Seronegative Spondyloarthropathies
Group of inflammatory arthritides that are RF-negative, HLA-B27 associated. Includes ankylosing spondylitis, psoriatic arthritis, reactive arthritis, IBD-associated arthritis. Axial inflammation + enthesitis are hallmarks. NSAIDs first-line, then biologics.
🔍 Overview
Classification
| Type | Key Features | HLA Association | Extra-articular Manifestations |
|---|---|---|---|
| Ankylosing Spondylitis | Inflammatory back pain, sacroiliitis, progressive spinal fusion ("bamboo spine"), kyphosis, enthesitis | HLA-B27 (~90%) | Anterior uveitis (#1 EAM), aortic insufficiency, apical pulmonary fibrosis, IgA nephropathy, cauda equina syndrome |
| Psoriatic Arthritis | Asymmetric oligoarthritis, DIP joints, dactylitis ("sausage digits"), enthesitis, arthritis mutilans, "pencil-in-cup" deformity | HLA-B27 (~50%), HLA-Cw6 (psoriasis) | Psoriatic skin plaques, nail pitting/onycholysis, uveitis, aortitis |
| Reactive Arthritis | Asymmetric oligoarthritis (large joints, lower extremity), post-infectious onset 1–4 weeks after GI/GU infection | HLA-B27 (~70%) | Conjunctivitis/uveitis, urethritis/cervicitis, keratoderma blennorrhagica, circinate balanitis, oral ulcers |
| IBD-Associated Arthritis | Peripheral (follows IBD activity, asymmetric, large joints) or axial (independent of IBD activity, sacroiliitis) | HLA-B27 (~50% axial, ~10% peripheral) | Erythema nodosum, pyoderma gangrenosum, uveitis, primary sclerosing cholangitis (UC) |
| Undifferentiated SpA | Features of SpA not meeting criteria for any specific subtype; inflammatory back pain, enthesitis, dactylitis | HLA-B27 (~70%) | Uveitis, psoriasiform rash. May evolve into AS or PsA over time. |
Reactive Arthritis Triad: "Can't see, Can't pee, Can't climb a tree", Conjunctivitis (or uveitis), urethritis (or cervicitis), arthritis (asymmetric oligoarthritis, lower extremities). Triggered by GI infection (Salmonella, Shigella, Campylobacter, Yersinia) or GU infection (Chlamydia trachomatis).
SPINE Mnemonic, Ankylosing Spondylitis Features:
- Sacroiliitis, bilateral, symmetric; earliest and most characteristic finding on imaging
- Psoriasis association, overlap with PsA; up to 10% of AS patients develop psoriasis
- Inflammatory back pain, morning stiffness >30 minutes, improves with exercise, worse at rest, onset <40 years
- NSAIDs first-line, full-dose continuous NSAIDs (indomethacin, naproxen); try at least 2 NSAIDs before escalating
- Extra-articular, anterior uveitis (most common), aortitis/aortic insufficiency, interstitial lung disease (apical fibrosis), IgA nephropathy
Shared Features (All SpA)
- HLA-B27 positive (AS ~90%, reactive ~70%, PsA ~50%)
- Seronegative -RF negative, anti-CCP negative
- Enthesitis -inflammation at tendon/ligament insertion sites (Achilles, plantar fascia)
- Dactylitis -"sausage digit" diffuse swelling of entire finger/toe
- Inflammatory back pain -onset < 40, insidious, morning stiffness > 30 min, improves with exercise, worse at rest
- Extra-articular: uveitis, psoriasis, IBD
🚨 Management
Treatment Approach
| Line | Axial Disease | Peripheral Disease |
|---|---|---|
| 1st | NSAIDs (full dose, continuous if needed) | NSAIDs, local steroids |
| 2nd | Anti-TNF (Adalimumab (Humira), Etanercept (Enbrel), Infliximab (Remicade)) | DMARDs (Methotrexate (Trexall), Sulfasalazine (Azulfidine)) |
| 3rd | Secukinumab (Cosentyx) (anti-IL-17) | Anti-TNF or anti-IL-17 |
Traditional DMARDs (methotrexate, sulfasalazine) do NOT work for axial disease. They only help peripheral joints. For axial SpA, go directly from NSAIDs → biologics (anti-TNF or anti-IL-17).
