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Rheumatology 2001; 40: 329-335
© 2001 British Society for Rheumatology

Minocycline-induced lupus: clinical features and response to rechallenge

T. M. Lawson, N. Amos, D. Bulgen1 and B. D. Williams

Department of Rheumatology, University Hospital of Wales, Cardiff CF14 4XN and
1 Department of Rheumatology, Countess of Chester Hospital, Liverpool Road, Chester CH2 1UL, UK


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Case 1
 Case 2
 Case 3
 Results
 Discussion
 References
 
Objective. To describe the spectrum of clinical features in patients with minocycline-induced lupus (MIL) and determine their response to rechallenge.

Methods. The clinical features and laboratory findings of 23 patients with MIL were recorded. Ten patients were rechallenged, and their C-reactive protein (CRP) levels were monitored.

Results. All subjects complained of polyarthralgia; three had metacarpophalangeal and proximal interphalangeal joint synovitis and one had bilateral knee effusions. Elevated hepatic transaminases were noted in eight subjects. Cutaneous vasculitis was a feature in two cases. None had renal or central nervous system disease, although five patients complained of impaired concentration and poor memory and a single patient had a peripheral sensory neuropathy. The following serological abnormalities were detected: antinuclear antibodies (19/23 patients); antibodies to double-stranded DNA (4/23); perinuclear antineutrophil cytoplasmic antibodies (10/15); IgG anti-cardiolipin antibodies (6/23); hypergammaglobulinaemia (12/19). Anti-histone antibodies were negative in 9/9 cases. Rechallenge resulted in rapid recurrence of symptoms and elevation of CRP levels.

Conclusion. MIL is associated with a wide spectrum of clinical and serological features. The diagnosis can be confirmed by rechallenge, which results in rapid reappearance of symptoms and a rise in CRP.

KEY WORDS: Minocycline, CRP, SLE, Drug-induced lupus, Rechallenge.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Case 1
 Case 2
 Case 3
 Results
 Discussion
 References
 
Since the original description in 1945 of a patient who developed a lupus-like illness following sulphadiazine consumption, many other drugs have been reported to cause this syndrome [1–3]. The most commonly associated drugs are procainamide and hydralazine, but these are not in common current use [4]. More recently, minocycline has been associated with a number of autoimmune syndromes, of which hepatitis and a lupus-like illness are the most common and can occur concurrently [5, 6]. Following the first report of minocycline-induced lupus (MIL) [7], several others have drawn attention to this association [8–20].

Minocycline is a semisynthetic tetracycline widely prescribed in the UK for the long-term treatment of acne vulgaris. It is also used as a disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA) and is significantly better than placebo [21–24]. Common side-effects associated with its use are nausea, vomiting, skin rashes, dizziness, photosensitivity and, more rarely, hepatotoxicity [25, 26] and pneumonitis [27, 28]. Although minocycline is prescribed widely, the incidence and prevalence of MIL are unknown. Approximately 57 cases of MIL have been fully reported to date [reviewed in 6], mostly from Europe. However, between 1972 and 1996 the FDA's MEDWATCH Reporting Program received 32 reports of MIL in the USA [29].

We describe the clinical and laboratory features of 23 patients referred to the rheumatology department at the University Hospital of Wales, Cardiff, who developed MIL. Twenty-two patients were taking minocycline for the treatment of acne and in one patient it was prescribed as a DMARD for RA. We highlight the wide spectrum of clinical features associated with this syndrome, which range from polyarthralgia to features typical of idiopathic systemic lupus erythematosus (SLE).

The role of rechallenge with minocycline in the diagnosis of MIL has not been studied objectively, although some patients have performed their own rechallenge before seeking medical advice and noted recurrence of symptoms [14, 19, 30]. We demonstrate that rechallenge with minocycline whilst the level of C-reactive protein (CRP) is being monitored is a rapid and objective means of confirming the diagnosis of MIL.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Case 1
 Case 2
 Case 3
 Results
 Discussion
 References
 
The patients were seen between 1994 and 2000 and were referred by general practitioners or consultant colleagues or were self-referrals following reports in the popular press of MIL. A diagnosis of MIL was based on the association of symptoms with long-term minocycline consumption, a positive test for antinuclear antibodies (ANA) and the resolution of symptoms after the cessation of minocycline therapy. The duration of minocycline therapy before the development of symptoms, the nature of the presenting symptoms, physical findings and the time to recovery after withdrawal of the drug were recorded in each case.

