side effects. A variety of Medline searches were done at the beginning of June 2004 using the terms 'etanercept', 'infliximab' and 'adalimumab' and the words 'lymphoma', 'infection', 'congestive heart failure', 'demyelinating disease', 'lupus', 'antibodies', 'injection site reaction', 'systemic', 'side effects' and 'skin'. Approximately 150 articles were so identified. In addition, FDA and manufacturers' data obtained by internet searches using Google were reviewed. The important side effects that have been most extensively related to TNFalpha blockers include: lymphoma, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects. The risk of these side effects is very low. Nevertheless, it is important for clinicians to be aware of these side effects when prescribing therapy.

Complement-fixing properties of antinuclear antibodies distinguish drug-induced lupus from systemic lupus erythematosus.

The immunofluorescence antinuclear antibody (ANA) test has been widely used to monitor autoimmune disease, but its value for diagnostic purposes is compromised by low specificity and high prevalence in disease-free individuals. The capacity of autoantibodies to fix serum complement proteins when bound to antigen is an important effector function because this property is associated with acute and chronic inflammatory processes. The current study evaluates the complement-fixing properties of antinuclear antibodies (CANA) in three well-defined and clinically-related patient groups: systemic lupus erythematosus (SLE), drug-induced lupus (DIL) and drug-induced autoimmunity (DIA). Of 20 patients diagnosed with SLE, 90% displayed complement-fixing ANA while this feature was present in only two of 18 patients with DIL and no patients with DIA without associated disease even though the mean ANA titres were similar among these patient groups. CANA was significantly correlated with anti-Sm activity. Because SLE but not DIL or DIA can be a life-threatening disease associated with complement consumption in vivo, these results demonstrate that measurement of CANA is a diagnostically useful tool and may have immunopathologic implications.

Complications mimicking lupus flare-up in a uremic patient undergoing pegylated liposomal doxorubicin therapy for cervical cancer.

Patients with systemic lupus erythematosus (SLE) have an increased risk for malignancy and end-stage renal disease itself might further augment the risk. Treating uremic patients with cervical cancer by cisplatin-based chemotherapy combined with radiation is hampered by the reduced renal excretion of cisplatin. Doxorubicin, a potential radiosensitizer with an established effect on carcinomas that arise in the ovary, uterine cervix and endometrium, might be applied in these cases. We describe a 36-year-old woman, who had a 9-year history of SLE and was maintained on dialysis, and who developed severe drug reaction manifesting as fever, skin rash and exfoliative dermatitis with positive lupus band test after infusion of pegylated liposomal doxorubicin therapy for advanced cervical cancer. These skin manifestations improved after i.v. methylprednisolone pulse therapy.