Our immune system fights against bacteria, viruses, fungi, protozoa, and rogue cancer cells. When the “army-within” fails to recognize our own cells and starts attacking them, it results in autoimmunity. Medications needed to treat autoimmune diseases, sadly, also weaken our own “army,” increasing risk of infections and malignancies.
11.1 Autoimmune Conditions: General Points
Sometimes it is helpful to think of autoimmune conditions in two broad categories:
Mostly seropositive, e.g., antinuclear antibody (ANA), rheumatoid factor (RF)b antimitochondrial antibody, anti-SSA, anti-SSB
Mostly seronegative, but may be p-ANCA positive
aPatients with one condition have increased risk of other conditions in the same group. For example, patients with RA have increased risk of Sjogren: patients with psoriasis have increased risk of ankylosing spondylitis.
bNote: ANA and RF are not only found in SLE and rheumatoid arthritis, but also in other autoimmune conditions and also in females and old patients with no connective tissue disease. Hence, presence of ANA and RF in serum is very nonspecific.
An old patient with positive RF and ANA, but no other features suggestive of inflammatory disorder
Positive ANA, RF, and symmetrical arthritis of hand-joints with deformity
When asked about the most common cause (MCC) of death in a specific condition (e.g., what is the MCC of death in SLE, RA, ankylosing spondylitis, peripheral vascular disease?), the safest bet is to answer cardiovascular cause (it is the MCC of death in general population too). Also note that chronic inflammatory conditions such as SLE and RA are associated with accelerated atherogenesis.
It is easier to remember only the exceptions to this rule, e.g., for scleroderma, the MCC of death is lung disease, and for primary biliary cirrhosis-liver failure, etc.
11.2 Joint Pathology
Inflammatory versus noninflammatory: Presence of any of the following suggests an inflammatory arthritis:
1 Inflammatory arthritis can present with joint stiffness alone without pain.
Joint stiffness lasting <1 hour can be due to the following: noninflammatory arthritis (e.g., osteoarthritis), nonerosive arthritis in SLE, or milder/early forms of inflammatory arthritis.
Elevated ESR (erythrocyte sedimentation rate) and/or CRP (C-reactive protein)
11.3 Rheumatoid Arthritis
Pathophysiology: In a patient with genetic susceptibility, an inciting factor (e.g., infection, smoking) leads to activation of autoimmune T-helper cells, causing joint inflammation.
Diagnosis: Made on clinical and lab findings, which include the following:
Inflammatory erosive arthritis involving three or more joints: arthritis is typically symmetric and commonly involves metacarpophalangeal and proximal interphalangeal joints.
Positive serum RF (rheumatoid factor)
or anticyclic citrullinated peptide.
2Rheumatoid factor is autoimmune antibody against our own Immunoglobulin G (IgG). Immunoglobulin M (IgM) rheumatoid factor is commonly tested and is specifically helpful in assessing the course and prognosis. But note that negative serum rheumatoid factor does not rule out rheumatoid arthritis.
Extra-articular features are rheumatoid nodules, anemia of chronic inflammation, splenomegaly, amyloidosis, interstitial lung disease, etc.
Duration of symptoms for > 6 weeks
Debilitating joint deformities are common.
Management: Initiate DMARD (disease-modifying antirheumatic drug) as soon as diagnosis is made. DMARDs slow the progression of disease.
As DMARDs take some time to work, we can use nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids for immediate symptomatic relief (bridging therapy).
Anti-TNF agents are INFliximab (MAB = monoclonal antibody to TNF), eTaNeRCept (TNF Receptor antagonist), etc.
11.3.1 Differential Diagnosis of Rheumatoid Arthritis
Parvovirus Infection in Adults
Risk factor: Frequent exposure to children (e.g., school teacher or day-care center worker).
Presentation: Recent-onset symmetrical polyarthralgia/arthritis with or without hx of classical rash (slapped cheek rash, or lacy rash that looks a like a fish net). It may be confused with RA due to symmetric inflammatory arthritis. Look for acute onset and history of contact with children.
Diagnosis: Check antiparvovirus IgM in immunocompetent patients. In immunosuppressed individuals, check viral polymerized chain reaction (PCR), as they are less likely to mount an antibody response.
Treatment: NSAIDs. It is usually a self-limiting condition.
Complication: Aplastic crisis or chronic pure red cell aplasia can occur in patients with hematologic disorder or who are immunosuppressed. Primary infection during pregnancy can lead to intrauterine fetal death and/or hydrops fetalis (due to severe fetal anemia).