Laboratory investigations included complete blood count (CBC), renal and hepatic profiles, immunoglobulin (Ig) and complement (C3 and C4) levels, erythrocyte sedimentation rate (ESR), CRP and autoantibodies [ANA, anti-double-stranded DNA (anti-dsDNA), antibodies to extractable nuclear antigens (ENAs), antineutrophil cytoplasmic antibodies (ANCA) and anti-cardiolipin (ACL) antibodies].

Rechallenge with minocycline
Ten patients were rechallenged with minocycline after resolution of their symptoms. One hundred milligrams of minocycline was administered at 9.00 a.m. and daily thereafter if symptoms failed to develop within the first 24 h. The nature and time of onset of symptoms were recorded. Serum CRP levels were measured before rechallenge and subsequently every 8 h.

Control subjects were also rechallenged; they comprised three healthy volunteers and three subjects who had been asymptomatic whilst on long-term minocycline.

Three patients are described in detail to illustrate the spectrum of clinical features associated with MIL.


   Case 1
Top
 Abstract
 Introduction
 Patients and methods
 Case 1
Case 2
 Case 3
 Results
 Discussion
 References
 
A 41-yr-old sales assistant was referred with a 1-yr history of polyarthralgia, early morning stiffness and intermittent fevers. She also complained of malaise, impaired concentration, Raynaud's phenomenon, alopecia, mouth ulcers and altered sensation over the left foot. She had been prescribed minocycline 100 mg daily for acne and had taken this for 1 yr before developing symptoms. She continued to take this medication despite feeling unwell.

Results of the investigations were as follows: haemoglobin (Hb) 11 g/dl, white cell count 3.9x109/l (lymphopenia 0.4x109/l), platelets 284x109/l; ESR 44 mm/h, normal renal and liver function; ANA positive (1:80); anti-dsDNA positive by ELISA and Crithidia assays; IgG ACL antibodies weakly positive; perinuclear ANCA (pANCA) positive (1:320); anti-myeloperoxidase (MPO) antibodies negative; antibodies to ENAs negative; IgG 16.5 g/l (normal range 5.10–15 g/l), IgA 1.28 g/l (normal range 0.80–4.00 g/l), IgM 3.03 g/l (normal range 0.48–1.90 g/l); C3, C4 normal; urinalysis negative for protein and blood. Nerve conduction tests showed evidence of a distal sensory peripheral neuropathy in the left foot.

A diagnosis of SLE was made and treatment with hydroxychloroquine 400 mg daily and prednisolone 10 mg daily was commenced. Because of her complaints of lack of concentration and memory loss, she was referred to a clinical psychologist for psychomotor testing. Despite normal intelligence, there were marked deficits in attention and immediate memory and significant impairment of visual perception and visual motor speed.

Three years after the onset of symptoms the patient stopped taking minocycline, and 10 months later she was asymptomatic. Because of the delay between the discontinuation of minocycline and the resolution of symptoms, she did not associate this drug with her illness. Her ANA remained positive at 1:100, but anti-dsDNA antibodies were negative. She agreed to a rechallenge with minocycline. Within 24 h of taking 100 mg minocycline she had developed a headache, polyarthralgia, malaise, anorexia, dizziness and a fever (38°C). By 48 h, her CRP had increased from <1 to 67 mg/l. Minocycline was discontinued and over the next 8 days her symptoms resolved and the CRP returned to normal.

This case illustrates how the clinical and serological features of MIL may be indistinguishable from idiopathic SLE and result in inappropriate long-term treatment and follow-up.


   Case 2
Top
 Abstract
 Introduction
 Patients and methods
 Case 1
 Case 2
Case 3
 Results
 Discussion
 References
 
A 16-yr-old student was prescribed minocycline 100 mg daily for acne vulgaris. Nine months later, he complained of weight loss and general malaise and after a further 3 months became jaundiced. He was referred to a gastroenterologist for investigation, but did not admit to taking minocycline. Initial investigations confirmed hepatitis [bilirubin 120 µmol/l (normal range 1–17 µmol/l); aspartate transaminase 284 IU/l (normal range 5–40 IU/l); alkaline phosphatase 127 IU/l (normal range 30–115 IU/l)]. CBC and renal function were normal and serology for hepatitis A, B and C was negative. No specific diagnosis was made and the abnormalities of liver function resolved gradually over the next 3 months in the absence of any specific therapy and whilst the patient continued to take minocycline.

