1. Presence of effusion of unexplained etiology
2. Steroid injection
3. Decompression of a hemorrhagic effusion in traumatized joints
4. Evaluation of abx response in pts w/infectious arthritis
5. Removal of purulent fluid in distended infected joints
Contraindications
1. Cellulitis or broken skin over the intended entry site
2. Coagulopathy
3. Unstable joint
Procedure
1. Palpate the joint and identify the extensor surface (vessels and nerves are less commonly found here).
2. With firm pressure, use a ballpoint pen that has the writing portion retracted to mark the specific area of the joint to be aspirated.
3. Clean the skin w/an antiseptic solution.
4. Use a 25-gauge needle to infiltrate the skin w/1% to 2% lidocaine.
5. Gently insert an 18- or 20-gauge needle connected to a 20- to 30-mL syringe; a slight “pop” may be felt as the needle penetrates the capsule.
6. Apply gentle suction to the syringe to aspirate the fluid.
7. Gently remove the needle, and apply slight pressure to the puncture site.
8. Process the aspirated synovial fluid:
a. Tube 1 (no heparin): viscosity, mucin clot
b. Tube 2 (containing heparin): glucose level
c. Tube 3 (containing heparin): Gram stain, C&S, cytology, CBC w/diff
d. Glass slide: Place a drop of fluid and examine under polarized light.
e. Plate w/Thayer-Martin medium (used in cases of suspected gonococcal arthritis); assessment for Lyme titer, cultures for anaerobes, Mycobacterium tuberculosis, and fungi should be ordered only when clearly indicated.
9. Draw samples for measurement of serum glucose level.
Interpretation of Results
1. Color: Normally it is clear or pale yellow; cloudiness indicates an inflammatory process or presence of crystals, cell debris, fibrin, or TGs.
2. Viscosity is high because of hyaluronate; when fluid is placed on a slide, it can be stretched to a string longer than 2 cm before separating (low viscosity indicates breakdown of hyaluronate [lysosomal enzymes from leukocytes] or the presence of edema fluid).
3. Mucin clot: Add 1 mL of fluid to 5 mL of a 5% acetic acid solution, and allow 1 min for the clot to form; a firm clot (does not fragment on shaking) is nl and indicates the presence of large molecules of hyaluronic acid (this test is nonspecific and infrequently done).
4. Glucose level: nl is approximately = serum glucose level; a difference of >40 mg/dL suggests infection.
5. Total protein concentration is <2.5 g/dL in nl synovial fluid; it is ↑ in cases of inflammatory and septic arthritis.
6. Microscopic examination for crystals:
a. Gout: monosodium urate crystals
b. Pseudogout: Ca2+ pyrophosphate dihydrate crystals
Figure 12-1 is an algorithm for analysis of joint fluid.
FIGURE 12-1 Algorithm for analysis of joint fluid. Examples of inflammatory arthritis are indicated, although many conditions can produce these findings. AS, ankylosing spondylitis; PsA, psoriatic arthritis. (From Goldman L, Schafer AI [eds]: Goldman’s Cecil Medicine, 24th edition. Philadelphia, Saunders, 2012.)
B. Arthritis, Monarticular and Oligoarticular
Septic arthritis (Staphylococcus aureus, Neisseria gonorrhoeae, meningococci, streptococci, Streptococcus pneumoniae, enteric gram(−) bacilli)
Crystalline-induced arthritis (gout, pseudogout, Ca oxalate, hydroxyapatite, and other basic Ca/phosphate crystals)
Traumatic joint injury
Hemarthrosis
Monarticular or oligoarticular flare of an inflammatory polyarticular rheumatic disease (RA, psoriatic arthritis, Reiter’s syndrome, SLE)C. Arthritis, Polyarticular
RA, juvenile (rheumatoid) polyarthritis
SLE, other connective tissue diseases, erythema nodosum, palindromic rheumatism, relapsing polychondritis
Psoriatic arthritis, ankylosing spondylitis
Sarcoidosis
Lyme arthritis, bacterial endocarditis, Neisseria gonorrhoeae infection, rheumatic fever, Reiter’s disease
Crystal deposition disease
Hypersensitivity to serum or drugs
Hepatitis B, HIV infection, rubella, mumps
Other: serum sickness, leukemias, lymphomas, enteropathic arthropathy, Whipple’s disease, Behçet’s syndrome, Henoch-Schönlein purpura, familial Mediterranean fever, hypertrophic pulmonary osteoarthropathyD. Vasculitic Syndromes
See Table 12-1.
