From the Archives: Summer 2004 Issue of Lupus Now Magazine
Death From Chicken Pox: An SLE Case Study
By Caroline P. Gordon, M.D., F.R.C.P., University of Birmingham, England
In November 1995, a 16 -year -old Caucasian female was seen for secondary amenorrhoea. She complained of some fatigue and hair loss, and investigations revealed hypothyroidism of autoimmune origin. She was started on thyroxine replacement and her thyroid function tests normalized over the next 6 months. However, her fatigue and diffuse hair loss persisted. She was also started on hormone replacement therapy (HRT) because her test results suggested autoimmune ovarian failure. There was no history of blood clots (thrombosis) or miscarriage or other relevant past medical history, and no family history of autoimmune disease.
Early the following June, the patient developed a severe photosensitive skin rash following a two-hour car journey in bright sunlight. This was a classical “butterfly” type rash across the nose and the cheeks which persisted for 3 weeks. During this time she also developed an inflammatory arthritis which caused her joints to be painful and stiff, especially in the morning. There was no response to ibuprofen (a non-steroidal anti-inflammatory medication, or NSAID).
Blood pressure: 115/65.
Skin: malar rash and diffuse hair loss.
Extremities: joint tenderness on palpation of her wrists, small joints of the hands (metacarpophalangeal and proximal interphalangeal joints), and knees. Small effusions in both knee joints.
Heart: normal sounds.
Laboratory Test Results
White blood cells (WBC) 4.7 x109/l (neutrophils 3.0 and lymphocytes 1.4).
Platelets 208 x 109/l.
ESR 118 mm/hr.
Coomb’s test positive.
Increased reticulocytes on blood film and low haptoglobins in serum, indicating an autoimmune hemolytic anemia.
Lupus anticoagulant negative.
Anticardiolipin antibodies strongly positive.
ANA positive at 1/400
Anti-double stranded DNA antibody strongly positive by Crithidia (3+) and ELISA (6,500 iu/l) (normal range < 75 iu/l).
C3 very low at 0.26g/l (normal >0.74 g/l), C4 low at 0.10g/l (normal >0.14 g/l), C3d (complement degradation product) elevated at 14.3 u/l (complement degradation product, normal < 2.0 u/l).
Negative Ro, La, RNP and Sm antibodies.
C-reactive protein 16g/l (normal >5 g/l).
Urinalysis: 2+ protein on dipstick and 500 mg protein in 24-hr urine. Serum creatinine elevated at 1.5 mg/dl. Creatinine clearance reduced at 41ml/min.
In late June 1996, the patient was diagnosed as having systemic lupus erythematosus (SLE) with skin, joint, kidney, and hematological involvement, which was confirmed by her immunological blood tests (ANA and anti-dsDNA antibodies). Both the ibuprofen and HRT were stopped. She was started on prednisolone 40 mg daily and was referred for renal biopsy, which was performed in September and showed WHO criteria class IV proliferative glomerulonephritis. She was then started on intravenous pulses of methylprednisolone and cyclophosphamide. Her symptoms resolved completely over the next three months, while her daily dose of oral prednisolone was gradually reduced.
By April of 1997, she was on 10 mg prednisolone and 100 mg azathioprine daily. She was completely asymptomatic. Urinalysis showed 1+ protein by dipstick. Investigation revealed ANA 1/100 and anti-ds DNA antibodies not significant (<75 iu/l). C3 was normal at 0.95 g/l, and C4 improved at 0.09 g/l. Serum creatinine was normal at 1.0 mg/dl, with creatinine clearance normal at 91 ml/min and only 0.1g protein in 24-hr urine excretion.
Her lupus remained in remission for three years until she started to complain of fatigue in October 2000. Her blood pressure rose from 110/60 to 135/78. At this time her urine protein by dipstick had increased from 0 to +3. Further investigations were consistent with a flare in her lupus, particularly affecting the kidneys. Her 24-hour urine protein excretion had increased to 1.7g but renal function was normal, with serum creatinine at 1.0 mg/dl and creatinine clearance of 132 ml/min. Hemoglobin remained normal at 12.4g/dl with no evidence of hemolysis, but platelet count had fallen to 61 x 109/l. Her WBC was normal and ESR 19mm/hr. She had no significant anticardiolipin antibodies and negative lupus anticoagulant. ANA had increased to 1/400, and anti-ds DNA antibodies were positive by Crithidia (2+) and by ELISA (191 iu/l). C3 had fallen to 0.52 g/l and C4 to 0.06g/l, with a rise in C3d to 7.1 u/l. CRP was 2g/l (normal).
Prednisolone was increased initially to 40 mg/day from 10 mg/day, and azathioprine was changed to intravenous methylprednisolone and cyclophosphamide pulses for six months. During this time the prednisolone was reduced back to 15 mg/day and subsequently reduced to 7 mg/day while azathioprine was restarted at 125 mg/day. Her lupus went into partial remission, with 1+ proteinuria on dipstick and 0.4 g proteinuria on 24-hour urine test, but renal function remained normal (serum creatinine 1.0 mg/dl and creatinine clearance 137 ml/min). Anti-ds DNA antibodies were not significant and C3 and C4 normalised completely. These results remained stable on prednisolone and azathioprine for the next three years.
However, in August 2003, just 14 days after a routine clinic visit when her lupus was confirmed not to be active and her blood results were stable, the patient developed severe back pain requiring hospital admission. A generalised vesicular rash, typical of chicken pox, appeared two days later. The patient had no history of chicken pox (varicella-zoster or herpes zoster) infection and no contact with a known case. Despite treatment with acyclovir, analgesics and anti-inflammatory drugs, she deteriorated rapidly, developed pneumonitis, and died of multi-system failure four days after admission.
Herpes virus particles were found on electron microscopy of vesicular fluid, and varicella-zoster infection was confirmed by isolating the virus in tissue cultures and by doing a polymerase chain reaction (PCR) test. There was no evidence of active lupus clinically and only a modest rise in dsDNA levels. Complement levels were normal, ESR was 7 mm/h and CRP <1 mg/L (0–10). A bacterial screen was negative. Samples on admission and retrospective analysis of previous serum samples did not show any evidence of antibodies to herpes zoster. Radiographs and magnetic resonance imaging of the lumbar spine showed no abnormalities.
1. The patient presented with autoimmune thyroid disease and ovarian failure and went on to develop multi-system SLE with renal involvement. Good response to intravenous pulse cyclophosphamide and methylprednisolone that was changed to maintenance therapy with oral prednisolone and azathioprine after six months.
2. There is no firm evidence that HRT can trigger SLE, but estrogens in the form of the combined oral contraceptive pill may increase the risk of lupus flares or contribute to triggering the disease, so HRT, which contains estrogen, was stopped. The HRT, if continued, also would have increased the risk of her developing a blood clot (thrombosis) because she had anticardiolipin antibodies (one of the antiphospholipid antibodies that predispose to recurrent thromboses and miscarriages in women with SLE).
3. NSAIDs such as ibuprofen can cause impairment of kidney function as a side effect, so ibuprofen was stopped when her raised creatinine result was obtained, and she was advised not to take such drugs in the future.
4. Recurrence of active lupus disease with kidney involvement (nephritis) and low platelets (thrombocytopenia) three years later—with only severe fatigue as a clinical symptom—highlights the importance of clinical and laboratory follow-up. She had a further good (but not as complete) response to a six-month course of IV methylprednisolone and cyclophosphamide, and was put back on azathioprine as maintenance therapy.
5. Serological tests (anti-dsDNA antibodies, complement C3 and C4, and C3d) did change before the fatigue and proteinuria appeared. These tests are particularly helpful in monitoring patients with renal and hematological involvement in lupus.
6. Although her lupus responded well to immunosuppression, she died from overwhelming infection due to herpes zoster (chicken pox) because she had not suffered from this disease when young, had not been immunized against it, and so did not have any antibodies to protect her against this infection.
THE RHEUMATOLOGIST’S VIEW
1. Patients with any autoimmune disease are at risk of developing other autoimmune diseases, and should be investigated for these if symptoms do not improve with initial therapy.
