We described a case of IPEX syndrome successfully controlled with dupilumab, an anti-IL4 receptor alpha subunit inhibitor. IPEX syndrome is a rare and generally fatal genetic disorder characterized by immune dysregulation, polyendocrinopathy and enteropathy, mostly diagnosed in early childhood. Nonetheless, cases reported in the last 20 years demonstrated that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features. A 21-year-old caucasian man presented with immune dysregulation (hypereosinophilia and elevated IgE), protein-losing enteropathy, polyendocrinopathy (thyroiditis, osteoporosis, delayed puberty), weight loss, eczema manifestations and celiac disease. IPEX syndrome was diagnosed because of the presence of a hemizygous mutation in FOXP3 gene (c.543C>T (p.S181S) in the exon 5). During the course of the disease, the patient developed erosive proctitis, pyoderma gangrenosum, and erythema nodosum. Symptoms improved only after enteral and parenteral corticosteroid therapy and the patient soon developed steroid-dependence. Notwithstanding various therapies including azathioprine, sirolimus, tacrolimus, adalimumab, vedolizumab, the patient failed to achieve a good control of symptoms without steroids. Almost exclusive enteral nutrition with a hypoallergenic, milk-protein free, amino acid-based food for special medical purposes. He continued to lose weight (BMI 14.5 kg/m2) with a consequent high limitation of physical activity and a progressive worsening of the quality of life. In consideration of the poor response to conventional immunosuppressants and the presence of type 2 inflammatory manifestations, treatment with dupilumab at an initial dose of 600 mg, followed by a maintenance dose of 300 mg every other week, according to atopic dermatitis labeled dose, was started and combined to oral budesonide 6 mg/day and 6-mercaptopurine 75 mg/day. The patient experienced a rapid improvement in bowel and skin symptoms, leading to a progressive tapering of steroids. By our knowledge, this is the first report of IPEX syndrome successfully treated by antiIL-4/IL-13 therapy. In this case dupilumab demonstrated to be an effective, safe and steroid-sparing option.

FDA-approved anti-TNFα biopharmaceuticals are successful in treating a range of autoimmune diseases. However, not all anti-TNFα products are identical in their patient outcomes, suggesting that there may be product-specific differences stemming from protein structural differences, doses and routes of administration. In this work, we focus only on structural and functional differences across three full-length anti-TNFα mAbs (Humira®, Remicade®, and Simponi Aria®) to better understand the implications of such differences on the products' efficacy. For structural characterization, we quantified N-glycans using mass spectrometry and fluorescence labeling. From these studies, we observed that Remicade® had the highest percent of afucosylated glycans (15.5 ± 1.3%) and the largest number of unique glycans, 28. While Humira® had the fewest unique glycans, 15, and 11.4 ± 0.8% of afucosylated, high-mannose glycans. For the functional studies we tested TNFα binding via ELISA, FcγRIIIa binding via AlphaLISA and effector function using an ADCC bioreporter assay. Humira® had a significantly lower EC50 (1.9 ± 0.1 pM) for ELISA and IC50 (10.5 ± 1.1 nM) for AlphaLISA, suggesting that Humira® has higher TNFα and FcγRIIIa binding affinity than Remicade® and Simponi Aria®. Humira® was also the most potent in the bioreporter assay with an EC50 value of 0.55 ± 0.03 nM compared to Remicade® (0.64 ± 0.04 nM) and Simponi Aria® (0.67 ± 0.03 nM). This comparison is significant as it highlights functional differences between mAbs with shared mechanisms of action when examined in a single laboratory and under one set of conditions.

We present a case of bilateral interstitial keratitis leading to perforation in a woman with hidradenitis suppurativa (HS). A woman in her mid-20s with a history of HS and Grave's disease was referred to the corneal service with loss of vision and pain in both eyes since childhood. She was found to have circumferential thinning and steepening affecting her peripheral cornea bilaterally. Corrected distance visual acuity with spectacles was in the right eye 6/7.5, and in the left 6/30, with local thinnest area of 209 and 217 µm in the right and left eyes, respectively. She experienced recurring episodes of redness and irritation, and perforation occurred. The corneal perforation was managed with cyanoacrylate glueing, followed by a local conjunctival flap. Systemic immunosuppression with mycophenolate mofetil and adalimumab was commenced, with improvement after 18 months of treatment. Dermatologists and ophthalmologists should be aware of this association given its potential severity.

Ulcerative colitis is a condition of chronic inflammation affecting the large intestine. The disease is typically characterized by periods of active inflammation alternating with periods of remission. For patients with moderate to severe ulcerative colitis, the first line for induction therapy options includes biologic agents (with or without an immunomodulator) or glucocorticoids. This case highlights the first successful case of ulcerative colitis treated with adalimumab with mesalamine and azathioprine. The patient was initially treated with mesalamine and azathioprine which did not result in significant clinical improvement but the addition of subcutaneous adalimumab showed a remarkable response with drastic improvement in just one year of treatment. Hence, adalimumab could be considered as an option in the management of severe cases in Nepal.

To date, adalimumab (ADA) is the only biotechnology drug approved for the management of hidradenitis suppurativa (HS), an inflammatory skin condition. However, it quickly became apparent that the efficacy of adalimumab in daily practice was highly variable. In our review, we highlighted the current evidence from literature on the use of biologics in HS in a real-life setting, particularly adalimumab, secukinumab and ustekinumab. Data on the effectiveness and safety of biologic drugs in HS management have been analyzed. Even if the results are promising, more studies are needed. In our opinion, the armamentarium of drugs for HS management is increasing, and treatment will be based on a tailored-tail approach, minimizing the risk of adverse events. In this context, we want to point out the reported effectiveness and safety data concerning adalimumab, ustekinumab and secukinumab as well as ixekizumab.

Non-infectious uveitis (NIU) in children and adolescents is a rare but treatable cause of visual impairment in children. Treatments for pediatric NIU and their side effects, alongside the risks of vision loss and need for long-term disease monitoring, pose significant challenges for young patients and their families. Treatment includes local and systemic approaches and this review will focus on systemic therapies that encompass corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and biological disease-modifying antirheumatic drugs (bDMARD). Treatment is generally planned in a stepwise approach. Methotrexate is well-established as the preferential csDMARD in paediatric NIU. Adalimumab, an anti-tumor necrosis factor (TNF) agent, is the only bDMARD formally approved for pediatric NIU and has a good safety and efficacy profile. Biosimilars are gaining increasing visibility in the treatment of pediatric NIU. Other bDMARD with some evidence in literature for treatment of pediatric NIU include infliximab, tocilizumab, abatacept, rituximab and, more recently, Janus kinase inhibitors. Important aspects of managing children on these systemic therapies include vaccination issues, risk of infection, and psychological distress. Also, strategies need to address regarding primary non-response/secondary loss of response to anti-TNF treatment, biological switching and monitoring regimens for these drugs. Optimal management of pediatric uveitis involves a multidisciplinary team, including specialist pediatric uveitis and rheumatology nurses, pediatric rheumatologists, psychological support, orthoptic and optometry support, and play specialists.

The genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab.

Lichen planus is a chronic, inflammatory, immune-mediated dermatosis affecting the patient's skin, scalp, mucous membranes, and nails. Drug-induced lichen planus is described after the administration of antimalarials, β-blockers, methyldopa, NSAIDs, penicillamines, and sodium aurothiomalate. The use of biologicals such as adalimumab, etanercept, and infliximab has also been linked with the appearance of lichenoid eruptions in the recent past. In this case, we report on a patient developing oral and cutaneous lichen planus after the administration of dupilumab. The lichenoid lesions occurred after 11 months of the drug's administration and involved the buccal walls, trunk, and extremities. Dupilumab had been administered in an effort to counter severe atopic dermatitis exacerbations. Dupilumab is associated with a downregulation of T-helper 2 cell activation by blocking the Interleukin-4/Interleukin-13 pathway, so leading to a TH1/TH2 imbalance. This imbalance may cause a shift toward a TH1-mediated immune response and be an explanation for the drug-induced lichen planus. Dupilumab was discontinued, and the patient was treated with oral corticosteroids and UVB phototherapy, leading to a significant improvement in the lichen planus lesions.