E. Systemic Lupus Erythematosus (SLE)
Chronic multisystemic disease characterized by production of antibodies and protean clinical manifestations
TABLE 12-1
Systemic Vasculitis∗
| Large-Vessel | Pathophysiology | Clinical Features/Dx | Management |
| Giant Cell Arteritis (Temporal Arteritis) |
Affects large-caliber vessels that contain internal elastic membranes Multinucleated giant cells w/in vessel wall or adventitia Age >50 yr Women 2:1 |
New-onset headache (temporal or occipital) in pt >50 yr Visual changes/loss (ischemia of optic nerve ± inflammation of ophthalmic artery) Jaw claudication (± ischemia of masseter or temporalis mm) PMR (pain in hip/shoulder girdle) UE limb claudication, subclavian steal Aortic regurgitation Dx: ↑↑↑ ESR and CRP Anemia + thrombocytosis Established via temporal artery bx |
Prednisone 1 mg/kg/day gives rapid response Treat immediately when dx is suspected; temporal artery biopsy findings will not change w/steroid administration until at least 4 wk Taper prednisone over 4-6 wk, guided by ESR and CRP Flares commonly occur during tapering and are managed by increasing the prednisone dose by 10 mg over dose that initially controlled the disease Low-dose aspirin to ↓ risk of CVA |
| Polymyalgia Rheumatica | Pain and stiffness in the proximal limbs associated w/elevated acute phase reactants Associated w/giant cell and late-onset RA |
Pain, stiffness, and limitation in passive ROM of the shoulder and hip girdle muscles No peripheral joint swelling Dx: ↑ ESR and CRP Mild normochromic, normocytic anemia |
Low-dose prednisone Tapered over a 6-mo period Can use MTX as steroid-sparing agent |
| Takayasu Arteritis | Affects aorta and its major branches, pulmonary arteries 2nd-4th decade of life Women 8:1 |
Inflammatory Phase Fever, arthralgias, myalgias, malaise, wt loss for several months Audible bruits over carotid, subclavian, renal, iliac vessels Pulseless Phase UE/LE claudication ± vascular insufficiency Pulse deficits and differential systolic BP’s HTN ± RAS Dx: ↑ ESR and CRP CTA or MRA or aorta and branches to show narrowing |
Inflammatory Phase High-dose corticosteroids Can use MTX of TNF-α blockers as corticosteroid-sparing agents Pulseless Phase Difficult to Rx because active vessel inflammation may be absent => Look for inflammation w/contrast MRI and PET scans Low-dose aspirin Treat lipids aggressively to prevent atherosclerosis |
| Medium-Vessel | Pathophysiology | Clinical Features/Dx | Management |
| Polyarteritis Nodosa | Inflammation and necrosis of medium-sized and small muscular artery walls Age of onset: 40-60 yr 50% cases associated with Hep B |
Fever, arthralgia, myalgia, abd pain, wt loss Peripheral nerve: mononeuritis multiplex HTN ± renoarteriolar involvement Testicular pain, painful cutaneous nodules/skin ulcers/palpable purpura/livedo reticularis Spares lungs Dx: P-ANCA Necrotizing arteritis on bx specimens of involved skin, sural nerve (do not use kidney given risk of hemorrhage) Aneurysms and stenoses on CTA |
High-dose corticosteroids × several weeks w/slow taper following Use cyclophosphamide in patients who do not respond In hep B(+) patients, give short course (1-2 wk) of steroids w/antiviral Rx (entecavir) (>50% HBeAg(+) Pts w/polyarteritis nodosa respond w/resolution of arteritis and seroconversion to hep B e-antibody positivity |
| Kawasaki’s Disease | Usually occurs in children Seen in adults w/HIV |
Fever >5 days + nonexudative conjunctivitis, erythema of oral mucosa Edema of extremities w/desquamation ACS or peripheral vascular occlusion Coronary aneurysms (MC in children) Dx: made by clinical features |
High-dose salicylates and early administration of IVIG TTE to r/o coronary artery aneurysm |
| Small-Vessel | Pathophysiology | Clinical Features/Dx | Management |
| Wegener’s Granulomatosis (Granulomatosis w/Polyangiitis) | Involvement of small to medium-sized arteries and can be associated w/a “pauci-immune” (no immune complexes) GN | Upper airway disease (70%): sinusitis, epistaxis, and nasal septal perforation/saddle nose deformity ± cartilage erosion Pulmonary: cough, hemoptysis, pleurisy, multifocal infiltrates or nodules on CXR Ocular symptoms: scleritis, uveitis, keratitis Purpura, ulcers on skin Pauci-immune GN (80%) Dx: C-ANCA Established by kidney or lung bx Antiproteinase-3 Abs’ |
High-dose corticosteroids w/3-6-mo course of cyclophosphamide B-cell depletion Rx w/rituximab has been shown to be equally as effective as cyclophosphamide Following remission: steroids are tapered and cyclophosphamide is stopped => Rx is continued for 18 mo w/azathioprine or wkly MTX (90% achieve remission, relapses are frequent w/MTX) Bactrim for PCP prophylaxis |
| Small-Vessel | Pathophysiology | Clinical Features/Dx | Management |
| Microscopic Polyangiitis | Necrotizing vasculitis that predominantly affects the lungs and kidneys Age of onset: 30-50 yr |
