Limited data exist on the clinical presentation of Muckle–Wells syndrome (MWS) during pregnancy. The purpose of this case report is to highlight the diagnosis of MWS in a pregnant woman. Many rheumatic diseases affect women of childbearing age, and their management during pregnancy can be challenging.
Case
A 33-year-old, 18-weeks’ pregnant woman was hospitalized for acute pain and swelling in her right knee. There was no preceding trauma, diarrheal illness, throat infection or tick exposure. She denied fevers, chills or rashes. She recalled a history of urticaria, precipitated by cold temperatures and prior episodes of vague joint pain.
On physical exam, she was afebrile without skin rashes. Her right knee revealed a large effusion associated with tenderness and warmth with limited range of motion. X-ray and MRI of the right knee showed a joint effusion. ESR was elevated at 57 mm/hr (reference range: 0–29 mm/hr), and CRP was 2.3 mg/dL (reference range: 0–10 mg/dL). Joint aspiration revealed an inflammatory infiltrate with 38,500 WBCs, 94% neutrophils and no crystals.
All cultures, ANA, rheumatoid factor, Lyme serology and HLA B27 antigen returned negative.
She was treated with intravenous ceftriaxone and ibuprofen with significant improvement. The remainder of her pregnancy was unremarkable.
Eight weeks postpartum, the patient noticed sudden deterioration in her hearing, along with subjective fever and fatigue. Audiometric studies were consistent with bilateral moderate sensorineural hearing loss. MRI of the brain and 8th cranial nerve were unremarkable. Treatment with oral prednisone, acyclovir and intratympanic steroid injections was not beneficial, and the patient experienced an ongoing decline in her hearing.
One year later, when she was 12 weeks’ pregnant, the patient noted repeat swelling and pain of her right knee. ESR was elevated at 47 mm/hr, and CRP was 4.1 mg/dL. The NLRP3 gene was sent for analysis. The R262W missense mutation was found, consistent with a diagnosis of Muckle–Wells syndrome. She was started on anakinra 100 mg/daily with significant improvement in well-being. After two weeks, her ESR had fallen to 1.0 mm/hr and CRP normalized at 1.0 mg/dL. The remainder of her pregnancy was without event, and her hearing loss stabilized.
Discussion
This case illustrates the unusual clinical presentation of Muckle–Wells syndrome as an inflammatory monoarticular arthritis during pregnancy. MWS is an inherited, autosomal-dominant, auto-inflammatory disorder, presenting with a variety of symptoms, including periodic fever, rash and arthralgia, as well as sensorineural hearing loss and the development of AA amyloidosis, the latter of which implies a poor prognosis.1 It was first identified by Thomas Muckle, MD, and John Wells, MD, in 1962 as a series of case reports of sensorineural deafness, urticaria and amyloidosis, affecting nine members of a family in Britain.2
Familial cold auto-inflammatory syndrome, MWS and neonatal onset multisystem inflammatory disease are linked to heterozygous mutations in the NALP3 gene and are characterized under the umbrella of cryopyrin-associated periodic syndromes (CAPS). CAPS diseases result from an underlying innate deficiency in the function of the inflammasome.
Inflammasomes are critical mediators of the immune system, composed of multicellular protein bridges. Two different receptor types exist: NOD-like receptors, which include the NLRP3 protein, and AIM receptors.3 The NLRP3 inflammasome is activated once the pattern-recognition receptor and caspase-recruitment domain interact, leading to the biologic maturation of IL-1β and IL-18—both inflammatory cytokines.3
Particular mutations in the inflammasome have been associated with auto-inflammatory diseases. This association is clearly present in CAPS, with a gain of function mutation in the NLRP3 gene, resulting in the production of cryopyrin3 (see Figure 1). Cryopyrin is known as a danger sensor, activating caspase and eventually cleaving pro-1L-1β to active IL-1β to trigger an inflammatory response in the setting of immunologic threat and active infection. MWS is due to overproduction of IL-1β, resulting in debilitating, ongoing, end-organ damage.
The diagnosis of CAPS diseases, particularly MWS, is most commonly made in childhood. The Eurofever group has tracked 136 CAPS patients in Europe to better learn about risk stratification in this patient population. They found the median age of symptom onset to be 0.8 years (1–5 years); however, median age of diagnosis was 15 years.3 Our patient was not diagnosed until mid-adulthood.
A diagnosis of MWS is established via a genetic test showing a mutation in the NLRP3 genotype, along with clinical signs and symptoms, including urticaria-like rash, musculoskeletal symptoms, sensorineural hearing loss and cold-induced attacks.1-4 MWS is a moderately severe CAPS-disease type with a wide range of organ involvement. Chronic urticarial rashes manifest in infancy and continue throughout childhood, usually occurring two to four hours after cold exposure. Skin biopsy is significant for a neutrophilic predominant infiltrate.4 Recurrent fever episodes are also common, lasting one to two days, and can be triggered by exercise, stress or cold temperatures.
Severe joint pain and arthralgias affect a majority of patients; however, cartilage, bony destruction and joint space damage are usually not seen on radiographic imaging. Knee, wrist and ankle joints are commonly involved. Sensorineural hearing loss is usually present in infancy and can worsen over time, due to degeneration of sensory cells in the Organ of Corti.4 Active deterioration in hearing during the postpartum period is uncommon and should prompt further investigation. Disease flares can be brought on by stress; however, the relation to an immunocompromised state during pregnancy is uncharacteristic. Scarce literature addresses the reasons for an MWS flare during pregnancy. A change in uric acid, cholesterol or toxin metabolization by the NLRP3 inflammasome during pregnancy may play a role and is subject to future investigation.
IL-1 inhibitors have been studied to mitigate symptoms and downregulate the inflammatory response. Anakinra is a synthetic form of IL-1 RA, acting within the body to inhibit IL-1β binding to its receptor type, preventing IL-1β biologic activity.5 Individuals with MWS don’t produce enough endogenous IL-1 receptors to control the excess amounts of circulating IL-1β. Anakinra has been used in pregnant patients with CAPS diseases, with successful symptom resolution and minor side effects on the fetus.6
A study consisting of 26 patients, 57% females, with severe MWS was conducted to assess the efficacy of both anakinra and canakinumab, a monoclonal IL-1β antibody that prevents IL-1β from binding to the receptor site. 75% of patients on anakinra achieved clinical remission compared with 99% of patients in the canakinumab treatment arm, with similar safety profiles.7 Both drugs led to clinical improvement and decreased ESR, CRP and MWS disease activity scores (MWS-DAS).
In patients refractory to anakinra, canakinumab has shown sustained disease control.8 A recently published study shows canakinumab crosses the placenta when administered during pregnancy.8 The safety profile and long-term effects of these medications on the fetus need to be explored.
Aiza Tariq, MD, is an internal medicine resident at the Icahn School of Medicine at Mount Sinai Beth Israel, New York. She completed her medical degree at the University of Florida. Her primary research interests include rheumatic disease.
Harry D. Fischer, MD, is chief of the Division of Rheumatology and associate chairman of medicine at Icahn School of Medicine at Mount Sinai Beth Israel, New York. He is also associate professor of medicine at the Icahn School of Medicine at Mount Sinai.
References
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- Muckle T, Wells M. Urticaria, deafness, and amyloidosis: A new heredo-familial syndrome. Q J Med. 1962 Apr;31:235–248. PubMed: 14476827.
- Sönmez HE, Özen S. Clinical update on inflammasomopathies. Int Immunol. 2017 Apr 6.
- Kuemmerle-Deschner JB, Haug I. Canakinumab in patients with cryopyrin-associated periodic syndrome: An update for clinicians. Ther Adv Musculoskelet Dis. 2013 Dec;5(6):315–329.
- Koné-Paut I. Galeotti C. Anakinra for cryopyrin-associated periodic syndrome. Expert Rev Clin Immunol. 2014 Jan;10(1):7–18.
- Chang Z, Spong CY, Jesus AA, et al. Anakinra use during pregnancy in patients with cryopyrin-associated periodic syndromes (CAPS). Arthritis Rheumatol. 2014 Nov;66(11):3227–3232.
- Kuemmerle-Deschner JB, Wittkowski H, Tyrrell PN, et al. Treatment of Muckle-Wells syndrome: Analysis of two IL-1 blocking regimens. Arthritis Res Ther. 2013;15(3):R64.
- Egawa M, Imai K, Mori M. et al. Placental transfer of canakinumab in a patient with Muckle Wells syndrome. J Clin Immunol. 2017 May;37(4):339–341.