Treatment Algorithm
| Step | Therapy | Agents | Notes |
|---|---|---|---|
| Step 1 | NSAIDs | Indomethacin (Indocin) 25–50 mg TID, Naproxen (Aleve) 500 mg BID | First-line for all SpA. Try ≥2 different NSAIDs (each for 2–4 weeks at full dose) before escalating. Continuous use for axial disease. |
| Step 2 | TNF Inhibitors | Adalimumab (Humira) 40 mg SC q2wk, Etanercept (Enbrel) 50 mg SC weekly, Infliximab (Remicade) 5 mg/kg IV q6–8wk | First-line biologic for axial SpA failing NSAIDs. Screen for TB/Hep B before starting. Monitor for infections. |
| Step 3 | IL-17 Inhibitors | Secukinumab (Cosentyx) 150 mg SC monthly, Ixekizumab (Taltz) 80 mg SC q4wk | Alternative to anti-TNF or after anti-TNF failure. Contraindicated in IBD-associated SpA (can trigger/worsen IBD). |
| PsA Special | DMARDs + PDE4i | Methotrexate (Trexall) 15–25 mg weekly, Apremilast (Otezla) 30 mg BID | Methotrexate for peripheral PsA + skin disease. Apremilast (PDE4 inhibitor) for mild PsA when biologics are not appropriate. Neither works for axial disease. |
Clinical Examples
📋 Case 1, Ankylosing Spondylitis
Patient: 24M presenting with 6 months of progressive low back pain and stiffness. Pain is worse in the morning (>1 hour of stiffness), improves with exercise, and wakes him in the second half of the night. No improvement with rest.
Workup:
- HLA-B27: Positive
- MRI SI joints: Bilateral sacroiliitis with bone marrow edema
- CRP: Elevated at 28 mg/L
- RF, anti-CCP: Negative (seronegative)
- X-ray spine: Early syndesmophytes
Management:
- Started on Indomethacin (Indocin) 50 mg TID, partial response after 4 weeks
- Escalated to Adalimumab (Humira) 40 mg SC q2 weeks after failing 2 NSAIDs
- TB screening (QuantiFERON) negative prior to biologic initiation
- Ophthalmology referral for uveitis screening
Key lesson: Young male + inflammatory back pain + bilateral sacroiliitis + HLA-B27+ = classic ankylosing spondylitis. NSAIDs first, then skip DMARDs and go directly to anti-TNF for axial disease.
📋 Case 2, Psoriatic Arthritis
Patient: 45F with known psoriasis × 10 years, now presenting with painful swollen fingers, “sausage-like” left 3rd toe, and pitting of multiple fingernails.
Exam findings:
- Dactylitis: Diffuse swelling of left 3rd toe
- DIP joint tenderness: Bilateral 2nd and 3rd fingers
- Nail pitting: Multiple nails with onycholysis
- Psoriatic plaques: Elbows, scalp, intergluteal cleft
- RF, anti-CCP: Negative
Management:
- Started on Methotrexate (Trexall) 15 mg weekly (peripheral + skin disease)
- Folic acid 1 mg daily supplementation
- Inadequate response at 3 months → switched to Secukinumab (Cosentyx) 150 mg SC monthly
- Baseline LFTs, CBC, Hep B/C screening before methotrexate
Key lesson: Psoriasis + DIP arthritis + dactylitis + nail changes = psoriatic arthritis. Methotrexate addresses both skin and peripheral joints. IL-17 inhibitors are excellent for both PsA and psoriasis.
📋 Case 3, Reactive Arthritis
Patient: 22M presenting 3 weeks after treated Chlamydia urethritis with acute right knee swelling, bilateral conjunctivitis, and persistent dysuria despite completed doxycycline course.
Classic triad present:
- Can't see: Bilateral conjunctivitis (painless, non-purulent)
- Can't pee: Sterile urethritis (urinalysis: pyuria, negative culture)
- Can't climb a tree: Asymmetric oligoarthritis (right knee effusion, left ankle pain)
- Additional: Keratoderma blennorrhagica (soles), circinate balanitis
Management:
- Naproxen (Aleve) 500 mg BID for joint inflammation
- Doxycycline 100 mg BID × 7 days (re-treat underlying Chlamydia if not fully eradicated)
- Ophthalmology referral for conjunctivitis monitoring
- HLA-B27: Positive (prognostic, higher risk of chronicity)
Key lesson: Post-GU infection + triad of conjunctivitis/urethritis/arthritis = reactive arthritis. Treat the underlying infection + NSAIDs for arthritis. Most cases self-limited (3–6 months), but HLA-B27+ patients have higher risk of chronic/recurrent disease.
🧪 Workup
- HLA-B27 -positive in 90% of AS, 70% reactive, 50% PsA. Not diagnostic alone (8% of general population is positive).
- X-ray pelvis (SI joints) -sacroiliitis (sclerosis, erosions, fusion). May take years to appear.