Fever, arthralgia, purpuric skin rash, mononeuritis multiplex Rapidly progressive GN or pulmonary hemorrhage Dx: P-ANCA Antimyeloperoxidase Ab (60%-80%) Confirm w/bx of affected tissue (skin, lung, kidney): lung: pulmonary capillaritis; kidney: pauci-immune or diffuse necrotizing GN similar to Wegener’s; skin: necrotizing arteritis of arterioles |
High-dose corticosteroids + cyclophosphamide OR rituximab Following remission, those treated w/cyclophosphamide should transition to azathioprine or wkly MTX |
| Churg-Strauss Syndrome | Systemic vasculitis in the spectrum of hypereosinophilic disorders | Most often occurs in setting of antecedent asthma, allergic rhinitis, sinusitis Eosinophilia (>10%) Migratory pulmonary infiltrates Fever, arthralgias, myalgias, purpura Dx: P-ANCA (50%); usually have pauci-immune GN and mononeuritis Established by bx and confirmed eosinophilic tissue infiltration |
High-dose corticosteroids allow full remission in 80-90% Oral or IV cyclophosphamide is recommended in pts w/neuro, GI, renal, or cardiac involvement Maintenance Rx w/azathioprine or MTX for 12-18 mo following remission |
| Henoch-Schönlein Purpura | “Systemic” IgA nephropathy Usually occurs in children In men >50 yr old, look out for association w/solid tumors or MDS |
Palpable purpura affecting distal LEs Abdominal pain, arthritis Hematuria/proteinuria Usually self-limiting Dx: Confirm w/bx of affected tissue (skin, lung, kidney): skin: shows presence of leukocytoclastic vasculitis w/IgA deposits; kidney: GN w/IgA deposition |
Short course of moderate-dose steroids (20-40 mg/day of prednisone) Decreases duration and severity of skin and joint symptoms associated w/HSP In patients w/proliferative GN give high-dose steroids and monthly cyclophosphamide |
| Small-Vessel | Pathophysiology | Clinical Features/Dx | Management |
| Essential Cryoglobulinemic Vasculitis | Immunoglobulins that precipitate from serum in the cold Type I cryoglobulins: monoclonal, self-aggregate, associated w/Waldenström’s and MM; associated w/hyperviscosity Type II cryoglobulins: monoclonal IgM or IgA rheumatoid factors that bind to Fc of IgG, associated w/hep C and HIV Type II cryoglobulins: seen in setting of autoimmune disorders (SLE, Sjögren’s, RA) |
Palpable purpura, mononeuritis multiplex LAD, HSM Renal failure ± GN Dx: ↓ C3, C4 (immune-complex GN) 80% of type-II cryoglobulinemic vasculitis is associated w/hep C |
Hep C–associated cryoglobulinemia responds to antiviral therapy w/interferon alfa + ribavirin Short course of corticosteroids In patients with renal failure, digital gangrene, neuro disease, 2-3-wk course of plasma exchange recommended |
| Cutaneous Leukocytoclastic Vasculitis | Seen in pts w/connective tissue diseases and as a reaction to drugs/viruses 40% idiopathic 60% ± autoimmune disease (SLE), drugs, infection, hematologic malignancy |
Palpable purpura, tender nodules, persistent urticaria, or shallow ulcers Lesions seen most commonly on distal LEs Dx: Neutrophils and mononuclear cells invading the walls of dermal capillaries, arterioles, and venules seen on bx |
Removal of offending drugs or treatment of the infectious etiology Favorably responds to NSAIDs, colchicine, or dapsone Manage urticarial lesions w/combining antihistamines (H1 and H2 blockers) |
∗ Vasculitis: Inflammation of blood vessel walls that causes vessel narrowing/occlusion, aneurysm, or rupture.
Etiology
The exact etiology and pathogenesis are uncertain.
Genetic susceptibility to lupus is likely inherited as a polygenic trait. Multiple genetic linkages including 1q23, 2q35-37, 6p21-11, and 12q24 show strong associations with SLE. Environmental factors such as ultraviolet light exposure and Epstein-Barr virus infection may have a triggering role. Autoantibodies can be present years before the diagnosis of SLE. Evidence supports the improper processing of nuclear proteins and nucleic acid from programmed cell death. This leads to the presentation of self-DNA to plasmacytoid dendritic cells. Plasmacytoid dendritic cells propagate antibody and immune complex production and other arms of specific autoimmunity.Diagnosis
H&P
Constitutional: unexplained fever, fatigue, malaise
Skin: malar rash sparing nasolabial folds (acute cutaneous lupus), annular or papulosquamous rash (subacute cutaneous lupus), raised erythematous patches with subsequent edematous plaques and adherent scales (discoid cutaneous lupus); alopecia, nasal, or oropharyngeal ulcerations; Raynaud’s phenomenon; petechiae, palpable purpura, skin ulceration, or digital ischemia (vasculitis); livedo reticularis or livedo racemosa (secondary antiphospholipid antibody syndrome)
Musculoskeletal: arthritis (tenderness, swelling, effusion) typically affecting peripheral joints; myositis
Cardiac: pericardial rub (pericarditis), heart murmur (Libman-Sachs endocarditis and other valvular heart disease), congestive heart failure (myocarditis), premature atherosclerotic heart disease
Pulmonary: pleuritis, pneumonitis, diffuse alveolar hemorrhage
Gastrointestinal: abdominal pain, intestinal vasculitis, ascites
