Anakinra as a diagnostic challenge and treatment option for systemic autoinflammatory disorders of undefined etiology (original) (raw)
uSAID patients presented with a range of nonspecific autoinflammatory symptoms including periodic fevers (11 of 11), fatigue/malaise (11 of 11), rash (8 of 11), myalgia (9 of 11), arthralgia (8 of 11), synovitis (6 of 11), arthritis (5 of 11), headaches (5 of 11), lymphoreticular (4 of 11) as well as gastrointestinal symptoms (3 of 11) and pericarditis/pleurisy (2 of 11) (Table 1). The average age of symptom onset was 43.7 years (range 24–76), and there was no family history of autoinflammatory disease or consanguinity.
Demographic data and presenting signs/symptoms for all uSAID patients (n = 11)
All patients experienced substantial delays between presentation and eventual diagnosis (mean 2.9 years [1.0–8.0]) requiring input from various other specialties, including hematology, infectious diseases, urology, respiratory, neurorehabilitation, and dermatology. In addition, uSAID patients were subjected to extensive investigation, including a full autoantibody screen, serum ferritin, CT (9 of 11), PET-CT (8 of 11), biopsies (skin/BM/liver/ kidney/lymph nodes) (6 of 11) and magnetic resonance imaging (MRI) (2 of 11) (Table 2), all of which failed to establish an underlying cause. Furthermore, uSAID patients tested negative for known autoinflammatory disease genes (NLRP3, MEFV, TNFRSF1A, and NLRC2 [_NOD2_]) (11 of 11). During the course of these investigations, management with nonspecific immunosuppressive agents (a combination of NSAIDs, DMARDs, and systemic corticosteroids) failed to control autoinflammatory symptoms. Systemic corticosteroid treatment was ineffective in 5 of 11 patients and only partially controlled symptoms in 6 of 11 patients, of which 3 of 11 experienced substantial adverse effects from prolonged steroid use, including intolerable weight gain and diabetes. In addition, 4 of 11 patients experienced adverse events as a consequence of DMARD treatment (Table 2).
uSAID patients’ biochemical profiles, investigations, and treatments (n = 11)
Contrastingly, anakinra produced full symptom control in 9 of 11 patients within 4–6 weeks of starting treatment (Table 2), which correlated with a clinically marked reduction in C-reactive protein (CRP), eventually enabling these patients to gradually withdraw concomitant corticosteroids and/or DMARD treatment. Anakinra was generally well tolerated. The treatment was discontinued in 2 patients only; in one due to an incomplete response and, in another, due to a marked adverse event, namely injection-site reactions. Two patients died during the follow-up period. Patient uSAID-10 died due to complications of influenza, which were not thought to be directly related to his treatment with anakinra. Patient uSAID-09 died from what was thought to be a progression of her underlying disease. A more detailed description of all cases is given below.
uSAID-01. uSAID-01 is a 74-year-old male who initially presented with an 8-year history of fatigue, malaise, arthritis, arthralgia, myalgia, and elevated CRP and serum amyloid A (SAA). Neutrophils and ferritin were within the reference range. Following further investigations, including autoimmune screening, a diagnosis of seronegative rheumatoid arthritis (RA) was made and methotrexate (MTX) plus corticosteroids commenced. Subsequently, the patient developed shoulder pain — in addition to sacroiliac and axial joint pain, jaw stiffness, and overwhelming fatigue — and was diagnosed with polymyalgia rheumatica (PMR). In 2013, uSAID-01 was admitted with a suspected PMR flare. Upon further questioning, it was noted that he had, in fact, experienced periodic fevers for several years. Despite having ongoing joint symptoms for over 8 years and seemingly poor disease control on MTX, he did not develop any joint erosions. Furthermore, uSAID-01’s PMR had an unusually severe systemic component and was only partially responsive to corticosteroids (the highest dose of prednisolone used was 60 mg daily orally [PO] and maintenance dose 10 mg daily PO), despite PMR being characteristically highly corticosteroid responsive. A PET-CT showed increased tracer activity in multiple joints, suggesting active arthropathy but showing no evidence of vasculitis or malignancy. Considering that some of his clinical features were atypical of seronegative RA and PMR, and as he had disproportionately elevated CRP (>100 mg/ml), the patient was given an empirical trial of anakinra, 100 mg daily s.c. This successfully controlled all symptoms, substantially alleviating the fatigue and malaise, and resulted in reduction of CRP (Figure 1). The patient has now successfully stopped cortiocosteroids without a flare of his symptoms.