Juvenile Rheumatoid or Idiopathic Arthritis (JRA aka JIA)
Pathology: Autoimmune joint inflammation. The difference between JRA and RA is that many people with JRA outgrow their disease, whereas RA is usually a lifelong disease.
Presentation: Can initially present with indolent isolated hip pain and progress on to polyarticular symmetric arthritis. Joint disease can progress rapidly.
Dx: Made clinically with the help of inflammatory markers such as elevated ESR, ferritin, and autoimmune markers.
May not be related with disease severity, but does signal increased risk of uveitis
May signal poor prognosis and increased chances of having disease into their adulthood
Management: NSAIDs + DMARDs (except in patients with low-disease activity). All patients are recommended to have periodic slit lamp examination, as coexistent asymptomatic iridocyclitis can lead to blindness, if left untreated.
Systemic-Onset Juvenile Idiopathic Arthritis (Formerly Known as Systemic JRA or Juvenile-Onset Form of Still’s Disease
Background: Idiopathic inflammatory condition that rarely occurs in patients older than 35 years. It is a subtype of JRA with prominent extra-articular manifestations.
History of fever (intermittent high-spiking fevers for at least 2 weeks)
Salmon-pink maculopapular skin rash
Increased inflammatory markers such as leukocytosis, elevated ESR, ferritin, etc.
Patients may also have reticuloendothelial system involvement (tender cervical lymph nodes, splenomegaly, sore throat, etc.), and
11.4 Sjogren’s Syndrome
Pathophysiology: Autoimmune destruction of salivary and lacrimal glands
Work-up: NSIDx is bedside Schirmer’s test (a filter paper is placed in the eye and the extent of wetness is measured). Check anti-Ro(SSA) and anti-La(SSB), which are specific serologic findings. Most specific test is salivary gland biopsy of lower lip, but may not be necessary.
Treatment: Maintain oral hygiene (avoid sugary drinks and drink water frequently to keep the mouth wet), and use artificial tears and/or saliva. Second-line agents are pilocarpine or cevimeline (these are procholinergic agents that promote glandular secretion).
Disease association: Other female-predominant autoimmune syndromes (e.g., RA, primary biliary cirrhosis).
Complication: Predisposes to malignant lymphomas. MC type is mucosa-associated lymphoid tissue (MALT) lymphoma, which commonly arises from salivary glands but can occur anywhere.
11.5 Systemic Lupus Erythematosus (SLE)
Description: SLE is an autoimmune disorder that can affect multiple systems.
Patients can present with any of the following:
Inflammation of serosal membranes (e.g., pleurisy, pericarditis)
Migratory, symmetrical arthritis that is nonerosive.a X-ray of joints is normal. (This is in contrast to RA, which is erosive, and X-ray is abnormal).
Antiphospholipid, anti-Smith, and anti-dsDNA antibody may be positive.
aAdditional MRS I’M SANE even though I have SLE arthritis. SLE has Migratory, Symmetrical Arthritis that is Non-Erosive.
bPresence of only discoid rash is called discoid lupus. Patients with discoid lupus can have positive ANA, but anti-dsDNA or anti-Smith antibody is usually negative.
Work-up: If patient has any of the features of “SOAP BRAIN MD,” NSIDx is serum ANA (which is the screening test). If ANA is positive, NSIDx is anti-Smith and anti-dsDNA antibodies (these antibodies are specific to SLE, but not sensitive).
11.5.1 Renal Involvement in SLE
SLE can cause nephrotic or nephritic syndrome.
Pathophysiology: Immune complexes (anti-dsDNA antibody and antigen complex) are deposited in the glomerulus with subsequent activation of complement pathway, hence anti-dsDNA titers usually correlate with the severity of renal disease. Patients with high anti-dsDNA titer and low complement levels most likely have severe renal disease.
Work-up: In patients with SLE, always check urinalysis and serum creatinine to screen for renal involvement. UA may show RBC casts and/or proteinuria. If significant renal involvement is suspected, NSIM is renal biopsy.
11.5.2 Management of SLE
Severe disease (organ threatening, e.g., diffuse proliferative glomerulonephritis)
High-dose IV steroids + mycophenolate or cyclophosphamidea
a Side effects of cyclophosphamide
11.5.3 Obstetric/Gynecological Issues Related with SLE
Combined oral-contraceptive pills are absolutely contraindicated in active SLE (can worsen disease) and in antiphospholipid syndrome (double trouble for the thrombotic state).
Screen all pregnant patients with SLE for SSA antibody (anti-Ro antibodies). These autoantibodies can cross the placenta causing neonatal lupus and congenital heart block.