Neurologic: headache, psychosis, seizure, acute confusional states, peripheral or cranial neuropathy, transverse myelitis, CVA, chronic cognitive impairment
Hematologic: anemia (hemolytic, anemia of chronic disease, aplastic anemia), thrombocytopenia, leukopenia, lymphadenopathy, secondary antiphospholipid antibody syndrome
Renal: ARF, proteinuria, nephritic syndrome, nephrotic syndromeW/Up
The diagnosis of SLE is suspected when any four or more of the following 1997 American College of Rheumatology criteria are present:• Malar rash
• Discoid rash
• Photosensitivity (recurrence of unusual skin rash in sun exposed areas)
• Oral or nasopharyngeal painless ulceration
• Arthritis
• Serositis (pleuritis, pericarditis)
• Renal disorder (persistent proteinuria >0.5 g/day, or 3+ on dipstick if quantitation not performed; cellular casts)
• Neurologic disorder (seizures, psychosis [in absence of offending drugs or metabolic derangement])
• Hematologic disorder:
• Hemolytic anemia with reticulocytosis
• Leukopenia (<4000/mm3 total on two or more occasions)
• Lymphopenia (<1500/mm3 on two or more occasions)
• Thrombocytopenia (<100,000/mm3 in the absence of offending drugs)
• Immunologic disorder:
• Anti–double-stranded DNA antibody (Anti-dsDNA)
• Anti-Smith antibody (Anti-Sm)
• Antiphospholipid antibodies (anticardiolipin IgM or IgG, lupus anticoagulant, or false(+) fluorescent treponemal antibody absorption test or Treponema pallidum immobilization for 6 mo)
• Antinuclear antibody (ANA): an abnormal titer of ANA by immunofluorescence or equivalent assay at any time in the absence of drugs known to be associated with drug-induced lupus syndrome
Labs
Suggested initial laboratory evaluation of suspected SLE:• CBC w/diff, BUN, creat, urinalysis, ESR, PT, PTT, complements (C3, C4, CH50)
• ANA
Consider additional laboratory testing:• Anti-dsDNA, anti-Sm, anti-SSA, anti-SSB, anti-RNP antibodies
• Lupus anticoagulant, anticardiolipin antibodies especially in pts with thrombotic events
• Random spot urine protein–to–urine creatinine ratio, 24-hour urine protein collection if proteinuria
Imaging
CXR for evaluation of pulmonary involvement (pleural effusion, pulmonary infiltrates)
ECG for complaint of unexplained chest pain
Echo if unexplained murmur, evidence of new or unexplained congestive heart failure, or suspected pericarditisTreatment
Defined courses of corticosteroids are useful for a variety of SLE symptoms.
Immunosuppressive drugs such as MTX or azathioprine are used as steroid-sparing drugs.
Joint pain and mild serositis are generally well controlled with NSAIDs or low-dose corticosteroids. Hydroxychloroquine and MTX are also effective for arthritis. Leflunomide or anti-TNF agents may be considered for difficult arthritis.
Cutaneous manifestations• Topical or intradermal corticosteroids are helpful for individual discoid lesions, especially in the scalp.
• Hydroxychloroquine is efficacious. Some studies support a combination of quinacrine and hydroxychloroquine for refractory skin disease.
Hematologic manifestations• Corticosteroids are first-line Rx.
• Azathioprine can be used for thrombocytopenia or hemolytic anemia.
• IV immunoglobulin and rituximab may be considered for severe leukopenia, autoimmune hemolytic anemia, or autoimmune thrombocytopenia.
Central nervous system manifestations• Headaches are treated symptomatically.
• Anticonvulsants and antipsychotics may be indicated.
• Standard Rx for other neuropsychiatric SLE symptoms is not established.
Renal disease (class III, IV, V lupus nephritis)• The use of high doses of IV cyclophosphamide with corticosteroids given at monthly intervals is more effective in preserving renal function than is treatment with glucocorticoids alone.
• Increasingly, mycophenolate mofetil at higher doses has become the induction treatment of choice because of its improved tolerability and better fertility profile. Studies show that pts treated with mycophenolate mofetil as induction Rx have similar renal and nonrenal outcomes as compared with high-dose IV cyclophosphamide.
Mycophenolate mofetil or azathioprine is used for maintenance Rx.
Severe nonrenal organ disease• Evidence from systematic RCTs for nonrenal lupus treatment is comparatively limited.
• High-dose IV cyclophosphamide is used as induction treatment. Azathioprine or mycophenolate mofetil may be used as maintenance drugs.
• IV immunoglobulin may be considered in severe disease when concomitant infection is present.
• Plasmapheresis may be considered in critical situations, but efficacy is not proven in controlled trials, and infectious complication is a substantial consideration.
New Rx• Rituximab: RCTs for rituximab as an adjunct induction agent were (−) in terms of both renal and nonrenal outcomes. Other clinical trials have shown an improvement in certain SLE parameters with rituximab.
• Belimumab: approved for Rx of active autoantibody(+) SLE in adults. It can modestly reduce disease activity and appears to have a glucocorticoid-sparing effect. Cost is a limiting factor (≈$35,000/yr).