uSAID-01: serial CRP measurements. This figure shows the serial CRP measurements recorded for uSAID-01 from initial presentation to Dec. 2015. CRP, C-reactive protein; PMR, polymyalgia rheumatica; Pred, prednisolone; PUO, pyrexia of unknown origin; RA, rheumatoid arthritis; MTX, methotrexate.
uSAID-02. uSAID-02 is a 39-year-old lady who presented at age of 26 with monthly periodic fever episodes, accompanied by fatigue, malaise, headaches, drenching night sweats, nausea, leg cramps, and occasional vomiting. Her CRP and SAA were markedly elevated during the attacks and would normalize when asymptomatic. Her serum ferritin levels remained within the reference at all times. Initially, her symptoms improved during pregnancy; however, following delivery, her attacks increased in frequency and she developed a generalized, blotchy, pruritic papular rash. She had extensive investigations and — apart from a positive lupus anticoagulant screen, which was not thought to be relevant to her symptoms — all other tests were negative (Table 2). uSAID-02 did not respond to maintenance prednisolone PO and was only partially responsive to high-dose methylprednisolone (80 mg) and 40 mg prednisolone PO during a flare. Therefore, uSAID-02 was commenced on 100 mg daily s.c. anakinra, following which she experienced only occasional mild residual breakthrough symptoms that were effectively managed with an extra dose of anakinra. Over time, uSAID-02’s response to anakinra greatly improved, and daily maintenance with anakinra alone is currently sufficient to achieve complete symptomatic control (Figure 2).
uSAID-02: serial CRP and SAA measurements. This figure shows the serial CRP/SAA measurements recorded for uSAID-02 from initial presentation to Dec. 2015. CRP, C-reactive protein; SAA, serum amyloid A.
uSAID-03. uSAID-03 is a 35-year-old gentleman who presented following admission to hospital with a 1-year history of pyrexia of unknown origin (PUO), weight loss, fatigue, and elevated CRP. uSAID-03 had a history of foreign travel; however, a complete infectious disease screen was negative. His other investigations showed normal wbc and elevated platelets (highest recoded platelet count was 520: range 150–400 × 109/l) and normal serum ferritin. His symptoms initially resolved following a course of high-dose oral corticosteroids (prednisolone 40 mg daily PO); however, the patient was readmitted 2 months later with a repeat febrile episode. Subsequently, the patient has continued to experience intermittent fevers (3–4 weekly lasting 24–48 hours), fatigue, joint swelling, and headaches. His symptoms were partially responsive to corticosteroids (15 mg prednisolone daily PO); however, uSAID-03 experienced intolerable weight gain as a result. MTX also failed to control break-through symptoms, necessitating admission to hospital for treatment and leaving the patient unable to work. Treatment with 100 mg daily s.c. anakinra partially controlled symptoms, with a decreased frequency of fever episodes and improved energy levels, as well as reduced CRP. However, CRP remained mildly elevated despite doubling the daily dose of anakinra, and the patient continued to be corticosteroid dependent. Furthermore, the patient developed a blistering skin rash with erythema at the injection site. Therefore, he was switched to tocilizumab (Actemra). His symptoms are now well controlled, his CRP has normalized, and he has now discontinued all corticosteroids (Figure 3).
uSAID-03: serial CRP measurements. This figure shows the serial CRP measurements recorded for uSAID-03 from initial presentation to Dec. 2015. CRP, C-reactive protein; MTX, methotrexate; Pred, prednisolone; TCZ, tocilizumab.