- MRI SI joints -bone marrow edema = early sacroiliitis. Gold standard for early disease.
- CRP, ESR -may be elevated
- RF, anti-CCP -negative (to confirm seronegative)
- X-ray spine -syndesmophytes, bamboo spine (late AS)
- Skin exam -psoriasis (nails, scalp, intergluteal fold)
💊 Medications
| Drug | Dose | Indication |
|---|---|---|
| Naproxen (Aleve) | 500 mg BID | First-line all SpA. Full-dose, continuous for axial disease. |
| Indomethacin (Indocin) | 25–50 mg TID | Traditional NSAID for AS. Very effective but GI side effects. |
| Adalimumab (Humira) | 40 mg SC q2 weeks | Anti-TNF. First biologic for axial or peripheral SpA failing NSAIDs. |
| Secukinumab (Cosentyx) | 150 mg SC monthly | Anti-IL-17. Alternative to anti-TNF. Avoid in IBD (can worsen). |
| Sulfasalazine (Azulfidine) | 1–1.5 g BID | Peripheral joints only. No axial benefit. |
📋 On Rounds
Pimp Questions
How do you differentiate inflammatory back pain from mechanical back pain?
Inflammatory: Age of onset < 40, insidious onset, morning stiffness > 30 min, improves with exercise, worse with rest, night pain (second half of night), alternating buttock pain. Mechanical: Any age, often acute onset, worse with activity, better with rest, no morning stiffness. Having 4+ inflammatory features has ~95% specificity for SpA. The key differentiator: inflammatory back pain gets BETTER with movement, mechanical gets WORSE.
Why are traditional DMARDs ineffective for axial SpA?
The pathophysiology of axial SpA involves entheseal inflammation and new bone formation at the spine/SI joints driven primarily by IL-17 and TNF pathways, not the same T-cell/B-cell mediated pathways targeted by traditional DMARDs (methotrexate, sulfasalazine). These drugs act on synovial inflammation (peripheral joints) but cannot penetrate or modulate the entheseal/axial inflammatory process.
What imaging finding differentiates ankylosing spondylitis from mechanical back pain?
Sacroiliitis on MRI is the key differentiator. MRI shows bone marrow edema (bright on STIR/T2 fat-sat sequences) at the sacroiliac joints, representing active inflammation, this is the gold standard for early AS before X-ray changes appear. X-ray findings of sacroiliitis (sclerosis, erosions, joint space narrowing, eventual fusion) may take years to develop. In contrast, mechanical back pain shows no SI joint inflammation on MRI.
Why are IL-17 inhibitors contraindicated in IBD-associated spondyloarthropathy?
IL-17 plays a paradoxical protective role in gut mucosal immunity. While IL-17 drives inflammation in the joints and spine, it is critical for maintaining the intestinal epithelial barrier and defense against gut pathogens. Blocking IL-17 with secukinumab or ixekizumab disrupts this protective function, leading to new-onset or exacerbation of IBD (both Crohn’s and UC).
⚡ Summary
What Ties the Group Together
Rheumatoid factor negative, HLA-B27 associated, with axial inflammation and enthesitis as the hallmarks. The family is ankylosing spondylitis, psoriatic arthritis, reactive arthritis and IBD-associated arthritis, plus undifferentiated disease that may evolve into one of them. Enthesitis, inflammation where tendon meets bone, is what distinguishes this group from rheumatoid arthritis, which inflames synovium.
Recognize Inflammatory Back Pain
Onset before age 45, insidious, lasting over 3 months, with morning stiffness beyond 30 min, improvement with exercise and not with rest, and night pain that wakes the patient in the second half of the night. That pattern is the opposite of mechanical back pain, and it is the single most useful piece of history in the whole topic.
Image the Sacroiliac Joints
Bilateral, symmetric sacroiliitis is the earliest and most characteristic finding. Plain films are normal for years, so a normal x-ray does not exclude disease. MRI shows bone marrow edema and diagnoses non-radiographic axial SpA, which is the same disease before structural change appears.
HLA-B27 Supports, It Does Not Diagnose
Present in about 90% of ankylosing spondylitis but also in 6 to 8% of the healthy population. A positive result in a patient with mechanical back pain means nothing, and a negative result does not exclude the diagnosis. Use it to raise or lower probability in a patient who already has inflammatory features.
Traditional DMARDs Fail in Axial Disease
Methotrexate and sulfasalazine do not work for spinal disease. They only help peripheral joints. For axial SpA go from NSAIDs straight to a biologic, an anti-TNF or an anti-IL-17 agent. Prescribing methotrexate for back pain in ankylosing spondylitis wastes months of a window in which fusion is still preventable.