In SLE patients with positive antiphospholipid antibody and history of prior fetal loss, use low-molecular-weight heparin and low-dose aspirin during pregnancy.
11.5.4 Drug-Induced Lupus
Etiology: It has been associated with the following drugs: Chlorpromazine (antipsychotic), Carbamazepine, Captopril, Hydralazine, Isoniazid, Methyldopa, Minocycline, Procainamide, Penicillamine, Phenytoin, Sulfasalazine, Sodium valproate, Quinidine, TNF inhibitors (e.g., infliximab, etanercept), Diltiazem, etc.
Presentation: Fever, arthralgia/arthritis, serositis, rash, pulmonary infiltrates, hepatospleno-megaly, etc.
Diagnosis: Specific test for drug-induced lupus is antihistone antibody. Presence of anti-dsDNA can occur with minocycline or TNF-inhibitor-induced disease. Low complement levels and kidney or CNS involvement are rare.
Management: Discontinue offending agent. Use NSAIDs for mild disease and steroids for severe disease. For persistent disease, start hydroxychloroquine.
11.5.5 Other Causes of Migratory Arthralgia or Arthritis Besides SLE
Presentation: Joint pain (arthralgia) ± swelling and redness (arthritis) in different joints at different times. For example, CCS: patient presents with pain in the right knee joint. He also gives history of pain, swelling in the right wrist 3 days ago and left knee involvement 7 days ago.
11.6 Sclerosis (Scleroderma
11.6.1 Systemic Sclerosis (aka Systemic Scleroderma)
Background: An autoimmune disorder involving multiple organs in which normal tissues are replaced by fibrous tissues.
Diagnosis: Made on clinical grounds and serology, as following:
Rx: Treatment is nonspecific and organ based. It also depends upon presence of ongoing inflammation. Commonly used drugs are immunosuppressants, such as methotrexate, steroids, hydroxychloroquine, etc.
11.6.2 CREST (Localized Form of Scleroderma)
Diagnosis: Made with clinical picture and presence of serum anti-centromere antibody.
Background: Can be primary (isolated disorder) or secondary (associated with underlying autoimmune condition such as scleroderma, SLE, RA, dermato/poly-myositis, etc.).
Presentation: Triggers such as cold exposure or emotional upset may incite an episode which typically occurs in the following sequence:
Pallor and Pain (due to vasoconstriction) — Cyanosis (deoxygenation) — Redness (reactive vasodilation after ischemia).
Severe Raynaud can result in prolonged cyanosis, finger-tip necrosis, and ulcer.
Diagnosis: Nailfold microscopy is most commonly used for aiding in diagnosis (underlying vascular changes point toward underlying autoimmune disorder). NSIDx: check ANA.
Treatment: Try conservative measures first—avoid smoking and cold exposure (use gloves and wool stockings). If not responding, use nifedipine or amlodipine (decreases vasoconstriction).
11.6.3 Differentiating CREST and Scleroderma
• In CREST syndrome, skin involvement is localized to the face, hands, and forearm (i.e., acral distribution only). In systemic sclerosis, the skin involvement can involve the whole body including trunk and arms.
Any feature of CREST with additional involvement of any other organ, except isolated pulmonary HTN, is systemic sclerosis. Note: CREST can also be associated with pulmonary HTN (loud P2 sound on heart auscultation), but is usually not accompanied by pulmonary parenchymal fibrosis.
Gadolinium contrast (given with magnetic resonance imaging [MRI]) is almost exclusively excreted by kidney. If given to patients with advanced kidney disease, it can remain in tissues causing reactive fibrosis. Skin findings include patches, plaques, and peau d’orange appearance, along with sclerodactyly and other features similar to systemic scleroderma.
11.7 Dermatomyositis and Polymyositis
Scaly, red or violaceous, papule or plaques on the dorsal surface of small hand joints (Gottron’s plaques)
Red or violaceous rash around eyes (aka heliotrope rash) and nose
Could be paraneoplastic (associated with underlying malignancy)a
First step: Muscle creatine kinase (CK) and enolase (both will be high). Additionally, check myositis-specific antibodies (e.g., anti-Jo-1 antibodyMRS-1).
Oral corticosteroids as a bridging therapy with initiation of azathioprine, methotrexate, or mycophenolate at the same time when steroid is started.
If patient remains stable, try to taper off steroids. If no flare-up after a slow steroid taper, can attempt to taper off immunosuppressant.
aThink of the following conditions when muscle weakness is associated with malignancy: