Clearly, a succession of second trimester losses indicates that this lady is at high risk of having antiphospholipid antibody syndrome. First trimester losses are more generally associated with genetic or chromosomal abnormalities. There are both simple screening tests, like the anticardiolipin test (aCL) or the lupus anticoagulant test (RVVT-PT), and more complex ones (anti β2 glycoprotein-1 antibody) that the physician can order. It’s now recognized that aCL IgG and high titre aCL IgM as well as a benign false positive (BFP) VDRL (syphilis test) can all signal elevated risk of thrombosis of the placenta. This can lead to premature births, small-for-date babies and miscarriages.

Classification

The photosensitive rash is suggestive of systemic lupus erythematosus (SLE). Antiphospholipid syndrome can occur by itself or in association with other autoimmune disorders — most frequently systemic lupus erythematosus. It’s easy to remember the 11 classification criteria for lupus by dividing them into:

A. Four cutaneous features

B. Four systemic features

C. Three immunological features, one of which is a positive result on the antinuclear antibody (ANA) test.

(A) Four cutaneous features

• malar rash — which spares the nasolabial folds (roseacea does not)
• discoid rash — with erythematous raised patches, keratotic scaling and follicular plugging followed later by atrophic scarring
• photosensitivity — by history or observation
• ulcers — oral or nasopharyngeal — generally painless, sometimes nasal septal perforation.

(B) Four systemic features

• arthritis — non-erosive and generally non-deforming with tenderness, swelling and sometimes effusion
• serositis — pleuritis or pericarditis
• neurological disorder — headaches, seizures or psychosis
• renal disease — persistent significant proteinuria or hematuria including casts.

(C) Three laboratory abnormalities

• hematological disorder — hemolytic anemia (Direct Coomb’s positive), leucopenia or lymphopenia and/or thrombocytopenia
• antinuclear antibody
• immunological disorder — including anti-double stranded DNA (dsDNA), or anti-Smith antibody (be careful not to confuse with anti-smooth muscle antibody) and the anti-phospholipid antibodies.

These classification criteria were designed for research purposes, but they have great sensitivity and specificity in diagnosis (97% if one uses 4 out of the 11) and are helpful in everyday practice.

Be careful when interpreting the antinuclear antibody test. I frequently have patients referred and am mistakenly told that because of their positive result they must have SLE. In considering this test we must look at both the titre and pattern to assess significance. If the pattern is speckled, the titre generally needs to be extremely high to be significant, and even then you must consider other types of connective tissue disease. If the pattern is rim, then even with a low titre one should consider systemic lupus.

Almost all SLE patients (99%) will show positive ANA results, but not all positive ANA results point to SLE. Other diseases and conditions that can cause a positive ANA include:

• drug induced lupus (100%)
• chronic active hepatitis (100%)
• systemic sclerosis (95%)
• mixed connective tissue disease, polymyositis/dermatomyositis (90%)
• Sjögren’s syndrome (80%)
• rheumatoid arthritis (60%)
• non-rheumatic diseases such as thyroid, primary biliary cirrhosis, primary sclerosing cholangitis, viral hepatitis, primary pulmonary hypertension, HIV, lymphoma, tuberculosis, myasthenia gravis (about 50%)
• … and even normal health (5-30%).

The easiest way to test for significant disease activity is to check blood pressure and do urinalysis. SLE may be one of the few rheumatologic emergencies a physician has to deal with. Renal involvement may present as hematuria (tea coloured urine) or proteinuria (which resembles frothy beaten egg white in urine). ESR and CRP are very non-specific as indicators of disease activity. Elevated dsDNA and depressed complement component 3 (C3) may both indicate that the disease has been active.

Raynaud’s phenomenon presenting in a 30- to 40-year old may be an indication of lupus or other connective tissue disease (especially scleroderma) but is not a criterion for SLE. Similarly, alopecia can be found in SLE, but is more common in other disorders.

Environmental influences

SLE is influenced by environmental factors, the strongest of which is ultraviolet light. Stress is clearly implicated in its effect on the adrenal cortex while factors such as alfalfa sprouts (rich in concalavin) are suspected of playing a part. Genetic contributions from HLA-DRB1, IRF5 and STAT 4 with components of chromosome 8 (C8orf13-BLK) and chromosome16 (ITGAM-ITGAX) are associated with SLE. It’s now recognized that patients with SLE typically have many more drug allergies than the general population. Hormonal influences are significant and the disease is 6-9 times more common in females than males. The exact cause is probably different for different individuals but apoptosis has long been known to play a role in the pathogenesis.

The list of possible causative mechanisms in drug-induced lupus (DIL) includes inhibition of DNA methylation, reactive drug metabolism, tumour necrosis factor (TNF) inhibition as well as genetic predisposition and the hormonal factor. Consider this diagnosis in the individual on procaine, hydralazine, minocycline, carbamazapine, phenytoin, sulfasalazine, isoniazid, and anti-TNF therapy. Clinical features — though less frequent than in typical SLE — include fever, serositis, rashes, mouth ulcers, renal and CNS manifestations. Levels of dsDNA and C3 are more normal than in SLE, but erythematous papules, purpura and antihistone antibody may be useful in proving DIL.

Treatment

While the family physician (FP) needs to feel comfortable with treatment given in SLE, much too often the FP resorts to corticosteroids with no baseline tests and no objective plan.

The antimalarial hydroxychloroquine is considered safer than chloroquin if used at less than 6.5 mg/kg and is useful for rashes and photosensitivity; it also has an effect of suppressing the disease, especially fatigability. This is a drug that can be used by the FP in conjunction with the local optometrist, except in the occasional patient with sulfa sensitivity. In those cases, use chloroquin, but bear in mind this has greater retinal toxicity and is not recommended above 250 mg. Generally, neither drug should be used for > 20 years but with annual eye exams and occasional dosage lowering (in winter) it is possible. Safety in pregnancy isn’t established.

In pregnancy, when there’s recognized antiphospholipid syndrome, anticoagulation and aspirin are frequently used in combination but consideration of risks to the developing fetus is necessary. When the time is appropriate, oral anticoagulant therapy is switched to low molecular weight subcutaneous forms. Roughly 3-6% of neonates born to women with the anti-Ro/La autoantibodies have congenital heart block.

The arthralgias of SLE are usually managed with various combinations of salicylates/NSAIDs. Beware of hypertension and watch the renal function tests. Proteinuria > 0.50 gm needs investigation with a 24-hr urine, and generally a renal biopsy is advisable before using high doses of corticosteroids (1-3 mg/kg). When treating with steroids at these doses, you should explain the reasons and risks to the patient again.

For over three decades, high IV dosage immunosuppressive “pulse therapy” has been useful while trying to stabilize the ill SLE patient when waiting for another investigation or treatment to work. Be sure to have the baseline tests done before considering pulse therapy and monitor carefully for hypertension and aggravation of congestive heart failure.

Other immunosuppressive agents such as azathioprine, methotrexate, cyclophosphamide and mycophenolate mofetil can be introduced if indicated by a rheumatologist, often in conjunction with a nephrologist. The general practitioner needs to know what side effects to watch for as these agents can lead to blood dyscrasias, infections, liver function abnormalities and amenorrhea. Cyclophosphamide has been a very effective agent in the past (and forgiving if blood disorders develop) but in the long term can also result in cystitis and bladder cancer; so the patient treated needs to be monitored every six months, long past its use for urine cytology. Cyclosporin A has been effective in nephrotic syndrome for its corticosteroid sparing effect in children with seemingly no sign of hypertension aggravation or other toxicities.

Biologic agents have been used but, as noted above, the TNF agents can all result in DIL. Rituximab, however, which depletes CD20 positive B cells, may prove beneficial. In uncontrolled studies, in patients failing conventional immunosuppressive therapies, it’s been helpful in treatment of cytopenias, renal and neurological involvement and serositis. Infections continued to be a problem and there were relapses in these studies.

Stem cell transplants are now being considered in some centres, when the disease is very resistant to therapy and mortality is considered imminent. The mortality of SLE has significantly declined since the 1950s but it’s still an unpredictable disease.

Further reading

Rheum D Clinics NA, August 2006, volume 32, number 3. ( www.theclinics.com ); NEJM 358:9, February 28, 2008 ( www.nejm.org ).