F. Rheumatoid Arthritis (RA)
Systemic autoimmune disease characterized by inflammatory polyarthritis, which affects peripheral joints, especially the small joints of the hands and feet. Chronic untreated inflammation may lead to joint erosions and joint destruction.
Etiology
Unknown. It is likely that a combination of genetic and environmental factors lead to aberrant immune activation and inflammatory response in the joint. Stages of disease development presumably include:• Initiation of immune response. The trigger is unknown.
• Perpetuation of inflammatory response involves migration of inflammatory cells into joint space, activation of macrophage-like and fibroblast-like synoviocytes, and development of “synovial pannus,” a thickened synovial membrane.
• The pannus releases proinflammatory cytokines (TNF-α, IL-1, IL-6, IL-8), as well as proteases, which erode cartilage and bone.
• Many of the newer “biologic” DMARDs are engineered to target these cytokines.
Genetics
Genetic factors account for more than 50% of risk of disease. RA is polygenic; identified genetic associations include HLA-DRB1, PTPN22, and PADI4.Diagnosis
The American College of Rheumatology and the European League Against Rheumatism developed newer classification criteria for RA. Four variables constitute these criteria.• The number and size of involved joints (score 0 to 5, with higher scores for a larger number of small joints affected)
• Results of RF and anti–citrullinated protein antibody testing (score 0 to 3, with more points for a high (+) RF or anti-CCP)
• Abnormal ESR or elevated CRP (1 point)
• Symptom duration >6 wk (1 point)
• Scores ≥6 points are considered to have “definite RA.” Max score is 10 points.
H&P
Initial presentation:• Pts have >6 wk of pain, swelling, warmth in one or more peripheral joints, frequently with symmetric joint involvement involving wrists, hands and/or feet, and often associated with >1 hr of morning stiffness.
• Most commonly involved joints include MCP, PIP, wrists, MTP, and ankles.
• The elbows, shoulders, hips, and knees are also affected.
• DIP joints are spared.
• Sacroiliac and vertebral joints are spared except for C1 to C2.
Chronic long-standing disease:• “Swan-neck” (DIP flexion and PIP hyperextension) and “boutonniere” (PIP flexion and DIP hyperextension) deformities occur, as well as MCP subluxation resulting in ulnar drift.
• C1 to C2 inflammation can lead to odontoid erosion and transverse ligament laxity, resulting in atlantoaxial subluxation and cord compression.
• Joint damage of wrists, elbows, shoulders, hips, and knees can lead to severe osteoarthritis, necessitating joint surgery and/or replacement.
Extra-articular manifestations:• Secondary Sjögren’s syndrome (∼35%): immune-mediated inflammation of lacrimal and salivary glands resulting in dry mouth and eyes (sicca syndrome)
• Rheumatoid nodules (25%): on extensor surfaces and pressure points, in RF(+) disease. Histopathology demonstrates palisading histiocytes surrounding fibrinoid necrosis.
• Normocytic normochromic anemia
• Felty’s syndrome: RA with splenomegaly and leukopenia
• Pulmonary disease
• Pleural disease (effusions, pleuritis)
• Interstitial lung disease (up to 10% clinically significant)
• Vasculitis
Ocular disease• Keratoconjunctivitis sicca (dry eye, without dry mouth/secondary Sjögren’s syndrome) (10%)
• Episcleritis, scleritis
• Amyloidosis: long-standing RA; can affect heart, kidney, liver, spleen, intestines, and skin
Labs
RF: an immunoglobulin directed against the Fc region of the IgG• Sensitivity <60%
• Specificity <80%. False(+) results are seen with hep C, subacute bacterial endocarditis, sarcoidosis, malignancy, Sjögren’s syndrome, SLE, increasing age
Anti–cyclic citrullinated peptide (anti-CCP) antibodies. More specific than RF for rheumatoid arthritis (up to 95% to 98%). Sensitivity similar to RF. The presence of either RF or anti-CCP (“sero[+] RA”) is associated with more severe RA.
↑ ESR, ↑ CRP
CBC w/diff: possible mild anemia and leukocytosis
Synovial fluid: inflammatory, with >2000 PMNsImaging
Plain radiography:• Earlier changes include soft tissue swelling, joint space narrowing, and periarticular osteopenia.
• Later changes include periarticular erosions, especially in MCPs, PIPs, MTPs, and wrist. This reflects cartilage and bone destruction secondary to pannus.
MRI and musculoskeletal ultrasound are more sensitive for detecting erosive disease and joint effusion/synovitis.Treatment
Early identification and treatment of RA with DMARDs are crucial. More than half of pts have radiographic joint damage within 2 yr of disease onset, but early aggressive treatment (with DMARDs) is associated with less damage.
NSAIDs: sometimes used initially to relieve pain and mild inflammation; may also be used later in the disease course for additional control of pain and inflammation. NSAIDs are not disease modifying.
Corticosteroids: oral or intra-articular, frequently used initially to reduce inflammation rapidly until oral DMARD treatments take effect. They may also be used during acute flares or in low doses for additional control of inflammation. They have many side effects, including but not limited to weight gain and increased risk of diabetes, osteoporosis, and avascular necrosis.