He subsequently developed severe polyarthralgia and myalgia, and was unable to dress without assistance. He had several episodes of pleuritic chest pain and intermittent fevers, which were treated with ibuprofen. There was marked tenderness of the small joints of the hands, metatarsalgia and tenderness of the proximal muscles. There was no evidence of synovitis.

Results of investigations were as follows: CBC normal; normal renal and hepatic function; ESR 20 mm/h; CRP 26 mg/l; ANA positive (1:80); anti-dsDNA negative; IgG ACL antibodies weakly positive; antibodies to ENAs negative; pANCA positive (1:160) with specificity for MPO; anti-histone antibodies negative; IgG 19.2 g/l (normal range 5.10–15 g/l), IgA 1.68 g/l (normal range 0.80–4.00 g/l) IgM 0.86 g/l (normal range 0.48–1.90 g/l); urinalysis negative for protein and blood.

A diagnosis of MIL was made and the minocycline was stopped. He remained severely disabled for several weeks and his symptoms resolved only after prescription of prednisolone 20 mg daily. Steroids were withdrawn gradually over the next 2 months. His failure to improve after withdrawal of the minocycline raised some doubt about the diagnosis. The patient agreed to a rechallenge with minocycline and was given a single dose of 100 mg. Within 6 h he developed a fever (38°C) and complained of malaise, myalgia and polyarthralgia. Before rechallenge the CRP was <1 mg/l but after 48 h it had increased to 103 mg/l. Renal and hepatic function remained normal. Because of the severity of the symptoms, oral prednisolone was prescribed at a daily dose of 10 mg and continued for 3 days. Symptoms resolved rapidly and the CRP returned to normal. The ANA test was negative 2 yr after withdrawal of minocycline and the patient remains asymptomatic 5 yr later.

This case illustrates how minocycline-induced hepatitis and MIL can coexist and how, in some cases, abnormal liver function tests can normalize despite the continuation of minocycline therapy.


   Case 3
Top
 Abstract
 Introduction
 Patients and methods
 Case 1
 Case 2
 Case 3
Results
 Discussion
 References
 
A 58-yr-old retired schoolteacher with a 15-yr history of seropositive erosive RA was treated with minocycline 200 mg daily as part of an open clinical trial. Her joint disease was well controlled, but after 2 yr of treatment with minocycline she suddenly complained of increasing malaise, fatigue polyarthralgia and myalgia, and developed an erythematous rash on her legs. At this time there was minimal synovitis of the metacarpophalangeal and proximal interphalangeal joints. Multiple raised purpuric lesions were visible over the anterior aspect of both shins and their appearance was thought to be typical of vasculitis. Skin biopsy was not performed.

Results of investigations were as follows: CBC normal; renal and hepatic function normal; ESR 79 mm/h, CRP 101 mg/l; C3, C4 and CH50 normal; ANA positive (1:1600); anti-dsDNA antibodies positive [900 IU/ml (normally <20)]; ACL antibodies negative; antibodies to ENAs negative. A diagnosis of MIL was made and the minocycline was stopped. Over the next 6 weeks her symptoms settled completely, the skin lesions resolved and the CRP returned to normal. Her RA was subsequently treated with methotrexate and remains well controlled. Five years after stopping minocycline, she is positive for ANA (1:1600), but negative for anti-dsDNA antibodies. There are no clinical features of idiopathic SLE. The patient refused rechallenge with minocycline.

This is the first case of MIL to be described in a patient taking minocycline for RA, a situation in which worsening joint symptoms could easily be misinterpreted as an exacerbation of RA.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Case 1
 Case 2
 Case 3
 Results
Discussion
 References
 
Twenty-three patients (20 female, three male) have been identified in our unit. Twenty-two subjects were taking minocycline at a dose of 100 mg daily for the treatment of acne vulgaris. A single patient was taking 200 mg minocycline daily for seropositive RA. The median duration of treatment with minocycline before the development of symptoms was 22.5 months (range 3 months to 6 yr).