NSAIDs Are First Line and Genuinely Disease-Modifying Here
Continuous rather than as-needed dosing may slow radiographic progression in axial disease, which is not true of NSAIDs in other arthritides. Physical therapy and posture-focused exercise are not optional adjuncts: they preserve the spinal mobility that fusion takes away permanently.
Recognize the Subtypes at the Bedside
Psoriatic arthritis: asymmetric oligoarthritis, DIP involvement, dactylitis (sausage digits), nail pitting and onycholysis. Reactive arthritis: asymmetric lower-limb oligoarthritis 1 to 4 weeks after a GI (Salmonella, Shigella, Campylobacter, Yersinia) or genitourinary (Chlamydia) infection, with the classic conjunctivitis, urethritis and arthritis triad. IBD-associated: peripheral disease follows bowel activity, axial disease does not.
Do Not Miss the Extra-Articular Disease
Anterior uveitis is the commonest extra-articular manifestation and is an ophthalmologic emergency: a red, painful, photophobic eye needs same-day slit-lamp assessment, not a wait-and-see. Also screen for aortic insufficiency and conduction disease, apical pulmonary fibrosis, and osteoporosis with an increased fracture risk. A fused cervical spine fractures with minimal trauma and is unstable, so any neck pain after a fall in ankylosing spondylitis needs CT, not plain films.
📄 One Pager
Text version
RHEUMATOLOGY · One Pager
Seronegative Spondyloarthropathies
RF-negative, HLA-B27-associated inflammatory arthritis where enthesitis and axial inflammation are the hallmarks. Every treatment decision starts with one question: is this axial or peripheral disease?
Recognize It
- Inflammatory back pain: onset < 40, insidious, morning stiffness > 30 min, improves with exercise, worse with rest, night pain in the second half of the night. Mechanical pain does the opposite: worse with activity, better with rest. 4+ inflammatory features is ~95% specific for SpA.
- Enthesitis: inflammation at tendon/ligament insertions (Achilles, plantar fascia). This is the lesion that traditional DMARDs cannot reach.
- Dactylitis: "sausage digit", diffuse swelling of an entire finger or toe rather than one joint.
- Seronegative: RF and anti-CCP negative. Check them to confirm, not to diagnose.
- HLA-B27: AS ~90%, reactive ~70%, PsA ~50%. Not diagnostic alone, since 8% of the general population is positive.
- Extra-articular: uveitis, psoriasis, IBD. Anterior uveitis is the #1 extra-articular manifestation of AS, so refer to ophthalmology.
The Subtypes
- Ankylosing spondylitis: inflammatory back pain, bilateral symmetric sacroiliitis, progressive spinal fusion ("bamboo spine"), enthesitis. Watch for anterior uveitis, aortic insufficiency, apical pulmonary fibrosis, IgA nephropathy, cauda equina syndrome.
- Psoriatic arthritis: asymmetric oligoarthritis, DIP joints, dactylitis, arthritis mutilans with "pencil-in-cup" deformity. Nail pitting and onycholysis are the tell when the plaques are hidden (scalp, intergluteal cleft).
- Reactive arthritis: asymmetric lower-extremity large-joint oligoarthritis starting 1–4 weeks after GI (Salmonella, Shigella, Campylobacter, Yersinia) or GU (Chlamydia trachomatis) infection. Triad: "can't see, can't pee, can't climb a tree", conjunctivitis/uveitis + urethritis/cervicitis + arthritis. Also keratoderma blennorrhagica and circinate balanitis. Most cases self-limited over 3–6 months, but HLA-B27+ patients have a higher risk of chronic or recurrent disease.
- IBD-associated arthritis: peripheral disease follows IBD activity, axial disease runs independent of it. Also erythema nodosum, pyoderma gangrenosum, uveitis, PSC (in UC).
- Undifferentiated SpA: SpA features not meeting any subtype's criteria. May evolve into AS or PsA over time, so keep re-examining.
Treatment Ladder: Axial vs Peripheral
1
NSAIDs first, both phenotypes: indomethacin 25–50 mg TID or naproxen 500 mg BID. Try at least 2 different NSAIDs, each for 2–4 weeks at full dose, before calling it a failure. Continuous rather than as-needed dosing for axial disease. Peripheral disease can also get local steroid injection.
2
Axial: skip the DMARDs entirely and go to anti-TNF. Adalimumab 40 mg SC q2wk, etanercept 50 mg SC weekly, or infliximab 5 mg/kg IV q6–8wk. Axial disease is driven by entheseal inflammation and new bone formation through IL-17 and TNF pathways, not the synovial inflammation traditional DMARDs act on, so methotrexate and sulfasalazine simply do not work above the pelvis.
2
Peripheral: DMARDs are the step 2. Methotrexate 15–25 mg weekly (covers skin plus peripheral joints in PsA, give with folic acid) or sulfasalazine 1–1.5 g BID. Apremilast 30 mg BID is an option for mild PsA when biologics are not appropriate. None of these help axial disease.
3
IL-17 inhibitors: secukinumab 150 mg SC monthly or ixekizumab 80 mg SC q4wk, as an alternative to anti-TNF or after anti-TNF failure. Excellent for both PsA joints and psoriatic skin.
4
Before any biologic: screen for TB and hepatitis B, because anti-TNF reactivates latent infection. Get baseline LFTs, CBC, and hepatitis B/C screening before methotrexate. Monitor for infection on therapy.
Key Drugs
Naproxen (Aleve)500 mg BID, first-line all SpA; full-dose and continuous for axial disease
Indomethacin (Indocin)25–50 mg TID, traditional NSAID for AS, very effective but GI side effects
Adalimumab (Humira)40 mg SC q2 weeks, first biologic for axial or peripheral SpA failing NSAIDs
Secukinumab (Cosentyx)150 mg SC monthly, anti-IL-17 alternative to anti-TNF; avoid in IBD
Methotrexate (Trexall)15–25 mg weekly, peripheral PsA plus skin disease; no axial benefit
Sulfasalazine (Azulfidine)1–1.5 g BID, peripheral joints only, no axial benefit
Apremilast (Otezla)30 mg BID, PDE4 inhibitor for mild PsA when biologics are not appropriate
Workup and Monitoring
- MRI SI joints is the gold standard for early disease: bone marrow edema on STIR/T2 fat-sat means active sacroiliitis, and it turns positive years before the X-ray does.
- X-ray pelvis for sacroiliitis (sclerosis, erosions, fusion), but a normal film does not exclude AS since changes may take years to appear.
- X-ray spine for syndesmophytes and bamboo spine, findings of late AS.
- CRP and ESR may be elevated and help track inflammatory activity, but normal values do not rule out active disease.
- RF and anti-CCP to confirm the seronegative phenotype and exclude RA.
- Skin and nail exam every visit: nails, scalp, intergluteal fold, the places psoriasis hides and reclassifies the patient as PsA.
- TB screening (QuantiFERON) before starting a biologic and per protocol thereafter.
Pitfalls
- Prescribing methotrexate or sulfasalazine for axial disease. They only help peripheral joints. For axial SpA the path is NSAIDs straight to a biologic; sending the patient through a DMARD trial just loses months.
- IL-17 inhibitors in IBD-associated SpA. IL-17 is protective in gut mucosa and maintains the intestinal epithelial barrier, so blocking it can trigger or worsen Crohn disease and UC. Use anti-TNF in that group.
- Escalating after one NSAID. The bar is at least 2 NSAIDs at full dose for 2–4 weeks each before declaring NSAID failure.
- Using HLA-B27 as a diagnostic test. 8% of the general population is positive; it supports the picture and carries prognostic weight in reactive arthritis, but it does not make the diagnosis.
- Starting a biologic without TB and hepatitis B screening.
Escalate / Refer When
- Axial disease with inadequate response to 2 full-dose NSAID trials: escalate directly to anti-TNF, do not detour through DMARDs.
- Peripheral PsA with inadequate response to methotrexate at 3 months: switch to an IL-17 inhibitor or anti-TNF.
- Any red eye, eye pain, or visual change: ophthalmology, anterior uveitis is the most common extra-articular manifestation of AS and needs prompt treatment.
- New neurologic deficit or bladder/bowel dysfunction in AS: cauda equina syndrome is a recognized AS complication and is a surgical emergency.
- New murmur or dyspnea in AS: evaluate for aortitis with aortic insufficiency and apical pulmonary fibrosis.
- Reactive arthritis after Chlamydia: treat or re-treat the underlying infection alongside NSAIDs, and refer to ophthalmology for conjunctivitis monitoring.
The Three Things to Remember
- Axial versus peripheral is the fork in the road. It determines whether DMARDs have any role at all.
- Inflammatory back pain gets better with movement, mechanical back pain gets worse. That single question sorts most referrals.
- MRI SI joints beats X-ray for early disease, so a young patient with inflammatory back pain and a normal pelvis film still needs the MRI before you accept a mechanical label.
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