DMARDs can be classified into “nonbiologic” and “biologic” treatments.
Nonbiologic DMARDs: commonly used agents are MTX, hydroxychloroquine, sulfasalazine, and leflunomide. Most of these are associated with potential toxicity and require close monitoring. They are also slow-acting drugs that require >8 wk to become fully effective.
MTX is the most commonly used DMARD worldwide for the treatment of RA.
“Triple Rx”(MTX, hydroxychloroquine, and sulfasalazine) is superior to MTX alone.
Biologic DMARDs: newer biologically engineered therapies that target cytokines and cells involved in the RA inflammatory response. Major side effects include an increased risk of severe infection, most notably reactivation of TB with anti-TNF agents. A (−) PPD is prerequisite to initiate Rx. Biologic DMARDs are most effective when used in combination with a nonbiologic DMARD, usually MTX.
TNF-α inhibitors (TNFIs): include infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab
Abatacept (CTLA-4Ig): a recombinant protein that prevents costimulatory binding of antigen presenting cell to T cell, thus preventing T-cell activation
Tocilizumab (anti-IL6): a monoclonal antibody against the IL-6 receptor
Rituximab (anti-CD20): a monoclonal antibody against CD20 antigen on B lymphocytesG. Spondyloarthropathies
Table 12-2 compares spondyloarthropathies with RA.
TABLE 12-2
Comparison of Rheumatoid Arthritis and the Spondyloarthropathies
| Feature | Rheumatoid Arthritis | Ankylosing Spondylitis | Enteropathic Arthritis | Psoriatic Arthritis | Reactive Arthritis |
| Male-to-female ratio | 1:3 | 3:1 | 1:1 | 1:1 | 10:1 |
| HLA association | DR4 | B27 | B27 (axial) | B27 (axial) | B27 |
| Joint pattern | Symmetric, peripheral | Axial | Axial and peripheral | Axial and asymmetric peripheral | Axial and asymmetric peripheral |
| Sacroiliac | 0 | Symmetric | Symmetric | Asymmetric | Asymmetric |
| Syndesmophyte | 0 | Smooth, marginal | Smooth, marginal | Coarse, nonmarginal | Coarse, nonmarginal |
| Eye | Scleritis | Iritis | ± | 0 | Iritis and conjunctivitis |
| Skin | Vasculitis | 0 | 0 | Psoriasis | Keratoderma |
| Rheumatoid factor | >80% | 0 | 0 | 0 | 0 |
From Goldman L, Schafer AI (eds): Goldman’s Cecil Medicine, 24th edition. Philadelphia, Saunders, 2012.
H. Systemic Sclerosis
Scleroderma (systemic sclerosis [SSc]) is a connective tissue disorder that is characterized by thickening and fibrosis of the skin and variably severe involvement of diverse internal organs. It can be subdivided into two major subgroups: (1) limited cutaneous SSc (lcSSc), which involves mainly the face, neck, arms, and hands, and (2) diffuse cutaneous SSc (dcSSc), which affects the skin in a more generalized distribution including the entire extremities, face, neck, and trunk. Both subgroups typically have characteristic internal organ involvement.
Etiology
The etiology of this condition is unknown. Genetic profiles show clustering of different alleles according to the subtype of SSc. There is abnormal selection of fibroblasts and aberrant control of connective tissue synthesis by fibroblasts and other cells. Although there are characteristic autoantibodies detected, it is not clear that they directly participate in the pathogenesis of the disease.
Extracellular connective tissue activation
Frequent immunologic abnormalities including autoantibodies
Inflammation in the early stages of disease
VasoconstrictionDiagnosis
Physical Findings
Skin• Tightening of the skin begins on the hands and then progresses to the forearms, face, and neck; the skin is shiny, taut, and sometimes red, with a loss of creases and hair.
• Later, skin tightening may limit movement by causing flexion contractures of the fingers, wrists, and elbows.
• Pigmentary changes may occur.
• Skin atrophy and digital gangrene of fingertips occurs during later stages.
Musculoskeletal• Joint pain and swelling
• Symmetric inflammatory arthritis
• Myopathy
Gastrointestinal involvement• Esophageal dysmotility with heartburn, dysphagia, and odynophagia
• Delayed gastric emptying
• Small bowel dysmotility with abdominal cramps and diarrhea
• Colon dysmotility with constipation
• Primary biliary cirrhosis
Pulmonary manifestations• Pulmonary fibrosis with symptoms of dyspnea and nonproductive cough, as well as fine inspiratory crackles on examination
• Pulmonary HTN
Cardiac involvement• Myocardial fibrosis that leads to congestive heart failure
Renal involvement• Malignant HTN
• Rapidly progressive renal failure
Other organ involvement• Hypothyroidism
• Erectile dysfunction
• Sjögren’s syndrome
• Entrapment neuropathies
CREST syndrome (term now replaced by lcSSc)• Calcinosis, Raynaud’s syndrome, esophageal dysmotility, sclerodactyly, telangiectasias—with CREST syndrome, scleroderma is limited to the distal extremities. This acronym is now considered obsolete by many because it does not accurately reflect the burden of internal organ involvement.