uSAID-04. uSAID-04 is a 39-year-old lady with an 8-year history of periodic fevers, headaches, polyarthralgia, a widespread urticarial rash, and elevated CRP that developed after her first pregnancy and delivery, which were uncomplicated. Ferritin and neutrophil counts were normal. Symptoms were partially responsive to corticosteroid depot injections and resolved within 2 years. However, during her third pregnancy, she relapsed, experiencing episodic fevers, polyarthralgia, synovitis, overwhelming fatigue, pericardial symptoms, and headaches, and she also developed a nonpainful, nonpruritic, generalized macular erythematous rash. CRP and SAA were both elevated at this time. PET-CT was negative, and skin biopsy showed a mild sprinkling of chronic inflammatory cells in perivascular areas and no obvious evidence of vasculitis, granulomatous inflammation, or malignancy, which was deemed to be essentially inconclusive. MTX failed to control symptoms, leaving uSAID-04 corticosteroid dependent (15–20 mg maintenance prednisolone daily PO) with incomplete control of her symptoms; however, 100 mg daily s.c. anakinra completely resolved symptoms and enabled her to gradually reduce and stop her corticosteroids. uSAID-04 attempted to reduce the frequency of her anakinra injections to once every 2 days, but this resulted in a flare of her underlying condition. However, upon recommencing her initial anakinra 100 mg daily regimen, uSAID-04 returned to being symptom free with well-controlled CRP levels (Figure 4).
uSAID-04: serial CRP and SAA measurements. This figure shows the serial CRP/SAA measurements recorded for uSAID-04 from initial presentation to Dec. 2015. CRP, C-reactive protein; DMARDs, disease-modifying antirheumatic drugs; Pred, prednisolone; SAA, serum amyloid A.
uSAID-05. uSAID-05 is a 43-year-old male who presented with periodic fevers (2–3 episodes annually) accompanied by lower back and shoulder girdle pain with elevated CRP. Ferritin and neutrophil counts were normal. Initial investigations ruled out recurrent pyelonephritis; however, we found no clear cause of his symptoms, which persisted and led to hospital admission on 3 occasions. He later developed oligoarthritis, tenosynovitis, mild swelling of his right hand and wrist, myalgia, moderate morning stiffness, and a macular erythematous rash (left flank and right abdomen). He was intolerant of azathioprine and only partially responsive to mycophenolate mofetil (MMF) and 10 mg daily maintenance prednisolone PO. Over time, he also developed a Cushingoid appearance, associated with the long-term corticosteroid use; however, we were unable to reduce his prednisolone without precipitating a flare of his symptoms. Treatment with 100 mg daily s.c. anakinra completely controlled his symptoms, enabling him to eventually completely withdraw his maintenance prednisolone and MMF. His disease remains fully controlled with daily injections of anakinra alone (Figure 5).
uSAID-05: serial CRP measurements. This figure shows the serial CRP measurements recorded for uSAID-05 from initial presentation to Dec. 2015. CRP, C-reactive protein; Pred, prednisolone.
uSAID-06. uSAID-06 is a 53-year-old gentleman who presented with a 2-year history of fever, flu-like symptoms, widespread intermittent nonpruritic papular erythematous rash, night sweats, arthralgia, headaches, and elevated CRP. His initial investigations revealed lymphopenia (0.34 × 109/l), with normal neutrophil and platelet count and haemoglobin levels. He also had normal urea and electrolytes (U&Es), liver function tests (LFTs), and serum ferritin levels. Extended viral screen was negative for HIV and hepatitis A, B, and C, and there was no evidence of acute EBV or CMV reactivation. The skin biopsy showed moderate perivascular chronic inflammatory cell infiltrate within the dermis, predominantly composed of lymphocytes, and there was no evidence of fibrinoid necrosis or malignancy. Urticarial vasculitis was suggested as a provisional diagnosis, and small vessel vaculitis was also considered as one of the differential diagnoses; however, his autoimmune screen was negative, and a CT of his sinuses and thorax was normal. uSAID-06 was initially treated with prednisolone, starting with a dose of 40 mg daily PO. Although he did respond to this, the response was only partial; he became corticosteroid dependent (20–30 mg of prednisolone daily PO) and developed corticosteroid-induced glaucoma and a Cushingoid appearance. His symptoms were also unresponsive to MTX, and the patient experienced adverse reactions to azathioprine and MMF, which exacerbated his underlying inflammatory condition. Therefore, 100 mg daily s.c. anakinra commenced; he experienced improvement in his symptoms and was able to reduce corticosteroids to 5 mg of prednisolone daily from a previous 20-mg maintenance dose. However, he developed a severe injection-site reaction with a painful blistering skin rash, and treatment was therefore withdrawn. The rash resolved without scarring after a few weeks; the patient was subsequently switched to tocilizumab (Actemra), to which he has shown a favorable response (Figure 6).
uSAID-06: serial CRP measurements. This figure shows the serial CRP measurements recorded for uSAID-06 from initial presentation to Dec. 2015. CRP, C-reactive protein; Pred, prednisolone; TCZ, tocilizumab; AKI, acute kidney injury.
uSAID-07. uSAID-07 is a 33-year-old lady of Israeli-Jewish ancestry who presented with PUO, fatigue, and a 1-month history of sore throat. Four months previously, she had developed a transient circular rash on her left thigh. Her sore throat resolved spontaneously; however, she continued to experience profound fatigue — with episodes of pyrexia lasting a few days — that resolved spontaneously and presented with persistently elevated CRP. Her other investigations showed normal wbc, marginally elevated platelet count (the highest recoded was 420 × 109/l: range 150–400 × 109/l), normal serum ferritin, and elevated SAA. Subsequently, she developed transient left knee and shoulder joint arthralgia and synovitis, which resolved completely within 48 hours after taking ibuprofen. Her genetic investigations identified an NLRP3 variant of unknown significance (Q703K) that not thought to be pathogenic. She was commenced on 100 mg daily s.c. anakinra, following which her symptoms improved and was associated with persistent normalization of CRP (Figure 7).
uSAID-07: serial CRP and SAA measurements. This figure shows the serial CRP and SAA measurements recorded for uSAID-07 from initial presentation to Dec. 2015. CRP, C-reactive protein; PUO, pyrexia of unknown origin; SAA, serum amyloid A.
uSAID-08. uSAID-08 is a 67-year-old lady who presented with a 2-year history of frequent attacks of episodic fever, sweats, arthralgia, and grossly elevated CRP. Serum ferritin and neutrophil counts were normal at the time of the initial presentation. She was initially treated with corticosteroids and MTX, which failed to control her symptoms. Her CRP normalized, and her symptoms resolved after starting 100 mg daily s.c. anakinra. Failure to take anakinra precipitated a flare on 2 separate occasions; one required admission to an intensive treatment unit (ITU), where the patient was found to have grossly elevated LFTs, raising suspicions of possible hemophagocytic syndrome. However, CT and liver biopsy were both inconclusive, and her LFTs spontaneously recovered. Despite maintenance of anakinra, some of her symptoms increased in severity, with increased frequency of episodic night sweats, aphthous ulceration, and a pruritic skin rash. These were initially managed with high-dose corticosteroids; however, management of subsequent flares with an increased dose of anakinra proved extremely effective, leading to long-term remission of disease (Figure 8).
uSAID-08: serial CRP measurements. This figure shows the serial CRP measurements recorded for uSAID-08 from initial presentation to Dec. 2015. CRP, C-reactive protein; Pred, prednisolone; TCZ, tocilizumab.
uSAID-09. uSAID-09 is a 42-year-old female who presented with a 2-year history of sore throat, widespread skin rash, lymphadenopathy, orogenital ulceration, and elevated CRP. Ferritin levels and neutrophil counts were all within the normal range, and a screen for autoantibodies was also negative. Whole body CT showed widespread lymphadenopathy, but multiple biopsies including BM, lymph nodes, skin, and liver showed reactive changes only and no evidence of malignancy. The autoimmune screen was negative, and serum ferritin was within normal limits. The skin rash was eventually diagnosed as pityriasis rubris pilaris. The patient was partially responsive to 20 mg oral prednisolone and was subsequently started on cyclosporine (2 mg/kg), which she had difficulty tolerating. Unfortunately, after a few weeks of treatment, and after having an additional single dose of MTX (7.5 mg), she developed pneumocystis jiroveci pneumonia, requiring ITU admission. Her LFT’s became briefly abnormal during this period but improved after cyclosporin and MTX were stopped. Subsequently, she remained dependent on high-dose corticosteroids (up to 40 mg of prednisolone daily PO) to control her skin rash and fevers. Following introduction of anakinra, her CRP normalized and corticosteroids were gradually tapered without flare of her symptoms (Figure 9). She remained on treatment with anakinra for a period of 8 months, during which time she remained generally well and was able to reduce prednisolone to 2 mg daily. Unfortunately, her condition worsened, and she again became unwell, with progressive lymphadenopathy, respiratory symptoms, and fevers. She was admitted to ITU, where no clear cause for her deterioration was found. She died of multisystem organ failure shortly afterward. Postmortem examination findings were largely inconclusive, and — although atypical T cell lymphoma was suggested as a differential diagnosis — skin, lymph node, and BM biopsies conducted during the postmortem examination failed to find objective evidence of changes consistent with T cell lymphoma.
uSAID-09: serial CRP measurements. This figure shows the serial CRP measurements recorded for uSAID-09 from initial presentation in 2012 until mortality in April 2015. CRP, C-reactive protein; ITU, intensive treatment unit; p.jiroveci pneumonia, pneumocystis jiroveci pneumonia (an aggressive atypical form of pneumonia).
uSAID-10. uSAID-10, an 81-year-old male, presented with fever, rigors, fatigue/malaise, and dermatitis with persistently elevated CRP. He also had a complex medical history, including chronic unexplained anemia, and was previously assessed for possible PMR. Initial investigations revealed narrowing of the ureter, raising the suspicion of transitional cell carcinoma; however, this was excluded following further urological tests. Over the next 4 years, further extensive investigations failed to establish the cause of uSAID-10’s symptoms, which continued to be poorly controlled, and he required hospital admission on 7 separate occasions. This patient’s symptoms were refractory to oral corticosteroids (15 mg prednisolone daily PO) and MTX; however, 100 mg daily s.c. anakinra produced complete symptom control with only residual fatigue, and he was able to begin tapering his maintenance prednisolone from 15 mg to 7.5 mg daily. Unfortunately, a few months after commencing anakinra, the patient was admitted with seasonal flu, which was complicated by pneumonia. Although he initially did improve with antibiotics, he subsequently suffered a fatal myocardial infarction (Figure 10).
uSAID-10: serial CRP measurements. This figure shows the serial CRP measurements recorded for uSAID-10 from initial presentation until mortality in April 2014. CAP, community acquired pneumonia; CRP, C-reactive protein; MI, myocardial infarction; Pred, prednisolone.
uSAID-11. A 35-year-old female presented 4 weeks after giving birth to her second child. She experienced severe abdominal pain with spiking fever. The fever was accompanied by cervical lymphadenopathy, mild aphthous stomatitis, headache, and malaise. At that point, she experienced similar attacks of 3–5 days durations every 4–6 weeks. Extensive investigations yielded no diagnosis, but it showed elevated CRP during episodes of fever. Because of the FMF-like phenotype, colchicine was initiated, but this had no effect on the frequency or severity of attacks. There was no clinical response to high-dose methylprednisolone (1 mg/kg), started at the onset of an attack. Three years after onset, the frequency of her attacks increased to every 2–3 weeks. The severity of attacks was disabling, and the patient was unable to perform her job. Eventually, a trial of anakinra was started. At the first signs of an attack, the patient self-injected 100 mg anakinra s.c. This led to fever resolution within hours, with relief from abdominal pain; cessation of anakinra resulted in disease flare. The patient was able to taper the dose to 5 injections per week and was able to restart her full-time job as a teacher. Currently, she uses anakinra approximately 5 days per month.