2. Fatigue in lupus patients needs careful evaluation because it can be due to active lupus, anemia (hemolytic due to autoimmune disease, or otherwise), hypothyroidism, renal failure, or non-specific factors. In many cases, the cause for fatigue is non-specific and studies have shown that it may be related to psychosocial issues. Patients who are sleeping a lot but still feel tired, are not depressed, and cannot perform their normal activities, are most likely to have a specific underlying condition that explains their fatigue.
3. Monitoring anti-dsDNA antibodies and complement levels is helpful in identifying patients at risk of lupus flare, but does not tell you when they will flare, and will not identify all patients at risk of disease flare. Patients with steadily increasing anti-dsDNA antibodies and falling C3 or C4 levels (or rising C3d levels) usually should not have their steroids reduced and should be monitored more frequently. The physician should pay special attention to renal and hematological assessment in these patients.
4. Thrombocytopenia (low platelets) may be associated with anticardiolipin antibodies and a risk of thrombosis, or may be associated with antibodies to platelets or drug toxicity and a risk of bleeding. In this patient, antibodies to platelets were found and the platelet count improved with increased steroids.
5. Patients who have not had chicken pox, or who have not mounted an effective antibody response to the herpes zoster virus when young, are at risk of severe multi-system infection if they come into contact with this common virus for the first time as adults and they are immunosuppressed. This is rare: only about 3 percent of the population have no antibodies to herpes zoster, even in a lupus cohort. But it is particularly important to identify this risk in individuals who may need, or who are taking, immunosuppressants (even if their total white cell count and total immunoglobulin levels are normal). There is no evidence that immunosuppression itself suppresses antibodies to herpes zoster. Shingles, which only occurs in people who have previously had chicken pox, rarely spreads to cause such severe disease, except in people who are very immunosuppressed by drugs and who have very low lymphocyte counts.
1. Patients with one autoimmune disease should be screened for others, if their symptoms persist despite appropriate therapy.
2. Patients with lupus and renal disease should be regularly monitored in the clinic, even if they are asymptomatic.
3. Serological tests such as anti-dsDNA antibodies and complement C3 and C4 can be used both to help identify patients at risk of lupus flare, and to guide steroid reduction.
4. Patients who are likely to need immunosuppression should be screened for antibodies to herpes zoster, and they should be counselled about immunization and the risks of developing this disease if no antibodies are found.
Amenorrhoea — absence or abnormal stopping of menstrual cycle.
Asymptomatic — without symptoms.
C3d (complement degradation product) — breakdown product of complement C3 generated by activation and consumption of complement.
Crithidia test — specific test for high affinity anti-dsDNA antibodies in SLE, often associated with renal disease.
ESR — erythrocyte (red blood cell) sedimentation rate
Effusions in the knees — fluid in the knees due to inflammation in the knee joints.
ELISA test — enzyme-linked immunosorbent assay.
haptoglobins — group of alpha2 globulins in human serum that can combine with hemoglobin; low values are seen in haemolytic anemia
hypothyroidism — diminished production of the thyroid hormone.
Immunosuppressants — corticosteroids such as prednisone or prednisolone, azathioprine (Imuran), cyclophosphamide (Cytoxan), methotrexate, cyclosporin A (Neoral), mycophenolate mofetil (CellCept)
reticulocytes — young red blood cells that occur during active blood regeneration.
Douglas KM, Gordon C, Osman H, Heaton S, Skan J, Situnayake D et al. Lupus and zoster. Lancet 2003;362:616.
Pyne D,.Isenberg DA. Autoimmune thyroid disease in systemic lupus erythematosus. Ann.Rheum.Dis. 2002;61:70-2.
Ho A, Barr SG, Magder LS, Petri M. A decrease in complement is associated with increased renal and hematologic activity in patients with systemic lupus erythematosus. Arthritis Rheum. 2001;44:2350-7.
Ho A, Magder LS, Barr SG, Petri M. Decreases in anti-double-stranded DNA levels are associated with concurrent flares in patients with systemic lupus erythematosus. Arthritis Rheum. 2001;44:2342-9.
Taylor J, Skan J, Erb N, Carruthers D, Bowman S, Gordon C et al. Lupus patients with fatigue-is there a link with fibromyalgia syndrome? Rheumatology.(Oxford) 2000;39:620-3.