Clinical Presentation
Raynaud’s phenomenon: initial complaint in 70% of pts (The prevalence of Raynaud’s phenomenon is 5% to 10% in the general population; most cases do not progress to scleroderma.)
Finger or hand swelling that is sometimes associated with carpal tunnel syndrome
Arthralgias/arthritis
Internal organ involvementLabs
(+) Anti-Th/To antibodies with lcSSC (associated with PAH)
Antinuclear antibodies (homogeneous, speckled, or nucleolar patterns) in both lcSSC and dcSSC
(−) antibody to native DNA
(−) anti–smooth muscle antibody
Autoantibodies against ribonucleoprotein (+) in 20% of pts, anti-U3RNP with dcSSC (associated with PAH, myositis)
RF (+) in 20% of pts
Anticentromere antibodies in one third of pts with lcSSc
(+) extractable nuclear antibody to Scl-70 in 40% of pts with dcSSc (also called anti-topoisomerase Ab, associated with ILD)
Routine biochemistry tests may indicate specific organ involvement (e.g., liver, kidney, muscle)Imaging
Arthritis: joint radiographs
Gastrointestinal• Endoscopy (diagnostic procedure of choice; may be therapeutic)
• Cine-esophagography (in rare circumstances)
• Barium swallow (occasionally indicated)
• Esophageal manometry (almost never necessary)
Pulmonary• CXR
• PFTs (especially single-breath diffusion capacity for CO)
• Chest CT
• Bronchoscopy with biopsy
• Gallium lung scan
• Bronchoalveolar lavage
Heart• ECG
• Ambulatory (Holter) ECG monitoring
• Echocardiography
• Cardiac catheterization
Kidney: renal biopsy
Skin: skin biopsyTreatment
No disease-modifying Rx available. Immunosuppressive agents used in individual pts. Prednisone should be used with extreme caution, especially in doses >20 mg/day
Raynaud’s syndrome:• Ca2+ channel blockers (i.e., long-acting dihydropyridines)
• Peripheral α1-adrenergic blockers
• Angiotensin II receptor blockers
• Pentoxifylline
• Phosphodiesterase inhibitors
• Stellate ganglionic blockades
• Digital sympathectomy
Arthralgias: nonsteroidal anti-inflammatory drugs
Skin: For extensive skin fibrosis, immunomodulatory drugs have been used such as MTX, mycophenolate, and cyclophosphamide but have not been proved to be beneficial.
Esophageal reflux• H2RB
• PPIs
Pulmonary HTN and fibrosis• O2
• Diuretics (with caution)
• Endothelin-1 receptor inhibitors (bosentan, ambrisentan)
• Sildenafil, tadalafil
• Prostacyclin analogues (epoprostenol, iloprost, treprostinil)
• Lung transplantation
• Cyclophosphamide chemoRx for symptomatic scleroderma-related interstitial lung disease
Renal involvement• ACEIs
• Dialysis
• Renal transplantation
I. Enteropathic Arthritis
See Table 12-3.
TABLE 12-3
Enteropathic Arthritis
| Feature | Peripheral Arthritis | Sacroiliitis, Spondylitis |
| Crohn’s Disease (CD) | ||
| Frequency in CD | 10%-20% | 2%-7% |
| HLA-B27 associated | No | Yes |
| Pattern | Transient, symmetric | Chronic |
| Course | Related to activity of CD | Unrelated to activity of CD |
| Effect of surgery | Remission of arthritis uncommon | No effect |
| Effect of anti-TNF therapy | Effective | Effective |
| Ulcerative Colitis (UC) | ||
| Frequency in UC | 5%-10% | 2%-7% |
| HLA-B27 associated | No | Yes |
| Pattern | Transient | Chronic |
| Course | More common in pancolitis than proctitis; related to activity of UC | Unrelated |
| Effect of surgery | Remission of arthritis | No effect |
From Goldman L, Schafer AI (eds): Goldman’s Cecil Medicine, 24th edition. Philadelphia, Saunders, 2012.
J. Crystal-Induced Arthritides
See Table 12-4.
1. GOUT
Disease characterized by deposition of monosodium urate crystals in and about joints, w/subsequent acute or chronic arthritis
Diagnosis
H&P
The typical presentation is monarticular and characterized by sudden severe pain involving the first metatarsophalangeal joint (podagra), although the midtarsal and ankle are also frequently affected; any joint may be involved, but acute polyarthritis is uncommon.TABLE 12-4
Comparison of Crystal-Induced Arthritides
| Crystal-Induced Arthritis | Characteristics of Crystals (from Joint Aspiration) | Commonly Involved Joints | Comments and Therapy |
| Gouty arthritis | Monosodium urate crystals | First metatarsophalangeal, ankles, midfoot | See text |
| Ca2+ pyrophosphate deposition disease (pseudogout) | Ca2+ pyrophosphate dihydrate crystals Rhomboid or polymorphic, weakly positive, birefringent crystals |
Knees, wrists | X-ray films of involved joint may reveal linear calcifications (chondrocalcinosis) on articular cartilage Possible associated conditions must be ruled out: Hyperparathyroidism
Hypothyroidism
Hemochromatosis
Hypomagnesemia
Therapy: NSAIDs, joint immobilization, intra-articular steroids |
| Hydroxyapatite arthropathy | Ca2+ hydroxyapatite crystals Crystals form nonbirefringent clumps w/synovial fluid when placed on slide Dx often requires microscopy because of the small size of the crystals |
Knees, hips, shoulders | Usually affects younger pts than the other crystal-induced arthritides do Therapy: NSAIDs, joint immobilization, intra-articular steroids |
| Ca2+ oxalate–induced arthritis | Ca2+ oxalate crystals Bipyramidal, positive birefringent crystals |
DIP, PIP joints of hands | Often seen in pts undergoing dialysis who take large doses of ascorbic acid (metabolized to oxalate) Therapy: NSAIDs, joint immobilization, intra-articular steroids |
PE reveals a warm, tender, swollen, erythematous joint; fever may be present, particularly if several joints are involved. Extensive soft tissue swelling, heat, and erythema extending to above and below the affected joint are frequently present and may be confused w/cellulitis.Labs
Serum uric acid level may be ↑, but it is often nl during the acute attack, later rising when the sx resolve.
Aspiration and analysis of synovial fluid from the inflamed joint confirm the dx; examination of the fluid w/a polarized light microscope w/compensator reveals monosodium urate crystals (needle-shaped, strongly (−) birefringent crystals) w/synovial fluid leukocytes.Treatment
NSAIDs: PO: indomethacin, naproxen, ibuprofen. Ketorolac may be given IM in NPO pts.
Colchicine can be given PO or IV; PO dose is 1.2 mg followed by a second dose of 0.6 mg 1 hr later. IV administration has been associated w/risk of bone marrow suppression and renal or hepatic cell damage. Extravasation can also cause tissue necrosis.
Glucocorticoids (triamcinolone acetonide or ACTH): reserved for pts w/contraindications to NSAIDs or colchicine or if PO medication is precluded (e.g., postop). Triamcinolone acetonide, 60 mg IM; or ACTH, 40 IM or 25 by slow IV infusion. Intra-articular steroids may be used to treat a single inflamed joint (dexamethasone PO4-3 1-6 mg).
Clinical Pearls
Xanthine oxidase inhibitors (allopurinol, febuxostat) are used in pts w/frequent recurrent attacks. Hypouricemic Rx should not be started for at least 4 wk after the acute attack has resolved because it may prolong the acute attack and can also precipitate new attacks by rapidly lowering the serum uric acid level.
Colchicine, 0.6 mg PO bid, is indicated for acute gout prophylaxis before hypouricemic Rx is started. It is generally discontinued 6-8 wk after normalization of serum urate levels. Long-term colchicine Rx (0.6 mg qd or bid) may be necessary in pts w/frequent gout attacks despite the use of uricosuric agents. It can also be used as an alternative to uricosuric agents.K. Idiopathic Inflammatory Myopathies
See Table 12-5.
TABLE 12-5
Classification of the Idiopathic Inflammatory Myopathies
| Classification Group | Associated Clinical Features | Severity of Myositis | Response of Myositis to Therapy | Prognosis (5-yr Survival) |
| Clinical Groups | ||||
| Polymyositis | None of the features below | Variable | Variable | Moderate (∼80%) |
| Dermatomyositis | Gottron’s papules or heliotrope rash | Mild to moderate | Good | Moderate (∼85%) |
| Connective tissue myositis | Overlap with other connective tissue diseases | Mild | Excellent | Good (∼90%) |
| Cancer-associated myositis | Cancer diagnosed within 2 yr of idiopathic inflammatory myopathy | Variable | Moderate to poor | Poor, secondary to cancer (∼60%) |
| Juvenile myositis | Dx before age 18 yr Dermatomyositis >> polymyositis Subcutaneous calcifications GI vasculitis |
Variable | Moderate to good | Good (>95%) |
| Inclusion body myositis | Insidious onset in older white men Distal involvement, atrophy, and asymmetric weakness Poor response to therapy |
Mild but progressive | Poor | Few deaths, but significant morbidity (>85%) |
| Serologic Groups | ||||
| Antisynthetases | Acute onset in polymyositis or dermatomyositis Interstitial lung disease, fever, dyspnea on exertion, arthritis, mechanic’s hands, Raynaud’s phenomenon |
Moderate to severe | Moderate, but flares with taper | Poor (∼75%) |
| Anti–signal recognition particle | Acute onset in black female pts Palpitations, cardiac disease, severe weakness No rash (clinically polymyositis) |
Severe | Poor | Very poor (∼30%) |
| Anti–Mi-2 | Classic dermatomyositis “V” and “shawl” rashes, cuticular changes | Mild | Good | Good (>90%) |
From Goldman L, Schafer AI (eds): Goldman’s Cecil Medicine, 24th edition. Philadelphia, Saunders, 2012.