Clinical features
A wide spectrum of clinical features were observed in the 23 patients. Polyarthralgia occurred in 23, malaise in 23, myalgia in 23, early morning stiffness in 23, fever in 15, metacarpophalangeal and proximal interphalangeal joint synovitis in three, knee effusions in one, cutaneous vasculitis in two (proven by biopsy in one case), hair loss in four, mouth ulcers in two, weight loss of more than 4 kg in two, jaundice in two, cognitive impairment in five (formally documented by a clinical psychologist in one case), peripheral sensory neuropathy in one, and Raynaud's phenomenon in one.

Laboratory variables
Haematology.
Three out of three male subjects had Hb levels <13.5 g/dl (13.0, 13.1 and 10.0 g/dl respectively; normochromic normocytic picture). Two of 20 female subjects had Hb levels <11.5 g/dl (11.0 and 11.1 g/dl respectively; normochromic normocytic picture). The mean Hb level for the female subjects was 12.4 (S.E. 0.2) g/dl. Lymphopenia was present in two of 23 patients (0.4 and 0.5x109/l respectively); both patients fulfilled the American College of Rheumatology (ACR) criteria for the diagnosis of SLE [31]. Platelet count was normal in 23 of 23 patients. Elevated ESR was found in 19 of 23 patients (mean 35 mm/h, S.E. 4.7 mm/h, median 32 mm/h, range 2–80 mm/h).

Biochemistry
Urea, creatinine and electrolytes were normal in 23 of 23 patients; hepatic aspartate transaminase was elevated (>40 IU/l) in eight of 23 (>500 IU/l in three of eight); alkaline phosphatase level was elevated in five of 23 (all in patients with abnormal transaminase levels); and bilirubin was elevated in two of 23 (both patients were clinically jaundiced). Hypergammaglobulinaemia (IgG) was present in twelve of 19 patients (mean 19.1 g/l, S.E. 7.7 g/l, range 10.1–33 g/l; normally <15 g/l); C3/C4 levels were normal in 23 of 23; CRP was elevated at presentation in 14 of 15 (mean 37 mg/l, S.E. 6 mg/l, range 2–101 mg/l; normally <6 mg/l). The only patient with a normal CRP at presentation had stopped taking minocycline 4 weeks before the consultation.

Serology
Serological abnormalities are summarized in Table 1Go. Nineteen of 23 patients were positive for ANA; four of 23 were positive for anti-dsDNA antibodies by ELISA and Crithidia assays; 10 of 15 were positive for pANCA (specific for MPO by ELISA in seven of 10); six of 23 were weakly positive for IgG ACL antibodies (none of the patients had a history of thrombotic events); nine of nine patients were negative for anti-histone antibodies; and 23 of 23 were negative for antibodies to ENAs.


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  		TABLE 1. Serological profiles of 23 patients with minocycline-induced lupus

 

Response to stopping minocycline
Discontinuation of minocycline therapy resulted in resolution of symptoms and signs in all cases, although there was considerable variation in the time taken to recover fully. Ten subjects were completely asymptomatic within 1 month; nine subjects were better in 1–6 months; three subjects improved in 6–12 months, and in a single subject symptoms took 2 yr to resolve. Four patients with severe disease required corticosteroids. There was no correlation between duration of treatment with minocycline and the time taken to recover after withdrawal of the drug.

Serological abnormalities resolved slowly. ANA became negative within 2 yr in the majority of cases, although in four patients ANA remained strongly positive several years after withdrawal of minocycline.

Rechallenge with minocycline
Five patients had suspected a link between minocycline and their illness before their initial consultation and had stopped minocycline. Each subject had subsequently restarted minocycline and noted recurrence of symptoms within hours of consuming a single 100-mg tablet of minocycline. Supervised rechallenge with minocycline was not performed in these individuals. However, 10 other patients consented to a supervised rechallenge with minocycline (Table 2Go). All patients were asymptomatic before rechallenge with CRP levels <1 mg/l. In seven subjects, symptoms of malaise and polyarthralgia developed within 12 h of consuming a single 100-mg tablet of minocycline. The remaining three patients developed symptoms after 26, 72 and 36 h respectively. In all cases, the development of symptoms was associated with elevation of the serum CRP level, and pyrexia was a feature in seven of 10 patients (Table 2Go), all of whom had experienced intermittent fever during their initial illness. All subjects were asymptomatic within 2 weeks of rechallenge, although two subjects were given a 3-day course of oral steroids. The CBC, renal and hepatic function tests and C3/C4 levels remained normal in all cases, notably in two subjects whose initial illness had been associated with elevated hepatic transaminase levels. Control subjects took minocycline for 3 days. None experienced symptoms after rechallenge with minocycline and the CRP remained <1 mg/l in each case.


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  		TABLE 2. Clinical response and change in CRP levels after minocycline rechallenge

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Case 1
 Case 2
 Case 3
 Results
 Discussion
References
 
The description of 23 patients with MIL represents the largest series of patients identified from a single unit and illustrates the spectrum of clinical and serological features that can be associated with this illness. In cases of drug-induced lupus, symptoms recur after rechallenge, but information concerning the rate of development of symptoms is scanty. In cases of hydralazine and procainamide-induced lupus, the onset of symptoms after rechallenge is often slow and may require prolonged re-exposure to the drug [2, 32–34]. An unusual feature of MIL is the ability of the drug, on rechallenge, to exacerbate the symptoms, usually within 12–24 h. This had been noted by a number of patients in our series and by others who had rechallenged themselves before seeking medical advice [14, 19, 29], but has not previously been studied objectively. The rapid response to rechallenge was seen in patients who had discontinued minocycline several years earlier, suggesting that MIL is associated with the development of long-term immunological memory. The rise in serum CRP levels observed in each case provided objective evidence of a systemic inflammatory response in conjunction with the appearance of symptoms.

When considering rechallenge with any drug suspected of causing disease, safety is an important issue. Minocycline has been reported to cause a wide range of adverse effects, which can have fatal consequences, particularly if associated with hepatic failure or pancytopenia [14, 26]. However, MIL is characterized by the development of non-specific symptoms after long-term consumption of the drug, and the patient usually continues to take minocycline despite their illness as the association is not immediately obvious (four of 23 patients continued taking minocycline for more than 3 yr after the development of symptoms). Rechallenge is therefore likely to be safe in this group of patients, and there were no instances in which rechallenge resulted in sustained illness in this study. Patients with a history of severe minocycline-related hepatitis, which can co-exist with MIL [5, 6, 35], should not be rechallenged. However, as seen in two of our patients, abnormal liver function tests may revert to normal, despite the patients’ continuing on minocycline. Rechallenge in such cases is also likely to be safe.

The importance of rechallenge in verifying a diagnosis of MIL in certain cases is illustrated by the wide variation in clinical features and serological abnormalities, which can often lead to diagnostic confusion. In several patients, the absence of any physical abnormalities despite the presence of severe symptoms resulted in a stress-related chronic pain syndrome being diagnosed by the general practitioner. In two patients, the presence of elevated hepatic transaminase, positivity for ANA and hypergammaglobulinaemia led to an initial diagnosis of chronic active hepatitis being made. Both patients underwent liver biopsy and were treated with steroids and azathioprine. Two patient were diagnosed with and treated for idiopathic SLE because of the clinical features and the presence of antibodies specific for dsDNA. These patients had been under follow-up in our clinic for several years and had received long-term treatment with steroids and azathioprine before the correct diagnosis was suspected and confirmed by rechallenge. Two other patients also had anti-dsDNA antibodies, which have been reported previously in MIL [36]. Therefore, although anti-dsDNA antibodies are unusual in drug-induced lupus [34], their detection does not help differentiate MIL from idiopathic SLE. Elevated CRP levels may be more useful in distinguishing MIL from idiopathic SLE. Whilst an increase in serum CRP is a typical feature of MIL, it is unusual in idiopathic SLE unless there is infection, widespread serositis or vasculitis.

Our observations show that a negative test for ANA does not exclude a diagnosis of MIL. Four of 23 patients were negative for ANA and would not therefore fulfil the proposed criteria for drug-induced lupus [32]. Other groups have also identified patients with MIL who were negative for ANA [19]. Conversely, a positive ANA test does not necessarily equate with the development of a lupus-like syndrome. Patients taking drugs known to be associated with the development of a drug-induced lupus syndrome, such as hydralazine and procainamide, are frequently found to have a high titre of ANAs, even though only 15–20% will develop clinical symptoms [37]. A low titre of ANAs is also present in up to one-third of the normal population [38]. The frequency of positive ANA tests in asymptomatic patients on long-term minocycline treatment is not known. Another difference between MIL and cases of drug-induced lupus secondary to hydralazine and procainamide [37] is the frequency with which anti-histone antibodies are detected. Whilst these antibodies are present in >95% of cases of hydralazine and procainamide-induced lupus [34] they were absent in nine out of nine of our patients with MIL.

Failure to admit to taking minocycline during the initial consultation was common, and most patients had not considered the possibility of a link between this drug and their symptoms. Treatment of the acne was clearly successful, as none of the subjects had physical findings which might otherwise have prompted the physician to enquire directly about minocycline treatment. This highlights the importance of considering the diagnosis, taking a careful drug history and asking specifically about minocycline use. It remains unclear whether patients with MIL are sensitive to other tetracyclines [39]. A single case has been reported in which a patient with MIL was subsequently prescribed doxycycline and developed a recurrence of symptoms within 4 days [19].

The use of minocycline as a DMARD in RA identifies a further area where drug-induced disease may occur. Worsening joint symptoms, myalgia and malaise could easily be misinterpreted as an exacerbation of RA, leading to an increase in the dose of minocycline rather than cessation of therapy. No cases of MIL were reported during trials of minocycline therapy in RA in the USA [21–24]. It is unclear whether this reflects differences in the genetic background of this group of patients or whether such cases will be identified in the future.

The pathogenesis of MIL is not known. A single case of minocycline-induced pneumonitis has been described in which rechallenge was performed to confirm the diagnosis [27]. In this case, minocycline was shown to sensitize alveolar macrophages to lysis by autologous CD8+ cytotoxic T cells. It is unclear whether a similar immunopathological process is involved in MIL. Many factors can influence the development of drug-induced lupus. Factors that influence drug metabolism, such as acetylator status [4], the involvement of the MHC class II genes [12, 34] and the presence of null alleles of C4 [1, 40] have all been implicated in the pathogenesis of the hydralazine-induced lupus syndrome. More recently it has been proposed that one of the common characteristics of lupus-inducing drugs is their ability, on exposure to MPO released from activated neutrophils, to generate a variety of cytotoxic products [40, 41]. A recent study of 14 patients with MIL detected pANCA in all cases (11 had elevated anti-MPO antibodies), but ANCA was negative in a control population of asymptomatic patients taking long-term minocycline [30]. All 14 MIL patients were either HLA-DR4- or HLA-DR2-positive, and the authors suggested that the presence of pANCA may be a marker for the development of lupus-like symptoms in genetically susceptible individuals taking minocycline [30]. In our series, pANCA was detected in 67% (10/15) of cases, and there was MPO specificity in six of these. This confirms the high frequency of these antibodies in MIL, as reported by others [30, 42], but also shows that their presence is not essential for the development of the syndrome. The identification of 23 patients with MIL will allow a more complete analysis of the HLA associations of MIL, and this work is currently under way.

It is important for physicians to be aware of the association between minocycline and the development of a lupus-like illness. Despite the publicity associated with this syndrome over the last few years, there has been no change in the number of minocycline prescriptions issued in Wales (32 000–35 000/yr), where it remains the most frequently prescribed treatment for acne (Welsh Health Information Services). Clinicians should be aware that MIL can closely resemble idiopathic SLE, and should enquire specifically about minocycline consumption in such cases. Clinicians should also be aware of the potential development of MIL in patients with RA treated with minocycline, in whom the diagnosis could easily be overlooked. We emphasize the importance of rechallenge whilst monitoring CRP levels in confirming the diagnosis in selected cases.


   Acknowledgments
 
TML is an ARC Lecturer in Rheumatology.


   Notes
 
Correspondence to: T. M. Lawson. Back


   References
Top
 Abstract
 Introduction
 Patients and methods
 Case 1
 Case 2
 Case 3
 Results
 Discussion
 References
 

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Submitted 13 April 2000; Accepted 2 October 2000


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A-B. Mongey and E. Hess
Importance of drugs and environmental agents in Lupus
Lupus, July 1, 2007; 16(7): 539 - 540.
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