Infection mimics pose a challenge in the world of infectious diseases. Fever of unknown origin (FUO) requires careful consideration for a broad range of diagnoses. The answer often lies in a careful history and dedicated clinical examination. A delay in diagnosis can result in greater morbidity for the patient. We present the diagnostic challenges in a patient with an infection mimic, Behcet's disease (BD), who presented with recurrent venous thromboembolism (VTE) and fever of unknown origin (FUO). We present the case of a 53-year-old male of Irish Caucasian ethnicity who presented with a history of fevers and recurrent VTE at a university hospital in Dublin, Ireland. Past medical history includes schistosomiasis, which was treated following a trip to sub-Saharan Africa. Our patient was previously diagnosed with a provoked deep vein thrombosis (DVT). He went on to experience four subsequent episodes of VTE, including DVT, pulmonary embolism (PE), and cerebral venous sinus thrombosis (CVST) while on different forms of anticoagulation. On each of these occasions, there was a concern for sepsis due to fevers > 38°C and a C-reactive protein (CRP) > 200 mg/L. The infection workup included routine laboratory tests, blood and urine cultures, CT of the abdomen and pelvis (CTAP), echocardiogram, and PET-CT, all of which were unrevealing. However, a focused clinical examination revealed evidence of subtle scrotal and oral ulceration, pustulation, and erythema at several sites in his upper limb following venesection and cannulation. In this context, a diagnosis of Behcet's disease was considered. A diagnosis of Behcet's disease can only be confidently made after the exclusion of other potential etiologies. In this case, we had to consider a broad range of infectious (malaria, schistosomiasis, rickettsial disease, and endocarditis) and noninfectious (malignancy, antiphospholipid syndrome (APS), myeloproliferative disorders, and paroxysmal nocturnal hemoglobinuria (PNH)) diseases. A delay in diagnosis comes at the cost of increased morbidity and mortality for the patient. A detailed history and clinical examination are key, in addition to a high index of suspicion. Following the induction of high-dose steroid, our patient is doing very well on maintenance adalimumab. From an anticoagulation perspective, he is warfarinized and has not had any further episodes of VTE.

Monoclonal antibodies against tumor necrosis factor-alpha (TNFα) are widely used for treatment of inflammatory diseases. However, despite the inhibitory effect this class of drugs has on the immune system, anti-drug antibodies are often formed with continuous use. Particles formed during stress conditions, which can be used to simulate storage and handling conditions of commercial antibodies, have previously been associated with the formation of anti-drug antibodies. This study investigates the relationship between particles, oligomerization, folding and chemical degradation on the in vitro cytokine response toward the TNFα inhibitor adalimumab. Adalimumab aggregates generated using stir and heat stress were fractionated into distinct sub-populations, and their structure and immunogenic potential were evaluated. A chemically degraded sample of adalimumab was included to compare particle composition with the milder accelerated heat and stir stressed conditions. Particles from stressed adalimumab samples induced elevated cytokine levels and CD4+ T cell proliferation in vitro compared to non-stressed samples. Samples enriched with both submicron and subvisible particles of adalimumab induced the strongest cytokine release and the strongest CD4+ T cell proliferation despite maintaining some TNFα inhibitory functionality. Samples that were stressed and subsequently purified of subvisible and submicron particles did not elicit a significantly higher cytokine response or show increased CD4+ T cell proliferation compared to a non-stressed sample. Oxidation-induced chemical modifications in adalimumab, mainly in Met, His, Trp, and Tyr, were not found to be sufficient in absence of particle formation to induce increased CD4+ T cell proliferation or cytokine release despite less decreased TNFα inhibitory activity of adalimumab. These observations provide further evidence that particles do indeed potentiate the immunogenic potential of adalimumab.

Limited information indicates that maternal adalimumab injections produce low levels in breastmilk and do not adversely affect the nursing infant. Because adalimumab is a large protein molecule with a molecular weight of about 148,000 Da, it is likely to be partially destroyed in the infant's gastrointestinal tract and absorption by the infant is probably minimal. Most experts and professional guidelines feel that the drug is acceptable to use during breastfeeding.[1-10]

Current treatments for Dupuytren's disease are limited to late-stage disease when patients have developed flexion contractures and have impaired hand function. They all have limitations, including the risk of recurrence and complications. The use of treatments for early-stage disease, such as intralesional steroid injections or radiotherapy which lack a clear biological basis or evidence of effectiveness based robust randomized, double blind, placebo-controlled trials, highlights the desire of patients to access treatments before they develop significant flexion contractures. A detailed understanding of the cellular landscape and molecular signalling in nodules of early-stage disease would permit the identification of potential therapeutic targets. This approach led to the identification of tumour necrosis factor (TNF) as a target. A phase 2a clinical trial identified 40 mg in 0.4 mL adalimumab as the most efficacious dose and a subsequent randomized, double blind, placebo-controlled phase 2b trial showed that four intranodular injections at 3-month intervals resulted in decrease in nodule hardness and size on ultrasound scan at 12 months, and both parameters continued to decrease further at 18 months, 9 months after the final injection. This type of approach provides clinicians with a robust evidence base for advising their patients.